levetiracetam and Disease-Models--Animal

Several new antiepileptic drugs (AEDs) have been introduced for clinical use recently. These new AEDs, like the classic AEDs, target multiple cellular sites both pre- and postsynaptically. The use of AEDs as a possible neuroprotective strategy in brain ischemia is receiving increasing attention and the antiepileptic drug levetiracetam, a 2S-(2-oxo-1-pyrrolidiny1) butanamide, belonging to the pyrrolidone family, could have a crucial role in regulation of epileptogenesis and neuroprotection. Recent observations suggest that levetiracetam is both safe and effective against post-stroke seizures. In this review, the potential neuroprotective role in brain ischemia and the therapeutic implications of levetiracetam in post-stroke epilepsy are discussed.

Topics: Animals; Anticonvulsants; Brain Ischemia; Clinical Trials as Topic; Disease Models, Animal; Epilepsy; Humans; Levetiracetam; Neuroprotective Agents; Piracetam; Stroke

Topics: Acute Disease; Allosteric Regulation; Animals; Anticonvulsants; Calcium; Calcium Channel Blockers; Calcium Channels, N-Type; Disease Models, Animal; Epilepsy; Humans; Levetiracetam; Membrane Glycoproteins; Nerve Tissue Proteins; Piracetam; Randomized Controlled Trials as Topic; Seizures

Although epilepsy surgery is most effective for patients with intractable epilepsy, a majority of them is not eligible for the surgery. Most of patients with refractory epilepsy are eventually treated with polypharmacy in hope of seizure control. Therefore, rational combinations of antiepileptic drugs are needed to control intractable seizures. Drug combinations should be rationally chosen based on the evidence of synergic efficacy and on avoidance of neurotoxicity. Several clinical studies suggest that the combination of valproate with lamotrigine has synergic antiepileptic effect. It has also been reported that the combination of carbamazepine with lamotrigine paradoxically decreases efficacy and increases toxicity. Animal studies using isobolography suggest that the combinations of topiramate with lamotrigine or levetiracetam are also promising on both seizure control and neurotoxicity. Clinical research is needed to examine these combinations.

Topics: Animals; Anticonvulsants; ATP Binding Cassette Transporter, Subfamily B, Member 1; Carbamazepine; Clinical Trials as Topic; Disease Models, Animal; Drug Interactions; Drug Resistance; Drug Therapy, Combination; Epilepsy; Fructose; Humans; Lamotrigine; Levetiracetam; Multidrug Resistance-Associated Proteins; Piracetam; Prognosis; Topiramate; Triazines; Valproic Acid

Levetiracetam (Keppra) is an antiepileptic drug (AED) characterized by a novel mechanism of action, unique profile of activity in seizure models, and broad-spectrum clinical efficacy. The present report critically reviews several preclinical studies focused on combination therapy with levetiracetam and other anticonvulsants in various seizure and epilepsy models. Administration of levetiracetam together with many different clinically used AEDs or other anticonvulsants generally enhances their protective activity and, among existing AEDs, this was particularly prevalent with valproate. The protective activity of other AEDs was also enhanced by levetiracetam, which seems to be a universal finding that is independent of seizure model or drug combination studied. However, particularly strong enhancement was observed when levetiracetam was combined with agents either enhancing GABAergic or reducing glutamatergic neurotransmission. Importantly, these combinations were not associated with exacerbation of side effects or pharmacokinetic interactions. Based on the available preclinical data, it appears that combination treatment with levetiracetam and other anticonvulsants provides additional therapeutic benefit that may be attributed to its novel and distinct mechanism of action. Moreover, combinations of levetiracetam with clinically used AEDs that enhance GABAergic inhibition may be considered for rational polytherapy, which is often necessary in drug-resistant patients.

Topics: Animals; Anticonvulsants; Brain; Disease Models, Animal; Drug Evaluation, Preclinical; Drug Interactions; Drug Therapy, Combination; Epilepsy; gamma-Aminobutyric Acid; Glutamic Acid; Humans; Levetiracetam; Membrane Glycoproteins; Nerve Tissue Proteins; Piracetam

Topics: Acetamides; Amines; Animals; Anticonvulsants; Benzodiazepines; Carbamates; Cyclohexanecarboxylic Acids; Disease Models, Animal; Drug Design; Gabapentin; gamma-Aminobutyric Acid; Humans; Lacosamide; Levetiracetam; Phenylenediamines; Piracetam; Pregabalin; Pregnanolone; Pyrrolidinones; Triazoles

The objective of this article was to review and summarize the available reports on the preclinical profile of the novel anticonvulsant drug levetiracetam (LEV). Therefore, a careful search was conducted in the MEDLINE database and combined with guidelines from regulatory agencies, proceedings of professional scientific meetings, and information provided by the manufacturers. This article provides detailed information on the anticonvulsant effects of LEV in various animal models of epilepsy and on its pharmacology in laboratory animals. The mechanism of action of LEV is reviewed, with special regard to its recently discovered binding site, the synaptic vesicle protein 2A. In general, LEV is shown to be a safe, broad-spectrum anticonvulsant drug with highly beneficial pharmacokinetic properties and a distinct mechanism of action. The clinical studies with LEV will be discussed in the second part of this review article to be published subsequently.

Topics: Animals; Anticonvulsants; Disease Models, Animal; Drug Evaluation, Preclinical; Epilepsy; Humans; Levetiracetam; MEDLINE; Piracetam

Epilepsy is a hetergenous syndrome characterized by recurrently and repeatedly occurring seizures. Although able to inhibit the epileptic seizures, the currently available antiepileptic drugs (AEDs) have no effects on epileptogenesis. Such AEDs should be classified as drugs against ictogenesis, which are transient events in ion and/or receptor-gated channels related with triggering to evoke seizures. Epileptogenesis involves long-term and histological/biochemical/physiological alterations formed in brain structures over a long period, ranging from months to years. This review focuses on the effects of AEDs on epileptogenesis and novel candidates of antiepileptogenic drugs using a genetically defined epilepsy model animal, the spontaneous epileptic rat (SER).

Topics: Animals; Anticonvulsants; Disease Models, Animal; Epilepsy; Levetiracetam; Models, Biological; Piracetam; Rats

Epilepsy is a neurological disorder consisting of recurrent seizures, resulting from excessive, uncontrolled electrical activity in the brain. Epilepsy treatment is successful in the majority of the cases; however; still one third of the epilepsy patients are refractory to treatment. Besides the ongoing research on the efficacy of antiepileptic treatments in suppressing seizures (anti-seizure effect), we want to seek for therapies that can lead to plastic, neuromodulatory changes in the epileptic network. Neuropharmacological therapy with levetiracetam (LEV) and vagus nerve stimulation (VNS) are two novel treatments for refractory epilepsy. LEV acts rapidly on seizures in both animal models and humans. In addition, preclinical studies suggest that LEV may have antiepileptogenic and neuroprotective effects, with the potential to slow or arrest disease progression. VNS as well can have an immediate effect on seizures in epilepsy models and patients with, in addition, a cumulative effect after prolonged treatment. Studies in man are hampered by the heterogeneity of patient populations and the difficulty to study therapy-related effects in a systematic way. Therefore, investigation was performed utilizing two rodent models mimicking epilepsy in humans. Genetic absence epilepsy rats from Strasbourg (GAERS) have inborn absence epilepsy and Fast rats have a genetically determined sensitivity for electrical amygdala kindling, which is an excellent model of temporal lobe epilepsy. Our findings support the hypothesis that treatment with LEV and VNS can be considered as neuromodulatory: changes are induced in central nervous system function or organization as a result of influencing and initiating neurophysiological signals.

Topics: Animals; Disease Models, Animal; Electric Stimulation Therapy; Epilepsy; Humans; Levetiracetam; Neurotransmitter Agents; Piracetam; Rats; Vagus Nerve

The search for antiepileptic drugs (AEDs) using drug screens that test for the ability to suppress paroxysmal events has primarily resulted in the discovery of AEDs that inhibit neuronal excitability. While profoundly reducing expression of epileptic seizures, current pharmacologic treatments have not been able to completely control seizures in all patients, and can impair normal neuronal excitation underlying cognition. A new approach to drug screening, including the process of epileptogenesis, may yield new classes of drugs that not only suppress seizures but also specifically act to protect against the neurobiological changes that contribute to the development of epilepsy. By preventing or reversing the neuronal circuit reorganizations that produce lowered seizure thresholds following brain insults such as head trauma or status epilepticus, these antiepileptogenic drugs could prevent, or reverse, progressive worsening of the epileptic process. It is likely that antiepileptogenic drugs will have mechanisms of action distinct from traditional AEDs, as the molecular mechanisms underlying epileptogenesis and ictogenesis probably differ. One new AED with potential antiepileptogenic properties is levetiracetam, which was discovered using non-conventional drug screens. It markedly suppresses kindling development at doses devoid of adverse effects, with persistent suppression of kindled seizures even after termination of treatment. Further design and implementation of antiepileptogenic drug screens are needed for the discovery of other novel disease-modifying agents.

Topics: Animals; Anticonvulsants; Disease Models, Animal; Epilepsy; Humans; Kindling, Neurologic; Levetiracetam; Neuroprotective Agents; Piracetam

To describe the data contained in the most important studies published on the pharmacokinetic and pharmacodynamic properties of levetiracetam, and also the main clinical trials carried out using this new antiepileptic drug.. Derived from piracetam, but with very different properties, levetiracetam is ineffective in the usual models of seizures induced in experimental animals, although it acts in models of prolonged activation, audiogenous seizures and absences and has a novel mode of action. It has pharmacokinetic properties which are nearer to that of the ideal anti epileptic drug. In clinical trials done in adults with partial epilepsies use of 1,000 to 4,000 mg of levetiracetam was significantly more effective than a placebo, and the drug was very well tolerated.. Levetiracetam is the newest antiepileptic drug to appear on the market. Its pharmacodynamic and pharmacokinetic characteristics are excellent. It has currently been approved for use in the polytherapy of patients with partial seizures aged over 16 years. Several studies indicate that its therapeutic spectrum is probably wider, particularly in generalized seizures such as the myoclonias, absences and seizures induced by light stimulation. Thus the indications for levetiracetam may become clear over the next few years.

Topics: Animals; Anticonvulsants; Disease Models, Animal; Dose-Response Relationship, Drug; Epilepsy; Humans; Ion Channels; Levetiracetam; Molecular Structure; Piracetam; Treatment Outcome

Levetiracetam is a new antiepileptic drug (AED) devoid of anticonvulsant activity in the two classic screening models for AEDs, the maximal electroshock and pentylenetetrazol seizure tests in both mice and rats. This contrasts a potent seizure suppression in genetic and kindled mice and rats and against chemoconvulsants inducing partial seizures in rats. The highly selective action in "epileptic" animals distinguishes levetiracetam from classic and other new AEDs that have nearly equipotent effects in normal and "epileptic" animals. Levetiracetam induces minor behavioral alterations in normal and in kindled mice and rats. This results in an unusually high safety margin in animal models reflecting both partial and primary generalized epilepsy. Furthermore, experiments in the kindling model suggest that levetiracetam may possess antiepileptogenic properties due to a potent ability to prevent the development of kindling in mice and rats at doses devoid of adverse effects. Electrophysiologic recordings from different experimental models suggest that levetiracetam exerts a selective action against abnormal patterns of neuronal activity, which probably explains its selective protection in epileptic animals and its unique tolerability. This effect appears to derive from one or more novel mechanisms of action that do not involve a conventional interaction with traditional drug targets implicated in the modulation of inhibitory and excitatory neurotransmission. Instead, ligand-binding assays have disclosed a brain-specific binding site for levetiracetam. These studies reveal a unique preclinical profile of levetiracetam, distinct from that of all known AEDs, suggesting that levetiracetam could represent the first agent in a new class of AEDs.

Topics: Amygdala; Animals; Anticonvulsants; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Electric Stimulation; Epilepsy; Kindling, Neurologic; Levetiracetam; Mice; Piracetam; Rats; Seizures

Valproate (VPA) and levetiracetam (LEV), the two broad spectrum antiseizure drugs with antiabsence effects were previously tested for their antiepileptogenic effects when administered in the early postnatal period and revealed possible modification of the epileptogenic process though the effect being not persistent. The aim of this study was to investigate the effects of in utero exposure to these drugs on the absence epilepsy seizures of Genetic Absence Epilepsy Rats from Strasbourg (GAERS) rats on electroencephalogram (EEG) which are characterised by bilateral, symmetrical, and synchronized spike-and-wave discharges (SWDs). Considering LEV was proposed as a safer drug of choice in pregnancy, its effects on the newborn histopathology of GAERS was also investigated. Adult female GAERS were randomly grouped as VPA-(400 mg/kg/day), LEV- (100 mg/kg/day), and saline-treated. The drugs were injected into the animals intraperitoneally starting before pregnancy until parturition. The lungs, kidneys, and brains of the LEV-exposed newborns were evaluated histologically to be compared with unexposed naïve Wistar and GAERS newborns. Rest of the VPA-, LEV-, and saline-exposed offsprings were taken for EEG recordings on postnatal day 90. VPA or LEV did not show significant effect on mean cumulative duration and mean number of SWDs on EEG. The lungs of the LEV-exposed offsprings showed thickened alveolar epithelium in most regions, suggesting incomplete development of the alveoli. The renal examination revealed dilated Bowman's spaces in some renal corpuscles, which may be interpreted as a deleterious effect of LEV on the kidney. In addition, brain examination of LEV- and saline-exposed groups revealed irregularities in cortical thickness compared to Wistar control group. Lack of significant difference on SWD parameters may indicate that the mechanism responsible for the antiepileptogenic effects of VPA and LEV may not be operating in the prenatal period. The detrimental effect of LEV exposure observed in our study on the lungs and the kidneys of the newborns should be investigated by further studies with advanced molecular and biochemical techniques.

Topics: Animals; Anticonvulsants; Disease Models, Animal; Electroencephalography; Epilepsy, Absence; Female; Levetiracetam; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar; Seizures; Valproic Acid

Current treatment of human status epilepticus (SE) relies on drugs developed for chronic treatment of epilepsy. Many potent compounds have been discovered in animal models of SE. But they may never be useful for chronic treatment of epilepsy and thus not available for human use. Naturally occurring canine SE may become a translational platform for evaluating these compounds for eventual use in human trials. A pilot study of levetiracetam in canine SE demonstrated a 56% response rate compared to 10% for placebo. Based on these results we have obtained an NIH R-21 to further evaluate canine SE as a translational platform for developing new approaches for treating human SE.

Topics: Animals; Anticonvulsants; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Double-Blind Method; Levetiracetam; Phenytoin; Pilot Projects; Piracetam; Reproducibility of Results; Status Epilepticus

Caffeine is the most widely used psychoactive substance in the world. Animal studies indicate that acute caffeine exposure at high doses may induce seizures and diminish the anticonvulsant activity of antiepileptic drugs (AEDs) at much lower doses. The aim of the current study was to assess the effect of caffeine on the anticonvulsant action of levetiracetam (LEV) and vigabatrin (VGB).. The anticonvulsant activity of LEV and VGB was examined in the maximal electroshock seizure threshold test in mice (MEST test). All drugs were administered intraperitoneally by single injections, and caffeine was applied at doses capable of interfering with AEDs. Effects of caffeine exposure on AEDs were also investigated in tests of memory and motor performance.. Caffeine reduced the protective effect of LEV against electroconvulsions. Total brain concentration of LEV was unaffected by caffeine as well as inversely; LEV had no significant impact on the brain caffeine concentration, suggesting a pharmacodynamic nature of the interaction between LEV and caffeine in the MEST test. VGB at applied doses did not affect the convulsive threshold. Administration of VGB, but not LEV, alone or in combination with caffeine, impaired memory retention. In the chimney test, the combined treatment with AEDs and caffeine did not cause motor coordination impairment.. It is suggested that caffeine may negatively affect the anticonvulsant action of LEV in patients with epilepsy.

Topics: Animals; Anticonvulsants; Caffeine; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Electroshock; Levetiracetam; Mice; Seizures

Post-traumatic epilepsy (PTE) occurs in some patients after moderate/severe traumatic brain injury (TBI). Although there are no approved therapies to prevent epileptogenesis, levetiracetam (LEV) is commonly given for seizure prophylaxis due to its good safety profile. This led us to study LEV as part of the Epilepsy Bioinformatics Study for Antiepileptogenic Therapy (EpiBioS4Rx) Project. The objective of this work is to characterize the pharmacokinetics (PK) and brain uptake of LEV in naïve control rats and in the lateral fluid percussion injury (LFPI) rat model of TBI after either single intraperitoneal doses or a loading dose followed by a 7-day subcutaneous infusion. Sprague-Dawley rats were used as controls and for the LFPI model induced at the left parietal region using injury parameters optimized for moderate/severe TBI. Naïve and LFPI rats received either a bolus injection (intraperitoneal) or a bolus injection followed by subcutaneous infusion over 7 days. Blood and parietal cortical samples were collected at specified time points throughout the study. LEV concentrations in plasma and brain were measured using validated high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) methods. Noncompartmental analysis and a naive-pooled compartmental PK modeling approach were used. Brain-to-plasma ratios ranged from 0.54 to 1.4 to 1. LEV concentrations were well fit by one-compartment, first-order absorption PK models with a clearance of 112 ml/h per kg and volume of distribution of 293 ml/kg. The single-dose pharmacokinetic data were used to guide dose selection for the longer-term studies, and target drug exposures were confirmed. Obtaining LEV PK information early in the screening phase allowed us to guide optimal treatment protocols in EpiBioS4Rx. SIGNIFICANCE STATEMENT: The characterization of levetiracetam pharmacokinetics and brain uptake in an animal model of post-traumatic epilepsy is essential to identify target concentrations and guide optimal treatment for future studies.

Topics: Animals; Anticonvulsants; Brain; Brain Injuries, Traumatic; Disease Models, Animal; Epilepsy, Post-Traumatic; Levetiracetam; Percussion; Rats; Rats, Sprague-Dawley; Tandem Mass Spectrometry

Kappa opioid receptor (KOR) agonists have anticonvulsant effect but their antiepileptogenic effect is unknown. U50488, a selective KOR agonist is used to determine its effect on status epilepticus (SE), spontaneous convulsive seizures (SS) and cognitive impairment in rat lithium-pilocarpine SE model. Effect of an antiepileptic drug levetiracetam is also studied.. Male Wistar rats with SE were divided into three groups namely, LiP, LiP + U50488 (10 mg/kg, i.p.) and LiP + levetiracetam (400 mg/kg, i.p.) group. SE was terminated after 90 min of its onset with diazepam (15 mg/kg, i.p.) and phenobarbitone (25 mg/kg, i.p.). Drug treatment was started after 15 min of onset of SE and repeated once after 4 h. Rats were video monitored 12 h daily (9 AM to 9 PM) to determine severity of SE using modified Racine scale and onset and frequency of SS from day 0 to day 21. Morris water maze (MWM) test was done at baseline i.e. day -1 (before lithium administration) and day 22, to assess cognitive impairment.. As compared to LiP, U50488 decreased the severity of SE (1.98 ± 0.13 vs 2.95 ± 0.12; p-value < 0.0001) but not levetiracetam (2.62 ± 0.09; p-value = 0.3112). Survival increased with both U50488 (90%, n = 10) and levetiracetam (81.8%, n = 11) as compared to NS (56.2%, n = 16). No effect on onset and frequency of SS was found in U50488/levetiracetam group. U50488 improved seizures-induced cognitive impairment. Levetiracetam group showed thigmotactic (wall hugging) behaviour in MWM in 8 out of 9 rats.. Acute treatment with U50488, a kappa opioid receptor agonist has a beneficial effect on SE, SE-related mortality and memory impairment. The dual protective effect of U50488 on seizures and related cognitive impairment is advantageous over currently used antiseizure drugs which are known to cause cognitive impairment.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Anticonvulsants; Disease Models, Animal; Levetiracetam; Lithium; Male; Pilocarpine; Rats; Rats, Wistar; Receptors, Opioid, kappa; Seizures; Status Epilepticus

Expression of inhibitory designer receptors exclusively activated by designer drugs (DREADDs) on excitatory hippocampal neurons in the hippocampus represents a potential new therapeutic strategy for drug-resistant epilepsy. To overcome the limitations of the commonly used DREADD agonist clozapine, we investigated the efficacy of the novel DREADD ligand JHU37160 in chemogenetic seizure suppression in the intrahippocampal kainic acid (IHKA) mouse model for temporal lobe epilepsy (TLE). In addition, seizure-suppressing effects of chemogenetics were compared to the commonly used anti-epileptic drug (AED), levetiracetam (LEV). Therefore, an adeno-associated viral vector was injected in the sclerotic hippocampus of IHKA mice to induce expression of a tagged inhibitory DREADD hM4Di or only a tag (control) specifically in excitatory neurons using the CamKIIα promoter. Subsequently, animals were treated with LEV (800 mg/kg), clozapine (0.1 mg/kg), and DREADD ligand JHU37160 (0.1 mg/kg) and the effect on spontaneous seizures was investigated. Clozapine and JHU37160-mediated chemogenetic treatment both suppressed seizures in DREADD-expressing IHKA mice. Clozapine treatment suppressed seizures up to 34 h after treatment, and JHU37160 effects lasted for 26 h after injection. Moreover, both compounds reduced the length of seizures that did occur after treatment up to 28 h and 18 h after clozapine and JHU37160, respectively. No seizure-suppressing effects were found in control animals using these ligands. Chemogenetic seizure treatment suppressed seizures during the first 30 min after injection, and seizures remained suppressed during 8 h following treatment. Chemogenetics thus outperformed effects of levetiracetam (p < 0.001), which suppressed seizure frequency with a maximum of 55 ± 9% for up to 1.5 h (p < 0.05). Only chemogenetic and not levetiracetam treatment affected the length of seizures after treatment (p < 0.001). These results show that the chemogenetic therapeutic strategy with either clozapine or JHU37160 effectively suppresses spontaneous seizures in the IHKA mouse model, confirming JHU37160 as an effective DREADD ligand. Moreover, chemogenetic therapy outperforms the effects of levetiracetam, indicating its potential to suppress drug-resistant seizures.

Topics: Animals; Clozapine; Disease Models, Animal; Kainic Acid; Levetiracetam; Ligands; Mice; Seizures

Alzheimer's disease (AD) is the most common neurodegenerative disease which affects more than 40 million people worldwide with progressive loss of memory and cognitive functions. It is reported, persistent AD is also one of the main causes of epilepsy in elders and comorbidity of both these will contribute to worsening the health status of AD patients. Recently, herbal plants with potent neuroprotective and antioxidant properties were used for increasing the quality of life in neurodegenerative disease patients. The present study was conceptualized to access the protective effect of Ocimum sanctum extract (OSE) and Levetiracetam (LEV) and their combination (OSE+LEV) against AD and epilepsy associated with AD in the rat AD model. AD was induced in aged male Wistar albino rats with Amyloid-β (Aβ) by intracerebroventricular administration. The results reveal, treatment with OSE, LEV and OSE+LEV significantly reversed the memory impairment, increases the BDNF expressions and decreases AChE activity in Aβ induced AD animals. Expression of A-β and p-tau in the hippocampus was significantly reduced in treatment group when compared to the control animals. Treatment with OSE and OSE+LEV also restored the hippocampal architecture by ameliorating the neuronal count in CA1, CA3 and DG regions. It also observed that treatment has decreased the excitoneurotoxicity evidenced by decreased glutamate and increased GABA levels and thus provided protection against epilepsy. Treatment groups also exhibited a potent antioxidant activity when tested endogenous antioxidant enzymes SOD, GSH and LPO in the brain hippocampus. Our findings provide evidence for use of OSE, LEV and OSE+LEV against AD and epilepsy associated with AD in Aβ induced AD animal model. However, further clinical studies are required to prove the use of OSE, LEV and OSE+LEV in the management of AD and AD-associated epilepsy in human volunteers.

Topics: Aged; Alzheimer Disease; Animals; Cognitive Dysfunction; Disease Models, Animal; Hippocampus; Humans; Levetiracetam; Male; Neurodegenerative Diseases; Neuroprotective Agents; Ocimum sanctum; Plant Extracts; Quality of Life; Rats; Rats, Wistar

Alzheimer's disease (AD) is the most common neurodegenerative disorder among the elderly. In the light of increasing AD prevalence and lack of effective treatment, new strategies to prevent or reverse this condition are needed. Levetiracetam (LEV) is a newer antiepileptic drug that is commonly used to treat certain types of seizures. Researches indicated that LEV has several other pharmacological activities, including improvement of cognitive function. In this study, the recovery effects of chronic (28 days) administration of LEV (50, 100, and 150 mg/kg, ip) on cognitive deficits caused by the intracerebroventricular (icv) injection of streptozotocin (STZ), as a model for sporadic AD, were evaluated in rats. We also considered the protective effects of LEV against hippocampal cell loss, oxidative damage, acetylcholinesterase (AChE) activity, neuroinflammation, and tauopathy caused by STZ. LEV (100 and 150 mg/kg) significantly attenuated the STZ-induced learning and memory impairments in the passive avoidance and Morris water maze (MWM) tasks. In addition, LEV suppressed STZ-induced hippocampal neuronal loss, while restored alterations in the redox status (lipid peroxides and glutathione), AChE activity, proinflammatory cytokines (IL-1β, IL-6, TNF-α), and hyperphosphorylation of tau linked to STZ administration. In conclusion, our study demonstrated that LEV alleviated hippocampal cell death and memory deficits in STZ-AD rats, through mitigating oxidative damage, suppression of proinflammatory cytokines expression, and inhibition of abnormal tau hyperphosphorylation.

Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Disease Models, Animal; Levetiracetam; Maze Learning; Oxidative Stress; Rats; Streptozocin

Levetiracetam (LEV) is an antiseizure medication prescribed to women during childbearing age. The impact of LEV on placental transporters is poorly understood. This study aimed to assess the effect of LEV exposure on the messenger RNA (mRNA) expression of placental transporters for hormones and nutrients and to correlate their expression with the drug's serum concentration in pregnant mice.. Studies were conducted on gestational days (GD) 13 and 18, following oral treatment with 100 mg/kg LEV or the vehicle every 24 h after weaning. Serum LEV measurements were performed by High-performance liquid chromatography with a UV detector (HPLC-UV). The weight, height, and width of the fetuses were also analyzed. In addition, the placental expression of transporters xCt, Lat1, Oatp4a1, Fr-α, Rfc, and Snat4 was evaluated through semi-quantitative real-time polymerase chain reaction (qPCR). The Kruskal-Wallis and the Mann-Whitney U tests were used to determine the statistical significance (p < .05). The correlation between serum LEV concentration and placental gene expression was evaluated using the Spearman test.. The weight, height, and width were lower in the fetuses exposed to LEV compared with the control group (p < .05). The number of fetuses was lower in the LEV-exposed group than in the control GD 13 group (p < .001). No significant differences were detected in the mRNA expression level at GD 13. At GD 18, the expression of Lat1, Oatp4a1, xCT, and Snat4 was higher in the group treated with LEV compared with the control group (p < .05), whereas the expression of Rfc was lower (p < .05). No correlation was identified between serum LEV concentrations and gene expression levels.. The repression of the Rfc transcript by LEV at GD 18 suggests that the protein expression would be abolished contributing to the observed intrauterine growth restriction (IUGR). Furthermore, the significant increase in mRNA of xCt, Snat4, Oatp4a1, and Lat1 might be a compensatory mechanism for fetal survival at GD 18.

Topics: Animals; Anticonvulsants; Disease Models, Animal; Female; Gene Expression; Humans; Levetiracetam; Membrane Transport Proteins; Mice; Placenta; Pregnancy; RNA, Messenger

Epileptic spikes and seizures seem present early in the disease process of Alzheimer's disease (AD). However, it is unclear how soluble and insoluble amyloid beta (Aβ) and tau proteins affect seizure development in vivo. We aim to contribute to this field by assessing the vulnerability to 6 Hz corneal kindling of young female mice from two well-characterized transgenic AD models and by testing their responsiveness to selected antiseizure drugs (ASDs).. We used 7-week-old triple transgenic (3xTg) mice that have both amyloid and tau mutations, and amyloid precursor protein Swedish/presenillin 1 dE9 (APP/PS1) mice, bearing only amyloid-related mutations. We assessed the absence of plaques via immunohistochemistry and analyzed the concentrations of both soluble and insoluble forms of Aβ. Mutations increasing Aβ only or both Aβ and tau in the brain enhance susceptibility for seizures and kindling in mice. The effect of ASDs on seizures measured by the Racine scale is less pronounced in both investigated AD models and suggests that seizures of young AD mice are more difficult to treat.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Anticonvulsants; Disease Models, Animal; Female; Lamotrigine; Levetiracetam; Mice; Mice, Transgenic; Seizures; tau Proteins

Levetiracetam (LEV) suppresses the upregulation of proinflammatory molecules that occurs during epileptogenesis after status epilepticus (SE). Based on previous studies, LEV likely helps prevent the onset of epilepsy after insults to the brain, unlike other conventional anti-epileptic drugs. Recently, we discovered that the increase in

Topics: Animals; Anticonvulsants; Disease Models, Animal; Epilepsy; Inflammation; Levetiracetam; Mice; Pilocarpine; Piracetam; Status Epilepticus

Acute brain inflammation after status epilepticus (SE) is involved in blood-brain barrier (BBB) dysfunction and brain edema, which cause the development of post-SE symptomatic epilepsy. Using pilocarpine-induced SE mice, we previously reported that treatment with levetiracetam (LEV) after SE suppresses increased expression levels of proinflammatory mediators during epileptogenesis and prevents the development of spontaneous recurrent seizures. However, it remains unclear how LEV suppresses neuroinflammation after SE. In this study, we demonstrated that LEV suppressed the infiltration of CD11b

Topics: Animals; Anticonvulsants; Cytokines; Disease Models, Animal; Encephalitis; Levetiracetam; Mice; Monocytes; Neutrophils; Pilocarpine; Proteome; Status Epilepticus

To assess the effects of synaptic vesicle protein 2A (SV2A) modulators brivaracetam and levetiracetam on amygdala kindling epileptogenesis in Tg2576 mice, a model of Alzheimer's disease which exhibits sensitivity to seizures.. First, aged Tg2576 mice (13-25 months; n = 17) were treated subcutaneously with either brivaracetam (10 mg/kg/day), levetiracetam (150 mg/kg/day) or vehicle via osmotic pumps for 28 days prior to, and during electrical amygdala kindling epileptogenesis. Next, we treated young (4-6 months; n = 24) Tg2576 mice with brivaracetam (10 mg/kg/day) or vehicle for 28 days and allowed one week's 'washout' before commencing kindling. Progression of seizure severity and duration were compared between treatment groups and wildtype mice (WT).. In older Tg2576 mice, treatment with brivaracetam (p < 0.001) and levetiracetam (p < 0.05) before and during kindling significantly delayed the progression of seizure severity, compared to vehicle. Animals treated with brivaracetam required significantly more stimulations to reach the first class V (convulsive) seizure and had a lower mortality rate (p < 0.05) compared to those treated with vehicle. Young Tg2576 mice also exhibited increased susceptibility to kindling epileptogenesis compared to WT. Treatment with brivaracetam in younger animals only prior to kindling also delayed kindling acquisition compared to vehicle treatment, increasing the number of stimulations required to experience class V seizures (p < 0.05).. Brivaracetam treatment displayed marked anti-epileptogenic effects in both aged and young Tg2576 mice, including when treatment is ceased prior to initiating kindling. Targeting SV2A might represent a strategy for prevention of epilepsy in patients with Alzheimer's disease.

Topics: Alzheimer Disease; Animals; Anticonvulsants; Disease Models, Animal; Kindling, Neurologic; Levetiracetam; Mice; Seizures; Synaptic Vesicles

Despite the availability of more than 20 clinical antiepileptic drugs, approximately 30% of patients with epilepsy do not respond to antiepileptic drug treatment. Therefore, it is important to develop antiepileptic products that function via novel mechanisms. In the present study, we evaluated data from one of the largest global databases to identify drugs with antiepileptic effects, and subsequently attempted to understand the effect of the combination of antiepileptic drugs and valacyclovir in epileptic seizures using a kindling model. To induce kindling in mice, pentylenetetrazol at a dose of 40 mg/kg was administered once every 48 h. Valacyclovir was orally administered 30 min before antiepileptic drug injection in kindled mice, and behavioral seizures were monitored for 20 min following pentylenetetrazol administration. Additionally, c-Fos expression in the hippocampal dentate gyrus was measured in kindled mice. Valacyclovir showed inhibitory effects on pentylenetetrazol-induced kindled seizures. In addition, simultaneous use of levetiracetam and valacyclovir caused more potent inhibition of seizure activity, and neither valproic acid nor diazepam augmented the anti-seizure effect in kindled mice. Furthermore, kindled mice showed increased c-Fos levels in the dentate gyrus. The increase in c-Fos expression was significantly inhibited by the simultaneous use of levetiracetam and valacyclovir. The findings of the present study indicate that a combination of levetiracetam and valacyclovir had possible anticonvulsive effects on pentylenetetrazol-induced kindled epileptic seizures. These results suggest that valacyclovir may have an antiseizure effect in patients with epilepsy.

Topics: Animals; Anticonvulsants; Cefepime; Databases, Factual; Disease Models, Animal; Drug Repositioning; Drug Therapy, Combination; Hippocampus; Humans; Kindling, Neurologic; Levetiracetam; Male; Mice; Pentylenetetrazole; Proto-Oncogene Proteins c-fos; Seizures; Valacyclovir

There have been recommendations to improve therapy discovery for epilepsy by incorporating chronic epilepsy models into the preclinical process, but unpredictable seizures and difficulties in maintaining drug levels over prolonged periods have been obstacles to using these animals. We report new protocols in which drugs are administered through a new chronic gastric tube to rats with higher seizure frequencies to minimize these obstacles.. Adult rats with spontaneous limbic seizures following an episode of limbic status epilepticus induced by electrical hippocampal stimulation were monitored with long-term video- electroencephalography (EEG). Animals with a predetermined baseline seizure frequency received an intragastric tube for drug administration. Carbamazepine, levetiracetam, phenobarbital, and phenytoin were tested with either an acute protocol (an increasing single dose every other day for a maximum of three doses) or with a chronic protocol (multiple administrations of one dose for a week). Drug levels were obtained to correlate the effect with the level.. With the acute protocol, all four drugs induced a clear dose-related response. Similar dose-related responses were seen following the week-long dosing protocol for carbamazepine, phenobarbital, and phenytoin, and these responses were associated with drug levels that were in the human therapeutic range. The response to chronic levetiracetam was much less robust. The gastric tube route of administration was well tolerated over a number of months.. Using rats with stable, higher seizure frequencies made it possible to identify the potential of a drug to suppress seizures in a realistic model of epilepsy with drug levels that are similar to those of human therapeutic levels. The acute protocol provided a full dose response in 1 week. The chronic administration protocol further differentiated drugs that may be effective long term. The gastric tube facilitates a less stressful, humane, and consistent administration of multiple doses.

Topics: Animals; Anticonvulsants; Carbamazepine; Disease Models, Animal; Epilepsy; Levetiracetam; Pharmaceutical Preparations; Phenobarbital; Phenytoin; Rats; Seizures

This study evaluated the anticonvulsant and neuroprotective effects of carbamazepine (CBZ), levetiracetam (LEV), and CBZ + LEV adjunctive treatment in convulsive status epilepticus (CSE) rat model. Twenty-five male Wistar rats were randomized into five groups (n = 5). Groups I and II received 0.2 ml of normal saline intraperitoneally (i.p), while groups III-V received CBZ (25 mg/kg i.p), LEV (50 mg/kg i.p) or combination of sub-therapeutic doses of CBZ (12.5 mg/kg i.p) and LEV (25 mg/kg i.p). Thirty minutes later, seizure was kindled with pilocarpine hydrochloride (350 mg/kg) in group II-V rats. Seizure indices, markers of excitotoxicity, and astroglioses were determined, while the hippocampal morphometry was also evaluated. The data was analysed using descriptive and inferential statistics, while the results were presented as mean ± SEM in graphs or tables, and the level of significance was taken at p < 0.05. The anticonvulsant treatments delayed the inception of seizure indices (p = 0.0006), while the percentage mortality decreased significantly (p = 0.0001) in all the treatment groups. The hippocampal concentrations of acetylcholine, malondialdehyde, and tissue necrotic factor-alpha decreased significantly (p = 0.0077) in all the treated group relative to the positive control. The reactive astrogliosis in the hippocampus (CA 1) increased significantly (p = 0.0001) compared with the control but abrogated in all the treatment groups relative to the positive control. The anticonvulsant and neuroprotective effects are in this order: LEV < CBZ + CBZ < CBZ. The drug efficacy is attributable to the inhibition of cholinergic transmission.

Topics: Acetylcholine; Animals; Anticonvulsants; Carbamazepine; Disease Models, Animal; Hippocampus; Levetiracetam; Male; Neuroprotective Agents; Random Allocation; Rats; Rats, Wistar; Status Epilepticus; Synaptic Transmission

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

Ocimum sanctum L. commonly known as tulsi (synonym of Ocimum tenuiflorum L.) is widely used in Ayurveda medicine and is having multitude neuromodulatory effect including the anticonvulsant effect in acute seizure models as per previous studies. In India, it is used for the treatment of epilepsy as traditional medicine. However, its role in chronic seizure model and interaction with newer antiepileptic drugs has not been investigated, which will enhance its translational value.. Current study investigated the effect of Ocimum on chronic seizure model and its interaction with levetiracetam (LEV), a newer antiepileptic drug.. The adjuvant role of Ocimum sanctum hydroalcoholic extracts (OSHE) 1000 mg/kg along with LEV 300 mg/kg was studied in adult male Wistar rats with mean weight of 227.84 ± 21.68 g using pentylenetetrazole (30 mg/kg, i.p.) kindling (K) (with maximum 24 injections on alternate days and challenge on 7th-day). Along with seizure score, neurobehavioral, brain tissue oxidative stress and histopathology status were assessed. Pharmacokinetic interaction was assessed between LEV and OSHE after 14 days of drug treatment.. Ocimum per se and combination with levetiracetam treatment exerted better seizure control, memory retention, oxidative stress reduction, and neuronal structure preservation than kindling control group. There was a very minimal drug interaction between Ocimum and LEV. So, Ocimum as an adjuvant to LEV may be shelpful in enhancing the antiepileptic effect and also in minimizing the adverse effects.

Topics: Animals; Anticonvulsants; Avoidance Learning; Disease Models, Animal; Drug Therapy, Combination; Epilepsy; Herb-Drug Interactions; Kindling, Neurologic; Levetiracetam; Male; Maze Learning; Ocimum sanctum; Oxidative Stress; Pentylenetetrazole; Plant Extracts; Rats; Rats, Wistar; Seizures

Intracranial hemorrhage (ICH) is a devastating disease that induces hematoma formation with poor neuronal outcome. Levetiracetam (LEV) has been approval for epilepsy seizures. In a previous study, LEV exerted protective effects on cerebral ischemia models; however, the detail effects and the influence of LEV on ICH are still unknown. The aim of this study was to investigate whether oral administration of LEV (50 or 150 mg/kg) has protective effects on ICH injury using both in vivo and in vitro experiments. In in vivo experiments, we utilized ICH models induced by autologous blood (bICH) or collagenase (cICH) injection. Moreover, we established a neuronal injury model using SYSH5Y human neuroblastoma cell lines. In the bICH model, frequently oral administration of LEV attenuated both cerebral edema and neurological deficits. In addition, the expression levels of phosphorylation-extracellular signal‑related kinase (ERK) 1/2 and cleaved caspase-7 were increased after ICH, and LEV suppressed such alterations. In in vitro experiments, hematoma releasing factors, such as hemoglobin (Hb) and hemin, induced neuronal cell death, and LEV treatment attenuated neuronal injury in a dose-dependent manner. In the cICH model, neurological deficits induced by extensive hematoma formation were attenuated by LEV without affecting hematoma volume. Taken together, these findings suggested that LEV has protective effect on neurons after ICH injury. Therefore, LEV may not only be an efficacious therapeutic agent for seizures, but also for post-hemorrhagic stroke brain injury.

Topics: Animals; Anticonvulsants; Cerebral Hemorrhage; Disease Models, Animal; Humans; Intracranial Hemorrhages; Levetiracetam; Neuroprotective Agents

To develop and characterize a mouse model of spontaneous recurrent seizures following nerve agent-induced status epilepticus (SE) and test the efficacy of existing antiepileptic drugs.. SE was induced in telemeterized male C57Bl6/J mice by soman exposure, and electroencephalographic activity was recorded for 4-6 weeks. Mice were treated with antiepileptic drugs (levetiracetam, valproic acid, phenobarbital) or corresponding vehicles for 14 d after exposure, followed by 14 d of drug washout. Survival, body weight, seizure characteristics, and histopathology were used to characterize the acute and chronic effects of nerve agent exposure and to evaluate the efficacy of treatments in mitigating or preventing neurological effects.. Spontaneous recurrent seizures manifested in all survivors, but the number and frequency of seizures varied considerably among mice. In untreated mice, seizures became longer over time. Moderate to severe histopathology was observed in the amygdala, piriform cortex, and CA1. Levetiracetam provided modest improvements in neurological parameters such as reduced spike rate and improved histopathology scores, whereas valproic acid and phenobarbital were largely ineffective.. This model of post-SE spontaneous recurrent seizures differs from other experimental models in the brief latency to seizure development, the occurrence of seizures in 100 % of exposed animals, and the lack of damage to CA4/dentate gyrus. It may serve as a useful tool for rapidly and efficiently screening novel therapies that would be effective against severe epilepsy cases.

Topics: Animals; Anticonvulsants; Disease Models, Animal; Levetiracetam; Mice; Nerve Agents; Phenobarbital; Soman; Status Epilepticus; Valproic Acid

Metabolic bone disease and fractures are a great problem for patients with epilepsy. The use of antiepileptic drugs (AEDs) is known to play an essential role in the progression of bone loss by various pathophysiological mechanisms. The aim of this study was to evaluate the effects of AEDs on bone microstructure as an additional cause of an increased fracture risk in patients with epilepsy.. Five groups of each of 12 female rats were orally dosed daily for 8 weeks with either carbamazepine (CBZ) (60 mg/kg), eslicarbazepine (ESL) (80 mg/kg), valproic acid (VPA) (300 mg/kg), levetiracetam (LEV) (50 mg/kg) or saline (control (CTL)). Following killing, dissected femurs were analyzed using X-ray micro-computed tomography (µCT), dual-energy X-ray absorptiometry (DXA) and biomechanical testing. In addition, serum bone turnover markers (BTM) were monitored throughout the experiment.. Compared to CTL treatment, VPA decreased bone volume fraction by 19%, decreased apparent density by 14% and increased structural model index by 41%. No changes were observed in bone biomechanics nor mineral density evaluated by DXA or in levels of BTM.. Our findings suggest that VPA affects the microarchitectural properties of the bone. The AEDs CBZ, ESL and LEV appear to have less adverse effects on bone biology and may be a better choice when treating patients with respect to bone health.

Topics: Animals; Anticonvulsants; Bone and Bones; Carbamazepine; Dibenzazepines; Disease Models, Animal; Epilepsy; Female; Levetiracetam; Rats; Rats, Sprague-Dawley; Valproic Acid; X-Ray Microtomography

Multiple recent instances of nerve agent (NA) exposure in civilian populations have occurred, resulting in a variety of negative effects and lethality in both adult and pediatric populations. Seizures are a prominent effect of NAs that can result in neurological damage and contribute to their lethality. Current anticonvulsant treatments for NAs are approved for adults, but no approved pediatric treatments exist. Further, the vast majority of NA-related research in animals has been conducted in adult male subjects. There is a need for research that includes female and pediatric populations in testing. In this project, adult and pediatric male and female rats were challenged with sarin or VX and then treated with fosphenytoin, levetiracetam, or propofol. In this study, fosphenytoin and levetiracetam failed to terminate seizure activity when animals were treated 5 min after seizure onset. Propofol was effective, exhibiting high efficacy and potency for terminating seizure activity quickly in pediatric and adult animals, suggesting it may be an effective anticonvulsant for NA-induced seizures in pediatric populations.

Topics: Age Factors; Animals; Anticonvulsants; Brain; Disease Models, Animal; Female; Levetiracetam; Male; Organothiophosphorus Compounds; Phenytoin; Propofol; Rats, Sprague-Dawley; Sarin; Sex Factors; Status Epilepticus

Pharmacotherapy with two antiepileptic drugs in combination is usually prescribed to epilepsy patients with refractory seizures. The choice of antiepileptic drugs in combination should be based on synergistic cooperation of the drugs with respect to suppression of seizures. The selection of synergistic interactions between antiepileptic drugs is challenging issue for physicians, especially, if 25 antiepileptic drugs are currently available and approved to treat epilepsy patients. The aim of this study was to determine all possible interactions among 5 second-generation antiepileptic drugs (gabapentin (GBP), lacosamide (LCM), levetiracetam (LEV), pregabalin (PGB) and retigabine (RTG)) in the 6-Hz corneal stimulation-induced seizure model in adult male albino Swiss mice. The anticonvulsant effects of 10 various two-drug combinations of antiepileptic drugs were evaluated with type I isobolographic analysis associated with graphical presentation of polygonogram to visualize the types of interactions. Isobolographic analysis revealed that 7 two-drug combinations of LEV+RTG, LEV+LCM, GBP+RTG, PGB+LEV, GBP+LEV, PGB+RTG, PGB+LCM were synergistic in the 6-Hz corneal stimulation-induced seizure model in mice. The additive interaction was observed for the combinations of GBP+LCM, GBP+PGB, and RTG+LCM in this seizure model in mice. The most beneficial combination, offering the highest level of synergistic suppression of seizures in mice was that of LEV+RTG, whereas the most additive combination that protected the animals from seizures was that reporting additivity for RTG+LCM. The strength of interaction for two-drug combinations can be arranged from the synergistic to the additive, as follows: LEV+RTG > LEV+LCM > GBP+RTG > PGB+LEV > GBP+LEV > PGB+RTG > PGB+LCM > GBP+LCM > GBP+PGB > RTG+LCM.

Topics: Animals; Anticonvulsants; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Electroshock; Gabapentin; Lacosamide; Levetiracetam; Male; Mice; Muscle Strength; Seizures

Topics: 3-Hydroxybutyric Acid; Action Potentials; Alzheimer Disease; Animals; Anticonvulsants; Atropine; Disease Models, Animal; Donepezil; Drug Administration Schedule; Electroencephalography; Epilepsy; Ethosuximide; GABA Antagonists; Humans; Injections, Intraperitoneal; Lactic Acid; Levetiracetam; Male; Mice; Mice, Transgenic; Nootropic Agents; Organophosphorus Compounds; Parasympatholytics; Plaque, Amyloid; Pyruvic Acid; Video Recording

Initial identification of new investigational drugs for the treatment of epilepsy is commonly conducted in well-established mouse acute and chronic seizure models: for example, maximal electroshock (MES), 6 Hz, and corneal kindling. Comparison of the median effective dose (ED50) of approved antiseizure drugs (ASDs) vs investigational agents in these models provides evidence of their potential for clinical efficacy. Inbred and outbred mouse strains exhibit differential seizure susceptibility. However, few comparisons exist of the ED50 or median behaviorally impairing dose (TD50) of prototype ASDs in these models in inbred C57Bl/6 vs outbred CF-1 mice, both of which are often used for ASD discovery.. We defined the strain-related ED50s and TD50s of several mechanistically distinct ASDs across established acute seizure models (MES, 6 Hz, and corneal-kindled mouse). We further quantified the strain-related effect of the MES ED50 of each ASD on gross behavior in a locomotor activity assay. Finally, we describe a novel pharmacoresistant corneal-kindling protocol that is suitable for moderate-throughput ASD screening and demonstrates highly differentiated ASD sensitivity.. We report significant strain-related differences in the MES ED50 of valproic acid (CF-1 ED50: 90 mg/kg [95% confidence interval (CI) 165-214] vs C57Bl/6: 276 mg/kg [226-366]), as well as significant differences in the ED50 of levetiracetam in the pharmacoresistant 6 Hz test (CF-1: 22.5 mg/kg [14.7-30.2] vs C57Bl/6: >500 mg/kg [CI not defined]). There were no differences in the calculated TD50 of these ASDs between strains. Furthermore, the MES ED50 of phenobarbital significantly enhanced locomotor activity of outbred CF-1, but not C57Bl/6, mice.. Altogether, this study provides strain-related information to differentiate investigational agents from ASD standards-of-care in commonly employed preclinical discovery models and describes a novel kindled seizure model to further explore the mechanisms of drug-resistant epilepsy.

Topics: Animals; Animals, Outbred Strains; Anticonvulsants; Behavior, Animal; Brain; Carbamazepine; Cornea; Diazepam; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Discovery; Drug Evaluation, Preclinical; Drug Resistant Epilepsy; Electroshock; Kindling, Neurologic; Lamotrigine; Levetiracetam; Locomotion; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Open Field Test; Phenobarbital; Seizures; Treatment Outcome; Valproic Acid

In recent years, aberrant neural oscillations in various cortical areas have emerged as a common physiological hallmark across mouse models of amyloid pathology and patients with Alzheimer's disease. However, much less is known about the underlying effect of amyloid pathology on single cell activity. Here, we used high-density silicon probe recordings from frontal cortex area of 9-month-old APP/PS1 mice to show that local field potential power in the theta and beta band is increased in transgenic animals, whereas single-cell firing rates, specifically of putative pyramidal cells, are significantly reduced. At the same time, these sparsely firing pyramidal cells phase-lock their spiking activity more strongly to the ongoing theta and beta rhythms. Furthermore, we demonstrated that the antiepileptic drug, levetiracetam, counteracts these effects by increasing pyramidal cell firing rates in APP/PS1 mice and uncoupling pyramidal cells and interneurons. Overall, our results highlight reduced firing rates of cortical pyramidal cells as a pathophysiological phenotype in APP/PS1 mice and indicate a potentially beneficial effect of acute levetiracetam treatment.

Topics: Action Potentials; Alzheimer Disease; Amyloid beta-Protein Precursor; Amyloidosis; Animals; Disease Models, Animal; Frontal Lobe; Levetiracetam; Male; Mice, Transgenic; Presenilin-1; Pyramidal Cells

There is a major clinical need for new therapies for the treatment of chronic itch. Many of the molecular components involved in itch neurotransmission are known, including the neuropeptide NPPB, a transmitter required for normal itch responses to multiple pruritogens in mice. Here, we investigated the potential for a novel strategy for the treatment of itch that involves the inhibition of the NPPB receptor NPR1 (natriuretic peptide receptor 1). Because there are no available effective human NPR1 (hNPR1) antagonists, we performed a high-throughput cell-based screen and identified 15 small-molecule hNPR1 inhibitors. Using in vitro assays, we demonstrated that these compounds specifically inhibit hNPR1 and murine NPR1 (mNPR1). In vivo, NPR1 antagonism attenuated behavioral responses to both acute itch- and chronic itch-challenged mice. Together, our results suggest that inhibiting NPR1 might be an effective strategy for treating acute and chronic itch.

Topics: Animals; Behavior, Animal; Cell-Free System; Dermatitis, Contact; Disease Models, Animal; Ganglia, Spinal; Humans; Mice, Inbred C57BL; Mice, Knockout; Neurons; Pruritus; Receptors, Atrial Natriuretic Factor; Reproducibility of Results; Signal Transduction; Small Molecule Libraries

Glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase (UCH-L1), markers of glial and neuronal cell body injury, respectively, have been previously selected by the Operation Brain Trauma Therapy (OBTT) pre-clinical therapy and biomarker screening consortium as drug development tools. However, traumatic axonal injury (TAI) also represents a major consequence and determinant of adverse outcomes after traumatic brain injury (TBI). Thus, biomarkers capable of assessing TAI are much needed. Neurofilaments (NFs) are found exclusively in axons. Here, we evaluated phospho-neurofilament-H (pNF-H) protein as a possible new TAI marker in serum and cerebrospinal fluid (CSF) across three rat TBI models in studies carried out by the OBTT consortium, namely, controlled cortical impact (CCI), parasagittal fluid percussion (FPI), and penetrating ballistics-like brain injury (PBBI). We indeed found that CSF and serum pNF-H levels are robustly elevated by 24 h post-injury in all three models. Further, in previous studies by OBTT, levetiracetam showed the most promising benefits, whereas nicotinamide showed limited benefit only at high dose (500 mg/kg). Thus, serum samples from the same repository collected by OBTT were evaluated. Treatment with 54 mg/kg intravenously of levetiracetam in the CCI model and 170 mg/kg in the PBBI model significantly attenuated pNF-H levels at 24 h post-injury as compared to respective vehicle groups. In contrast, nicotinamide (50 or 500 mg/kg) showed no reduction of pNF-H levels in CCI or PBBI models. Our current study suggests that pNF-H is a useful theranostic blood-based biomarker for TAI across different rodent TBI models. In addition, our data support levetiracetam as the most promising TBI drug candidate screened by OBTT to date.

Topics: Animals; Biomarkers; Brain Injuries, Traumatic; Disease Models, Animal; Levetiracetam; Neurofilament Proteins; Niacinamide; Nootropic Agents; Rats; Rats, Sprague-Dawley; Theranostic Nanomedicine; Vitamin B Complex

The aim of the study was to evaluate the impact of second generation antiepileptic drug levetiracetam (LEV) with arachidonyl-2'-chloroethylamide (ACEA) on proliferating neural precursor cells in mouse brain. Additionally, we established the relationship between treatment with ACEA in combination with LEV and hippocampal neurogenesis in mouse brain. All experiments were performed on male CB57/BL mice injected i.p. with LEV (10 mg/kg), ACEA (10 mg/kg) and PMSF (30 mg/kg) for 10 days. Experiments were provided in two stages: stage 1- an acute response of proliferating neural precursor cells to ACEA and LEV administration (Ki-67 staining), stage 2 - a long term response to ACEA and LEV administration (BrDU, NeuN, GFAP staining). Results indicate that ACEA + PMSF and ACEA + PMSF + LEV significantly increased the total number of Ki-67 positive cells comparing to the control group. PMSF and LEV administered alone and in combination had no significant impact on cell proliferation compared to the control group. Results from neurogenesis study indicated that ACEA + PMSF administered alone and in combination with LEV increased the total number of BrDU cells compared to the control group, although LEV on its own decreased the number of BrDU cells. Moreover, the combination of ACEA + PMSF + LEV significantly increased the total number of newborn neurons compared to the control group. In turn, LEV significantly decreased the process of neurogenesis. Astrocytes were considerably reduced in all treated groups as compare to the control mice. These data provide substantial evidence that LEV administered chronically decreases the proliferation and differentiation of newly born cells while combination of LEV + ACEA significantly increases the level of newborn neurons in the dentate subgranular zone.

Topics: Animals; Anticonvulsants; Astrocytes; Avoidance Learning; Brain; Disease Models, Animal; Electroshock; Levetiracetam; Male; Mice, Inbred C57BL; Neural Stem Cells; Neurogenesis; Phenylmethylsulfonyl Fluoride; Receptor, Cannabinoid, CB1; Valproic Acid

Gulf War Illness (GWI) is a chronic multi-symptom disorder afflicting the veterans of the First Gulf War, and includes neurological symptoms characterized by depression and memory deficits. Chronic exposure to organophosphates (OPs) is considered a leading cause for GWI, yet its pathobiology is not fully understood. We recently observed chronic elevations in neuronal Ca2+ levels ([Ca2+]i) in an OP-diisopropyl fluorophosphate (DFP)-based rat model for GWI. This study was aimed at identifying mechanisms underlying elevated [Ca2+]i in this DFP model and investigating whether their therapeutic targeting could improve GWI-like neurological morbidities. Male Sprague-Dawley rats (9 weeks) were exposed to DFP (0.5 mg/kg, s.c., 1×-daily for 5 days) and at 3 months postDFP exposure, behavior was assessed and rats were euthanized for protein estimations and ratiometric Fura-2 [Ca2+]i estimations in acutely dissociated hippocampal neurons. In DFP rats, a sustained elevation in intracellular Ca2+ levels occurred, and pharmacological blockade of Ca2+-induced Ca2+-release mechanisms significantly lowered elevated [Ca2+]i in DFP neurons. Significant reductions in the protein levels of the ryanodine receptor (RyR) stabilizing protein Calstabin2 were also noted. Such a posttranslational modification would render RyR "leaky" resulting in sustained DFP [Ca2+]i elevations. Antagonism of RyR with levetiracetam significantly lower elevated [Ca2+]i in DFP neurons and improved GWI-like behavioral symptoms. Since Ca2+ is a major second messenger molecule, such chronic increases in its levels could underlie pathological synaptic plasticity that expresses itself as GWI morbidities. Our studies show that treatment with drugs targeted at blocking intracellular Ca2+ release could be effective therapies for GWI neurological morbidities.

Topics: Animals; Calcium; Disease Models, Animal; Hippocampus; Isoflurophate; Levetiracetam; Male; Maze Learning; Persian Gulf Syndrome; Rats; Rats, Sprague-Dawley

Retinopathy is a neurodegenerative complication associating diabetes mellitus. Diabetic retinopathy (DR) is the primary reason of visual loss during early adulthood. DR has a complicated multifactorial pathophysiology initiated by hyperglycaemia-induced ischaemic neurodegenerative retinal changes, followed by vision-threatening consequences. The main therapeutic modalities for DR involve invasive delivery of intravitreal antiangiogenic agents as well as surgical interventions. The current work aimed to explore the potential anti-inflammatory and retinal neuroprotective effects of levetiracetam.. This study was performed on alloxan-induced diabetes in mice (n: 21). After 10 weeks, a group of diabetic animals (n: 7) was treated with levetiracetam (25 mg/kg) for six weeks. Retinal tissues were dissected and paraffin-fixed for examination using (1) morphometric analysis with haematoxylin and eosin (HE), (2) immunohistochemistry (GLUT1, GFAP and GAP43), and (3) RT-PCR-detected expression of retinal inflammatory and apoptotic mediators (TNF-α, IL6, iNOS, NF-κB and Tp53).. Diabetic mice developed disorganized and debilitated retinal layers with upregulation of the gliosis marker GFAP and downregulation of the neuronal plasticity marker GAP43. Additionally, diabetic retinae showed increased transcription of NF-κB, TNF-α, IL6, iNOS and Tp53. Levetiracetam-treated mice showed downregulation of retinal GLUT1 with relief and regression of retinal inflammation and improved retinal structural organization.. Levetiracetam may represent a potential neuroprotective agent in DR. The data presented herein supported an anti-inflammatory role of levetiracetam. However, further clinical studies may be warranted to confirm the effectiveness and safety of levetiracetam in DR patients.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetic Retinopathy; Disease Models, Animal; GAP-43 Protein; Glucose Transporter Type 1; Immunohistochemistry; Inflammation; Interleukin-6; Levetiracetam; Male; Mice; Neuroprotective Agents; NF-kappa B; Nitric Oxide Synthase Type II; Retina; Retinal Diseases; Tumor Necrosis Factor-alpha

Topics: Animals; Calcium-Calmodulin-Dependent Protein Kinases; Cognitive Dysfunction; Disease Models, Animal; Electroencephalography; GAP-43 Protein; Hippocampus; Levetiracetam; Male; Phosphorylation; Protein Kinase C; Rats; Rats, Sprague-Dawley; Seizures; Signal Transduction; Valproic Acid

White matter lesions due to cerebral hypoperfusion may be an important pathophysiology in vascular dementia and stroke, although the inherent mechanisms remain to be fully elucidated. The present study, using a mouse model of chronic cerebral hypoperfusion, examined the white matter protective effects of levetiracetam, an anticonvulsant, via the signaling cascade from the activation of cAMP-responsive element binding protein (CREB) phosphorylation. Mice underwent bilateral common carotid artery stenosis (BCAS), and were separated into the levetiracetam group (injected once only after BCAS [LEV1] or injected on three consecutive days [LEV3]), the vehicle group, or the anti-epileptic drugs with different action mechanisms phenytoin group (PHT3; injected on three consecutive days with the same condition as in LEV3). Cerebral blood flow analysis, Y-maze spontaneous alternation test, novel object recognition test, immunohistochemical and Western blot analyses, and protein kinase A assay were performed after BCAS. In the LEV3 group, SV2A expression was markedly increased, which preserved learning and memory after BCAS. Moreover, as the protein kinase A level was significantly increased, pCREB expression was also increased. The activation of microglia and astrocytes was markedly suppressed, although the number of oligodendrocyte precursor cells (OPCs) and GST-pi-positive-oligodendrocytes was markedly higher in the cerebral white matter. Moreover, oxidative stress was significantly reduced. We found that 3-day treatment with levetiracetam maintained SV2A protein expression via interaction with astrocytes, which influenced the OPC lineage through activation of CREB to protect white matter from ischemia.

Topics: Animals; Astrocytes; Brain; Brain Ischemia; Carotid Stenosis; Cognition; Cognitive Dysfunction; Cyclic AMP Response Element-Binding Protein; Cyclic AMP-Dependent Protein Kinases; Disease Models, Animal; Levetiracetam; Membrane Glycoproteins; Memory; Mice; Microglia; Nerve Tissue Proteins; Neuroprotective Agents; Phosphorylation; White Matter

Status epilepticus (SE) is characterized by recurrent seizure activity and can be drug- resistant. Knowledge of neuronal and metabolic activity of the brain during SE may be helpful to improve medical care. We here report the effects of three anti-seizure drugs on changes of acetylcholine energy metabolites and oxidative stress during SE.. We used the lithium-pilocarpine model in rats to induce SE and in vivo- microdialysis to monitor cholinergic and metabolic activity in the hippocampus. We measured extracellular concentrations of acetylcholine, glucose, lactate, pyruvate, glycerol and isoprostanes before and during SE, and after acute treatment with pregabalin, valproic acid, and levetiracteam.. Upon onset of  SE, acetylcholine (ACh) release increased six- to eightfold. Glucose was increased only transiently by 30% but lactate levels rose four-fold, and extracellular concentrations of glycerol ten-fold. Isoprostanes are markers of oxidative stress and increased more than 20-fold. Two hours after pilocarpine adminstration, rats were treated with pregabalin (100 mg/kg), levetiracetam (200 mg/kg) or valproic acid (400 mg/kg) by i.p. injection. All three drugs stopped seizure activity in a delayed fashion, but at the doses indicated, only animals that received levetiracetam reached consciousness. All drugs reduced ACh release within 60-120 minutes. Lactate/pyruvate ratios, glycerol and isoprostanne levels were also reduced significantly after drug administration.. Hippocampal ACh release closely follows seizure activity in SE and is attenuated when SE subsides. Pregabalin, valproic acid and levetiracetam all terminate seizures in the rat SE model and attenuate cholinergic and metabolic changes within two hours.

Topics: Acetylcholine; Animals; Anticonvulsants; Behavior, Animal; Cholinergic Agents; Chromatography, High Pressure Liquid; Disease Models, Animal; Levetiracetam; Male; Oxidative Stress; Pregabalin; Rats; Rats, Sprague-Dawley; Seizures; Status Epilepticus; Valproic Acid

Cannabidiol and cannabidiol-enriched products have recently attracted much attention as an add-on therapy for epilepsy, especially drug-resistant seizures. It should be, however, remembered that concomitant use of cannabidiol and antiepileptic drugs may pose a risk of interactions between them. For this reason, the aim of our study was to assess the effect of cannabidiol on the activity of selected new antiepileptic drugs in the electrically-induced seizure models in mice. We studied the effect of cannabidiol on the anticonvulsant action of topiramate, oxcarbazepine, lamotrigine, and pregabalin in the maximal electroshock-induced seizure test as well as on the activity of levetiracetam, tiagabine, lacosamide, and gabapentin in the 6 Hz seizure test in mice. We showed that cannabidiol increased the activity of topiramate, oxcarbazepine, pregabalin, tiagabine, and gabapentin. It did not affect the anticonvulsant effect of lamotrigine and lacosamide. Interestingly, cannabidiol attenuated the anticonvulsant activity of levetiracetam. Co-administration of antiepileptic drugs with cannabidiol did not cause adverse effects such as impairment of motor coordination, changes in neuromuscular strength or potentiation of the cannabidiol-induced hypolocomotion. Serum and brain levels of antiepileptic drugs and cannabidiol were determined by using HPLC in order to ascertain any pharmacokinetic contribution to the observed behavioral effects. Only interaction with levetiracetam was purely pharmacodynamic in nature because no changes in serum and brain concentration of either levetiracetam or cannabidiol were observed. Increased anticonvulsant activity of topiramate, oxcarbazepine, pregabalin, tiagabine, and gabapentin could be, at least in part, related to pharmacokinetic interactions with cannabidiol because there were changes in serum and/or brain concentrations of antiepileptic drugs and/or cannabidiol. Pharmacokinetic interactions cannot be also excluded between lacosamide and cannabidiol because cannabidiol increased brain concentration of lacosamide and lacosamide increased brain concentration of cannabidiol. Further pharmacokinetic studies are required to evaluate the type of interactions between cannabidiol and novel antiepileptic drugs.

Topics: Animals; Anticonvulsants; Brain; Cannabidiol; Chromatography, High Pressure Liquid; Disease Models, Animal; Drug Interactions; Drug Resistant Epilepsy; Electric Stimulation; Gabapentin; Lacosamide; Lamotrigine; Levetiracetam; Male; Mice; Oxcarbazepine; Pregabalin; Seizures; Tiagabine; Topiramate

WAG/Rij rats represent a validated genetic animal model of epileptogenesis, absence epilepsy and depressive-like comorbidity. Some treatments (e.g. ethosuximide), using specific protocols, prevent the development of spontaneous absence seizures. Accordingly, ethosuximide increases remission occurrence in children with childhood absence epilepsy in comparison to valproic acid. Considering that in this animal model, antiepileptogenic effects are, in some cases, not retained over time, we studied whether the antiepileptogenic effects of both ethosuximide and levetiracetam (which also possesses antiepileptogenic effects in this and other animal epilepsy models) would be retained 5 months after drug suspension.. WAG/Rij rats of ˜1 month of age were treated long-term with one of the two drugs at a dose of ˜80 mg/kg/day for 17 consecutive weeks; 1 and 5 months after drug suspension, the development of absence seizures as well as depressive-like behaviour were assessed by EEG recordings and the forced swimming test (FST).. In agreement with a previous report, both drugs continued to show antiepileptogenic effects 1 month after their discontinuation. Furthermore, ethosuximide improved depressive-like behaviour, whereas in contrast, levetiracetam worsened this symptom. However, none of the drugs maintained their antiepileptogenic effects 5 months after suspension, and in addition, animal behaviour in the FST returned to control conditions.. Overall, these results demonstrate that the antiepileptogenic effects of both ethosuximide and levetiracetam on absence seizure development and associated depressive-like behaviour in this model are only temporary.

Topics: Animals; Anticonvulsants; Behavior, Animal; Depression; Disease Models, Animal; Duration of Therapy; Epilepsy, Absence; Ethosuximide; Levetiracetam; Male; Motor Activity; Rats; Rats, Inbred Strains; Seizures; Time Factors

Imbalance in neural excitation and inhibition is associated with behavioral dysfunction in individuals with schizophrenia and at risk for this illness. We examined whether targeting increased neural activity with the antiepileptic agent, levetiracetam, would benefit memory performance in a preclinical model of schizophrenia that has been shown to exhibit hyperactivity in the hippocampus. Adult rats exposed to ketamine subchronically during late adolescence showed impaired hippocampal-dependent memory performance. Treatment with levetiracetam dose-dependently improved memory performance of the ketamine-exposed rats. In contrast, the antipsychotic medication risperidone was not effective in this assessment. Levetiracetam remained effective when administered concurrently with risperidone, supporting potential viability of adjunctive therapy with levetiracetam to treat cognitive deficits in schizophrenia patients under concurrent antipsychotic therapy. In addition to its pro-cognitive effect, levetiracetam was also effective in attenuating amphetamine-induced augmentation of locomotor activity, compatible with the need for therapeutic treatment of positive symptoms in schizophrenia.

Topics: Amphetamine; Animals; Central Nervous System Stimulants; Cognition Disorders; Disease Models, Animal; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Ketamine; Levetiracetam; Locomotion; Male; Maze Learning; Memory Disorders; Nootropic Agents; Piracetam; Rats; Rats, Long-Evans; Schizophrenia

Background Migraine is a highly prevalent and disabling disorder of the brain with limited therapeutic options, particularly for preventive treatment. There is a need to identify novel targets and test their potential efficacy in relevant preclinical migraine models. Traditional Chinese medicines have been used for millennia and may offer avenues for exploration. Methods We evaluated two traditional Chinese medicines, gastrodin and ligustrazine, and compared them to two Western approaches with propranolol and levetiracetam, one effective and one ineffective, in an established in vivo rodent model of nociceptive durovascular trigeminal activation. Results Intravenous gastrodin (30 and 100 mg/kg) significantly inhibited nociceptive dural-evoked neuronal firing in the trigeminocervical complex. Ligustrazine (10 mg/kg) and propranolol (3 mg/kg) also significantly inhibited dural-evoked trigeminocervical complex responses, although the timing of responses of ligustrazine does not match its pharmacokinetic profile. Levetiracetam had no effects on trigeminovascular responses. Conclusion Our data suggest gastrodin has potential as an anti-migraine treatment, whereas ligustrazine seems less promising. Interestingly, in line with clinical trial data, propranolol was effective and levetiracetam not. Exploration of the mechanisms and modelling effects of Chinese traditional therapies offers novel route for drug discovery in migraine.

Topics: Animals; Benzyl Alcohols; Disease Models, Animal; Dura Mater; Glucosides; Levetiracetam; Male; Medicine, Chinese Traditional; Migraine Disorders; Neurons, Afferent; Nociceptive Pain; Pain Management; Propranolol; Pyrazines; Rats, Sprague-Dawley; Trigeminal Nerve

Animal models are valuable tools for screening novel therapies for patients who suffer from epilepsy. However, a wide array of models are necessary to cover the diversity of human epilepsies. In humans, neonatal hypoxia (or hypoxia-ischemia) is one of the most common causes of epilepsy early in life. Hypoxia-induced seizures (HS) during the neonatal period can also lead to spontaneous seizures in adulthood. This phenomenon, i.e., early-life hypoxia leading to adult epilepsy - is also seen in experimental models, including rats. However, it is not known which anti-seizure medications are most effective at managing adult epilepsy resulting from neonatal HS. Here, we examined the efficacy of three anti-seizure medications against spontaneous seizures in adult rats with a history of neonatal HS: (1) phenobarbital (PHB), the oldest epilepsy medicine still in use today; (2) levetiracetam (LEV); and (3) tiagabine (TGB). Both LEV and TGB are relatively new anticonvulsant drugs that are ineffective in traditional seizure models, but strikingly effective in other models. We found that PHB and LEV decreased seizures in adult rats with a history of HS, whereas TGB exacerbated seizures. These divergent drug effects indicate that the HS model may be useful for differentiating the clinical efficacy of putative epilepsy therapies.

Topics: Animals; Animals, Newborn; Anticonvulsants; Brain; Disease Models, Animal; Hypoxia; Levetiracetam; Male; Phenobarbital; Prohibitins; Rats, Long-Evans; Seizures; Tiagabine

Levetiracetam (LEV) is a novel anticonvulsant with proven antinociceptive properties. However, the antinociceptive and pronociceptive effect of this drug has not yet been fully elucidated in a tonic pain model.. Thirty-six male rats (Wistar) were randomized into six groups and underwent the formalin test as follows: rats in the control group were administered 50μL of 1% formalin in the paw; sham-group rats were administered 50μL of saline in the paw to mimick the application of formalin; the four experimental groups were administered LEV intragastrically (ig) (50, 100, 200 and 300mg/kg), and 40min later 50μL of 1% formalin was injected in the paw.. LEV exhibited antinociceptive effect in the 300mg/kg LEV group (p<0.05) and a pronociceptive effect in the 100mg/kg LEV group (p<0.05) and in the 50mg/kg LEV group (p<0.001).. The antinociceptive and pronociceptive effect of LEV in a tonic pain model is dose-dependent.

Topics: Analgesics; Animals; Anticonvulsants; Disease Models, Animal; Dose-Response Relationship, Drug; Levetiracetam; Male; Nociception; Pain; Pain Measurement; Piracetam; Rats; Rats, Wistar

Status epilepticus (SE) is a neurological condition that frequently induces severe neuronal injury in the hippocampus, subsequent epileptogenesis and pharmacoresistant spontaneous recurrent seizures (SRS). The repeated administration of LEV (a broad-spectrum antiepileptic drug) during the post-SE period does not prevent the subsequent development of SRS. However, this treatment reduces SE-induced neurodegeneration in the hippocampus. Conversely, propylparaben (PPB) is a widely used antimicrobial that blocks voltage-dependent Na

Topics: Animals; Anticonvulsants; Behavior, Animal; Disease Models, Animal; Hippocampus; Levetiracetam; Lithium; Male; Neurons; Neuroprotective Agents; Parabens; Pilocarpine; Rats, Wistar; Seizures; Status Epilepticus; Time

We have reported that levetiracetam, a novel anticonvulsant with analgesic properties, synergizes with ibuprofen/aspirin/paracetamol in a model of diabetic painful neuropathy (DPN). Most guidelines recommend gabapentin, pregabalin, and duloxetine as first- or second-line agents for DPN.. We examined the effects of combination treatment of first-/second-line analgesics with levetiracetam in a model of DPN. Additionally, the levetiracetam's combinations with antioxidants, low dose of aspirin, coenzyme Q10, or α-lipoic acid were evaluated.. Diabetes was induced in C57BL/6 mice with a single high dose of streptozotocin. The antinociceptive effects of orally administered levetiracetam, gabapentin, pregabalin, duloxetine (acute treatment) and aspirin, coenzyme Q10, and α-lipoic acid (preventive 7-day treatment), as well as combinations of levetiracetam with individual drugs were examined in the tail-flick test. In combination experiments, the drugs were coadministered in fixed-dose fractions of single-drug ED. About 60-, 32-, 30-, 26-, 18-, and 6-fold reductions of doses of both drugs in levetiracetam combinations with pregabalin, gabapentin, coenzyme Q10, aspirin, duloxetine, and α-lipoic acid, respectively, were detected.. Combinations of levetiracetam with gabapentin/pregabalin/duloxetine that target different mechanisms/sites of action involved in DPN, as well as combinations of levetiracetam and low-dose aspirin/coenzyme Q10/α-lipoic acid that target underlying causes of DPN, produce marked synergistic interactions in reducing nociception in diabetic mice. This suggests that these combination treatments might be of great benefit for diabetic patients and should be explored further in clinical trials.

Topics: Amines; Analgesics; Animals; Anticonvulsants; Antioxidants; Cyclohexanecarboxylic Acids; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Duloxetine Hydrochloride; Gabapentin; gamma-Aminobutyric Acid; Levetiracetam; Male; Mice; Mice, Inbred C57BL; Piracetam; Pregabalin

Dysfunction in topographical memory is a core feature of several neurological disorders. There is a large unmet medical need to address learning and memory deficits as a whole in central nervous system disease. There are considerable efforts to identify pro-cognitive compounds but current methods are either lengthy or labour intensive. Our test used a two chamber apparatus and is based on the preference of rodents to explore novel environments. It was used firstly to assess topographical memory in mice at different retention intervals (RI) and secondly to investigate the effect of three drugs reported to be beneficial for cognitive decline associated with Alzheimer's disease, namely: donepezil, memantine and levetiracetam. Animals show good memory performance at all RIs tested under four hours. At the four-hour RI, animals show a significantly poorer memory performance which can be rescued using donepezil, memantine and levetiracetam. Using this test we established and validated a spatial recognition paradigm to address topographical memory in mice by showing a decremental time-induced forgetting response and reversing this decrease in performance using pharmacological tools. The spatial recognition test differs from more commonly used visuospatial laboratory tests in both throughput capability and potentially neuroanatomical substrate. This test has the potential to be used to assess cognitive performance in transgenic animals, disease models and to screen putative cognitive enhancers or depressors.

Topics: Alzheimer Disease; Animals; Cognition; Disease Models, Animal; Donepezil; Indans; Levetiracetam; Male; Maze Learning; Memantine; Memory; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nootropic Agents; Piperidines; Piracetam; Recognition, Psychology

Nocturnal frontal lobe epilepsy (NFLE) is an idiopathic partial epilepsy with a family history in about 25% of cases, with autosomal dominant inheritance (autosomal dominant NFLE [ADNFLE]). Traditional antiepileptic drugs are effective in about 55% of patients, whereas the rest remains refractory. One of the key pathogenetic mechanisms is a gain of function of neuronal nicotinic acetylcholine receptors (nAChRs) containing the mutated α4 or β2 subunits. Fenofibrate, a common lipid-regulating drug, is an agonist at peroxisome proliferator-activated receptor alpha (PPARα) that is a ligand-activated transcription factor, which negatively modulates the function of β2-containing nAChR. To test clinical efficacy of adjunctive therapy with fenofibrate in pharmacoresistant ADNFLE\\NFLE patients, we first demonstrated the effectiveness of fenofibrate in a mutated mouse model displaying both disease genotype and phenotype.. We first tested the efficacy of fenofibrate in transgenic mice carrying the mutation in the α4-nAChR subunit (Chrna4S252F) homologous to that found in humans. Subsequently, an add-on protocol was implemented in a clinical setting and fenofibrate was administered to pharmacoresistant NFLE patients.. Here, we show that a chronic fenofibrate diet markedly reduced the frequency of large inhibitory postsynaptic currents (IPSCs) recorded from cortical pyramidal neurons in Chrna4S252F mice, and prevented nicotine-induced increase of IPSC frequency. Moreover, fenofibrate abolished differences between genotypes in the frequency of sleep-related movements observed under basal conditions. Patients affected by NFLE, nonresponders to traditional therapy, by means of adjunctive therapy with fenofibrate displayed a reduction of seizure frequency. Furthermore, digital video-polysomnographic recordings acquired in NFLE subjects after 6 months of adjunctive fenofibrate substantiated the significant effects on control of motor-behavioral seizures.. Our preclinical and clinical studies suggest PPARα as a novel disease-modifying target for antiepileptic drugs due to its ability to regulate dysfunctional nAChRs.

Topics: Adult; Animals; Anticonvulsants; Benzodiazepines; Carbamazepine; Clobazam; Disease Models, Animal; Drug Resistant Epilepsy; Drug Therapy, Combination; Electroencephalography; Epilepsy, Frontal Lobe; Female; Fenofibrate; Humans; Lamotrigine; Levetiracetam; Male; Mice; Mice, Transgenic; Middle Aged; Mutation; Oxcarbazepine; Piracetam; Polysomnography; PPAR alpha; Receptors, Nicotinic; Triazines; Valproic Acid; Young Adult

Accumulating evidence indicates that cannabinoid CB1 receptor ligands play a pivotal role in seizures, not only in preclinical studies on animals, but also in clinical settings. This study was aimed at characterizing the influence of arachidonyl-2'-chloroethylamide (ACEA-a selective cannabinoid CB1 receptor agonist) co-administered with phenylmethylsulfonyl fluoride (PMSF) on the anticonvulsant potency of various antiepileptic drugs (clobazam, lacosamide, levetiracetam, phenobarbital, tiagabine and valproate) in the 6-Hz corneal stimulation model. Psychomotor seizures in male albino Swiss mice were evoked by a current (32 mA, 6 Hz, 3 s stimulus duration) delivered via corneal electrodes. Potential adverse effects produced by the antiepileptic drugs in combination with ACEA+PMSF were assessed using the chimney test (motor performance), passive avoidance task (remembering and acquisition of learning), and grip-strength test (muscular strength). Brain concentrations of antiepileptic drugs were measured by HPLC to exclude any pharmacokinetic contribution to the observed effect. ACEA (5 mg/kg, i.p.) + PMSF (30 mg/kg, i.p.) significantly potentiated the anticonvulsant potency of levetiracetam (P<0.05), but not that of clobazam, lacosamide, phenobarbital, tiagabine or valproate in the 6-Hz corneal stimulation model. Moreover, ACEA+PMSF did not significantly affect total brain concentrations of levetiracetam in mice. No behavioral side effects were observed in animals receiving combinations of the studied antiepileptic drugs with ACEA+PMSF. In conclusion, the combined administration of ACEA+PMSF with levetiracetam is associated with beneficial anticonvulsant pharmacodynamic interaction in the 6-Hz corneal stimulation model. The selective activation of cannabinoid CB1 receptor-mediated neurotransmission in the brain may enhance levetiracetam-related suppression of seizures in epilepsy patients, contributing to the efficacious treatment of epilepsy in future.

Topics: Acetamides; Animals; Anticonvulsants; Arachidonic Acids; Avoidance Learning; Benzodiazepines; Clobazam; Cornea; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Electroshock; Epilepsy, Complex Partial; Lacosamide; Levetiracetam; Male; Mice; Muscle Strength; Nipecotic Acids; Phenobarbital; Phenylmethylsulfonyl Fluoride; Piracetam; Psychomotor Performance; Receptor, Cannabinoid, CB1; Tiagabine; Valproic Acid

Perinatal arterial stroke is the most frequent form of cerebral infarction in children. Neonatal seizures are the most frequent symptom during the neonatal period. The current management of perinatal stroke is based on supportive care. It is currently unknown if treatment of the seizures modifies the outcome, and no clinical studies have focused on seizures during neonatal stroke. We studied the effect of phenobarbital and levetiracetam on an ischemic-reperfusion stroke model in P7 rats using prolonged electroencephalographic recordings and a histologic analysis of the brain (24h after injury). The following two types of epileptic events were observed: 1) bursts of high amplitude spikes during ischemia and the first hours of reperfusion and 2) organized seizures consisting in discharges of a 1-2Hz spike-and-wave. Both phenobarbital and levetiracetam decreased the total duration of the bursts of high amplitude spikes. Phenobarbital also delayed the start of seizures without changing the total duration of epileptic discharges. The markedly limited efficacy of the antiepileptic drugs studied in our neonatal stroke rat model is frequently observed in human neonatal seizures. Both drugs did not modify the stroke volume, which suggests that the modification of the quantity of bursts of high amplitude spikes does not influence the infarct size. In the absence of a reduction in seizure burden by the antiepileptic drugs, we increased the seizure burden and stroke volume by combining our neonatal stroke model with a lithium-pilocarpine-induced status epilepticus. Our data suggest that the reduction of burst of spikes did not influence the stroke volume. The presence of organized seizure with a pattern close to what is observed in human newborns seems related to the presence of the infarct. Further research is required to determine the relationship between seizure burden and infarct volume.

Topics: Animals; Animals, Newborn; Anticonvulsants; Brain; Brain Ischemia; Disease Models, Animal; Epilepsy; Female; Levetiracetam; Lithium Compounds; Male; Phenobarbital; Pilocarpine; Piracetam; Random Allocation; Rats, Wistar; Reperfusion Injury; Stroke

Epilepsy is one of the major neurological disorders frequently associated with psychiatric disorders such as depression. The predisposition of tryptophan metabolism towards kynurenine pathway has been reported as one of the plausible reasons for association of depression in epilepsy. Hence, this study was envisaged to evaluate the dose dependent inhibition of indoleamine 2,3-dioxygenase (IDO) enzyme employing quercetin (screened employing in vitro method) with levetiracetam for combined management of epilepsy and comorbid depression. Kindling was induced in male swiss albino mice by administration of pentylenetetrazole subconvulsive doses (35 mg/kg, i.p.) at an interval of 48 ± 2 h. Kindled animals were treated with vehicle, levetiracetam (40 mg/kg/day i.p.) levetiracetam in combination with different doses of quercetin (10 mg/kg; 20 mg/kg; 40 mg/kg)/day/p.o. for 15 days. Except naïve, all the groups were challenged with pentylenetetrazole (35 mg/kg i.p.) on day 5, 10, and 15 to evaluate the seizure severity score. Depression was evaluated in all experimental groups using the tail suspension and sucrose preference test on days 1, 5, 10 and 15, 2 h after pentylenetetrazole challenge. Results suggested that vehicle treated kindled animals were significantly associated with depression. Chronic levetiracetam treatment significantly reduced seizure severity score, but further worsened the associated depression. Quercetin supplementation with levetiracetam dose dependently ameliorated depression associated with epilepsy. Neurochemical and biochemical findings also supported the behavioural findings of the study. Thus, our results suggested that supplementation of quercetin with levetiracetam could be explored further for combined treatment of epilepsy and comorbid depression.

Topics: Animals; Anticonvulsants; Behavior, Animal; Brain; Combined Modality Therapy; Convulsants; Depression; Depressive Disorder; Disease Models, Animal; Epilepsy; Levetiracetam; Male; Mice; Pentylenetetrazole; Piracetam; Quercetin

Elevated excitability in the hippocampus has emerged as a key contributor to reduced memory function in aging and in cognitive impairment prodromal to Alzheimer's disease. Here, we investigated the relationship between neural activity and memory in the hippocampus and a connectional cortical network using an aged rat model of individual differences for memory impairment. The expression of cFos was used as a measure of pharmacologically induced neural activity. Aged memory-impaired rats exhibited elevated cFos relative to young adult and aged unimpaired rats in the CA3 subfield of the hippocampus and in several cortical regions including the retrosplenial, parietal, and orbitofrontal cortices. Strong correlations between cFos intensity and task performance across the activated network showed a tight coupling between excitability and cognitive phenotype in aging. Elevated neural excitability extending beyond the hippocampus to interconnected posterior cortex (retrosplenial/parietal) was reduced by treatment with levetiracetam, a therapeutic with behavioral efficacy that has previously translated from rodent models of age-related impairment and Alzheimer's disease to humans with amnestic mild cognitive impairment.

Topics: Animals; CA3 Region, Hippocampal; Cerebral Cortex; Cognition; Disease Models, Animal; Levetiracetam; Male; Memory; Memory Disorders; Piracetam; Proto-Oncogene Proteins c-fos; Rats, Long-Evans

The purpose of this study was to synthetize the focused library of 34 new piperazinamides of 3-methyl- and 3,3-dimethyl-(2,5-dioxopyrrolidin-1-yl)propanoic or butanoic acids as potential new hybrid anticonvulsants. These hybrid molecules join the chemical fragments of well-known antiepileptic drugs (AEDs) such as ethosuximide, levetiracetam, and lacosamide. Compounds 5-38 were prepared in a coupling reaction of the 3-methyl- or 3,3-dimethyl-2-(2,5-dioxopyrrolidin-1-yl)propanoic (1, 2) or butanoic acids (3, 4) with the appropriately substituted secondary amines in the presence of the N,N-carbonyldiimidazole reagent. The initial anticonvulsant screening was performed in mice (ip) using the 'classical' maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) tests as well as in the six-Hertz (6Hz) model of pharmacoresistant limbic seizures. The acute neurological toxicity was determined applying the chimney test. The broad spectra of activity across the preclinical seizure models in mice ip displayed compounds 7, 15, and 36. The most favorable anticonvulsant properties demonstrated 15 (ED50 MES=74.8mg/kg, ED50scPTZ=51.6mg/kg, ED50 6Hz=16.8mg/kg) which showed TD50=213.3mg/kg in the chimney test that yielded satisfying protective indexes (PI MES=2.85, PI scPTZ=4.13, PI 6Hz=12.70) at time point of 0.5h. As a result, compound 15 displayed comparable or better safety profile than clinically relevant AEDs: ethosuximide, lacosamide or valproic acid. In the in vitro assays compound 15 was observed as relatively effective binder to the neuronal voltage-sensitive sodium and L-type calcium channels. Beyond the anticonvulsant properties, 6 compounds diminished the pain responses in the formalin model of tonic pain in mice.

Topics: Analgesics; Animals; Anticonvulsants; Disease Models, Animal; Dose-Response Relationship, Drug; Electroshock; Injections, Intraperitoneal; Mice; Molecular Structure; Pain; Pain Measurement; Pentylenetetrazole; Piperazines; Pyrrolidinones; Seizures

This paper describes the synthesis of the library of 22 new 3-methyl- and 3-ethyl-3-methyl-2,5-dioxo-pyrrolidin-1-yl-acetamides as potential anticonvulsant agents. The maximal electroshock (MES) and the subcutaneous pentylenetetrazole (scPTZ) seizure models were used for screening all the compounds. The 6 Hz model of pharmacoresistant limbic seizures was applied for studying selected derivatives. Six amides were chosen for pharmacological characterization of their antinociceptive activity in the formalin model of tonic pain as well as local anesthetic activity was assessed in mice. The pharmacological data indicate on the broad spectra of activity across the preclinical seizure models. Compounds 10 (ED50=32.08 mg/kg, MES test) and 9 (ED50=40.34 mg/kg, scPTZ test) demonstrated the highest potency. These compounds displayed considerably better safety profiles than clinically relevant antiepileptic drugs phenytoin, ethosuximide, or valproic acid. Several molecules showed antinociceptive and local anesthetic properties. The in vitro radioligand binding studies demonstrated that the influence on the sodium and calcium channels may be one of the essential mechanisms of action.

Topics: Amides; Animals; Anticonvulsants; Disease Models, Animal; Dose-Response Relationship, Drug; Electroshock; Injections, Intraperitoneal; Injections, Subcutaneous; Male; Mice; Molecular Structure; Pentylenetetrazole; Pyrrolidines; Seizures

Levetiracetam (LEV) is an antiepileptic agent targeting novel pathways. Coupled with a favorable safety profile and increasing empirical clinical use, it was the fifth drug tested by Operation Brain Trauma Therapy (OBTT). We assessed the efficacy of a single 15 min post-injury intravenous (IV) dose (54 or 170 mg/kg) on behavioral, histopathological, and biomarker outcomes after parasagittal fluid percussion brain injury (FPI), controlled cortical impact (CCI), and penetrating ballistic-like brain injury (PBBI) in rats. In FPI, there was no benefit on motor function, but on Morris water maze (MWM), both doses improved latencies and path lengths versus vehicle (p < 0.05). On probe trial, the vehicle group was impaired versus sham, but both LEV treated groups did not differ versus sham, and the 54 mg/kg group was improved versus vehicle (p < 0.05). No histological benefit was seen. In CCI, there was a benefit on beam balance at 170 mg/kg (p < 0.05 vs. vehicle). On MWM, the 54 mg/kg dose was improved and not different from sham. Probe trial did not differ between groups for either dose. There was a reduction in hemispheric tissue loss (p < 0.05 vs. vehicle) with 170 mg/kg. In PBBI, there was no motor, cognitive, or histological benefit from either dose. Regarding biomarkers, in CCI, 24 h glial fibrillary acidic protein (GFAP) blood levels were lower in the 170 mg/kg group versus vehicle (p < 0.05). In PBBI, GFAP blood levels were increased in vehicle and 170 mg/kg groups versus sham (p < 0.05) but not in the 54 mg/kg group. No treatment effects were seen for ubiquitin C-terminal hydrolase-L1 across models. Early single IV LEV produced multiple benefits in CCI and FPI and reduced GFAP levels in PBBI. LEV achieved 10 points at each dose, is the most promising drug tested thus far by OBTT, and the only drug to improve cognitive outcome in any model. LEV has been advanced to testing in the micropig model in OBTT.

Topics: Animals; Biomarkers; Brain Injuries, Traumatic; Disease Models, Animal; Glial Fibrillary Acidic Protein; Levetiracetam; Male; Nootropic Agents; Piracetam; Rats; Rats, Sprague-Dawley; Recovery of Function; Ubiquitin Thiolesterase

Diabetic neuropathy (DNP) is a frequent and serious complication of diabetes mellitus (DM) that leads to progressive and length-dependent loss of peripheral nerve axons. The purpose of the present study is to assess the neuroprotective effects of levetiracetam (LEV) on DNP in a streptozotocin (STZ)-induced DM model in rats.. Adult Sprague-Dawley rats were administered with STZ (60mg/kg) to induce diabetes. DNP was confirmed by electromyography (EMG) and motor function test on 21st day following STZ injection. Study groups were assigned as follows; Group 1: Naïve control (n=8), Group 2: DM+1mL/kg saline (n=12), Group 3: DM+300mg/kg LEV (n=10), Group 4: DM+600mg/kg LEV (n=10). LEV was administered i.p. for 30 consecutive days. Then, EMG, motor function test, biochemical analysis (plasma lipid peroxides and total anti-oxidant capacity), histological and immunohistochemical analysis of sciatic nerves (TUNEL assay, bax, caspase 3, caspase 8 and NGF) were performed to evaluate the efficacy of LEV.. Treatment of diabetic rats with LEV significantly attenuated the inflammation and fibrosis in sciatic nerves and prevented electrophysiological alterations. Immunohistochemistry of sciatic nerves showed a considerable increase in bax, caspase 3 and caspase 8 and a decrease in NGF expression in saline-treated rats whereas LEV significantly suppressed apoptosis markers and prevented the reduction in NGF expression. Besides, LEV considerably reduced plasma lipid peroxides and increased total anti-oxidant capacity in diabetic rats.. The results of the present study suggest that LEV may have therapeutic effects in DNP through modulation of anti-oxidant and anti-apoptotic pathways.

Topics: Animals; Apoptosis; Caspase 3; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Disease Models, Animal; Electromyography; Electrophysiology; Immunoenzyme Techniques; Levetiracetam; Lipid Peroxides; Male; Neuroprotective Agents; Nootropic Agents; Oxidative Stress; Piracetam; Rats; Rats, Sprague-Dawley

We assessed the therapeutic efficacy of FDA-approved anti-epileptic drug Levetiracetam (LEV) to reduce post-traumatic nonconvulsive seizure (NCS) activity and promote neurobehavioral recovery following 10% frontal penetrating ballistic-like brain injury (PBBI) in male Sprague-Dawley rats.. Experiment 1 anti-seizure study: 50 mg/kg LEV (25 mg/kg maintenance doses) was given twice daily for 3 days (LEV3D) following PBBI; outcome measures included seizures incidence, frequency, duration, and onset. Experiment 2 neuroprotection studies: 50 mg/kg LEV was given twice daily for either 3 (LEV3D) or 10 days (LEV10D) post-injury; outcome measures include motor (rotarod) and cognitive (water maze) functions.. LEV3D treatment attenuated seizure activity with significant reductions in NCS incidence (54%), frequency, duration, and delayed latency to seizure onset compared to vehicle treatment. LEV3D treatment failed to improve cognitive or motor performance; however extending the dosing regimen through 10 days post-injury afforded significant neuroprotective benefit. Animals treated with the extended LEV10D dosing regimen showed a twofold improvement in rotarod task latency to fall as well as significantly improved spatial learning performance (24%) in the MWM task.. These findings support the dual anti- seizure and neuroprotective role of LEV, but more importantly identify the importance of an extended dosing protocol which was specific to the therapeutic targets studied.

Topics: Analysis of Variance; Animals; Disease Models, Animal; Electroencephalography; Gait Disorders, Neurologic; Gene Expression Regulation; Head Injuries, Penetrating; Levetiracetam; Male; Maze Learning; Motor Activity; Neuroprotective Agents; Piracetam; Rats; Rats, Sprague-Dawley; Reaction Time; Seizures; Statistics, Nonparametric; Time Factors; Trauma Severity Indices; Treatment Outcome

Resistance to antiepileptic drugs (AEDs) is a major problem in epilepsy therapy, so that development of more effective AEDs is an unmet clinical need. Several rat and mouse models of epilepsy with spontaneous difficult-to-treat seizures exist, but because testing of antiseizure drug efficacy is extremely laborious in such models, they are only rarely used in the development of novel AEDs. Recently, the use of acute seizure tests in epileptic rats or mice has been proposed as a novel strategy for evaluating novel AEDs for increased antiseizure efficacy. In the present study, we compared the effects of five AEDs (valproate, phenobarbital, diazepam, lamotrigine, levetiracetam) on the pentylenetetrazole (PTZ) seizure threshold in mice that were made epileptic by pilocarpine. Experiments were started 6 weeks after a pilocarpine-induced status epilepticus. At this time, control seizure threshold was significantly lower in epileptic than in nonepileptic animals. Unexpectedly, only one AED (valproate) was less effective to increase seizure threshold in epileptic vs. nonepileptic mice, and this difference was restricted to doses of 200 and 300 mg/kg, whereas the difference disappeared at 400mg/kg. All other AEDs exerted similar seizure threshold increases in epileptic and nonepileptic mice. Thus, induction of acute seizures with PTZ in mice pretreated with pilocarpine does not provide an effective and valuable surrogate method to screen drugs for antiseizure efficacy in a model of difficult-to-treat chronic epilepsy as previously suggested from experiments with this approach in rats.

Topics: Animals; Anticonvulsants; Diazepam; Disease Models, Animal; Drug Resistance; Epilepsy; GABA Antagonists; Levetiracetam; Male; Mice; Pentylenetetrazole; Phenobarbital; Pilocarpine; Piracetam; Rats; Seizures; Status Epilepticus; Valproic Acid

To determine whether post-traumatic seizure severity would be affected by the interval between seizures and head injury, we measured seizures after various times with or without fluid percussion brain injury (2atm fluid percussion injury; FPI). To determine efficacy of anti-seizure medication, we also determined if levetiracetam (LEV) would alter the relationship between injury and subsequent seizures. Early post-traumatic seizures were induced by Kainic acid (KA) at one week after 2atm fluid percussion injury (FPI) in one group (FPI-ES). Seizures were induced at two weeks after FPI by KA in another group (FPI-LS). In addition, one group had induced seizures by KA without FPI, (sham-ES). Finally one group of animals received the antiepileptic agent (levetiracetam) infusion for one week after FPI and then had seizures induced by KA (FPI-LEV-ES). We measured seizure onset time, ictal duration and severity of seizures using a modified Racine's scale. Histopathological changes in the hippocampus CA1 region were also analyzed. Severity of seizures were increased in the FPI-ES group compared with sham-ES animals. Severity was also enhanced in early post-injury seizures induced by KA (FPI-ES vs. FPI-LS); this exacerbation of seizure severity could be ameliorated by levetiracetam infusion (FPI-ES vs. FPI-LEV-ES). Neuronal degeneration in CA1 was more severe in the FPI-ES group and this degeneration was also diminished by LEV. We conclude that early post injury seizures exacerbate susceptibility and severity of post traumatic seizures and increase neuronal degeneration in the CA1 layer of hippocampus. These changes are partially reversed by LEV infusion after FPI.

Topics: Animals; Anticonvulsants; Brain Injuries, Traumatic; CA1 Region, Hippocampal; Disease Models, Animal; Drug Evaluation, Preclinical; Epilepsy, Post-Traumatic; Kainic Acid; Levetiracetam; Male; Neurons; Neuroprotective Agents; Piracetam; Rats, Sprague-Dawley; Seizures; Severity of Illness Index; Time Factors

Temporal lobe epilepsy (TLE), the common form of epilepsy in adults, often displays complex partial seizures and cognitive deficits. The underlying mechanisms of such deficits are not yet well understood. Many contributing factors, such as initial epileptogenic lesion, seizure type, age of onset, and treatment side effects have been proposed. Levetiracetam (LEV) is a novel anti-epileptic drug (AED) used to treat partial seizures and idiopathic generalized epilepsy. It has been suggested that LEV exerts antiepileptic properties by modulation of synaptic release of neurotransmitters. However, its neuroprotective effects on learning and memory are not yet well demonstrated. Here we showed the impairment of spatial memory in the pilocarpine-induced experimental TLE rats, which can be improved by LEV. Furthermore, we found chronic LEV treatment partially reversed the SE-induced synaptic dysfunction in hippocampal LTP induction in vivo. In addition, LEV treatment can alleviate the SE-induced abnormal GluR1 phosphorylation at Ser(831) site, which may contribute to the rescue of synaptic transmission. These results indicate the neuroprotective role for LEV while it exhibits an antiseizure effect on experimental epileptic models.

Topics: Animals; Anticonvulsants; Disease Models, Animal; Epilepsy, Temporal Lobe; Hippocampus; Levetiracetam; Long-Term Potentiation; Male; Maze Learning; Muscarinic Agonists; Neuroprotective Agents; Pilocarpine; Piracetam; Rats; Rats, Sprague-Dawley; Spatial Memory

Our previous study showed that treatment with levetiracetam (LEV) after status epilepticus (SE) termination by diazepam might prevent the development of spontaneous recurrent seizures via the inhibition of neurotoxicity induced by brain edema events. In the present study, we determined the possible molecular and cellular mechanisms of LEV treatment after termination of SE. To assess the effect of LEV against the brain alterations after SE, we focused on blood-brain barrier (BBB) dysfunction associated with angiogenesis and brain inflammation. The consecutive treatment of LEV inhibited the temporarily increased BBB leakage in the hippocampus two days after SE. At the same time point, the LEV treatment significantly inhibited the increase in the number of CD31-positive endothelial immature cells and in the expression of angiogenic factors. These findings suggested that the increase in neovascularization led to an increase in BBB permeability by SE-induced BBB failure, and these brain alterations were prevented by LEV treatment. Furthermore, in the acute phase of the latent period, pro-inflammatory responses for epileptogenic targets in microglia and astrocytes of the hippocampus activated, and these upregulations of pro-inflammatory-related molecules were inhibited by LEV treatment. These findings suggest that LEV is likely involved in neuroprotection via anti-angiogenesis and anti-inflammatory activities against BBB dysfunction in the acute phase of epileptogenesis after SE.

Topics: Acute Disease; Animals; Anticonvulsants; Astrocytes; Blood-Brain Barrier; Brain Edema; Capillary Permeability; Cytokines; Disease Models, Animal; Endothelial Cells; Gliosis; Hippocampus; Levetiracetam; Male; Mice, Inbred ICR; Microglia; Neovascularization, Pathologic; Piracetam; Status Epilepticus

The aim of this study was to determine if levetiracetam (LEV) is neuroprotective in neonatal rats with hypoxic-ischemic brain injury (HIBI).. The study included 7-d-old male Wistar rats that were randomly divided into the LEV400, LEV800, control, and sham groups. All the rats, except those in the sham group, underwent ligation of the carotid artery and were then kept in a hypoxic chamber containing 8% oxygen for 2 h. At the end of the hypoxic period the rats in the control group were administered saline solution 0.5 mL, the rats in the LEV400 group were administered LEV 400 mg.kg-1, and rats in the LEV800 group were administered LEV 800 mg.kg-1 via the intraperitoneal route. The terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) method was used to evaluate neuronal apoptosis in the rats. The Morris Water Maze (MWM) test was performed at age 14 weeks in order to evaluate cognitive function.. The number of apoptotic neurons in the right hemispheres was significantly lower in the sham, LEV400, and LEV800 groups than in the control group (p < 0.001, p < 0.001, and p < 0.001, respectively). In addition, the number of apoptotic neurons in the right hemispheres was significantly lower in the LEV800 group than in the LEV400 group (p = 0.001). Platform finding time (PFT) during MWM testing was significantly shorter in the sham and LEV800 groups on d 4 than on d 1 (p = 0.001 and p = 0.006, respectively); however, PFT did not significantly change between d 1 and d 4 in the control or LEV400 groups (p = 0.91 and p = 0.096, respectively).. Based on the present findings, LEV exhibited a dose-dependent neuroprotective effect in neonatal rats with HIBI (Ref. 27).

Topics: Animals; Animals, Newborn; Apoptosis; Brain; Brain Injuries; Disease Models, Animal; Dose-Response Relationship, Drug; Hypoxia-Ischemia, Brain; In Situ Nick-End Labeling; Injections, Intraperitoneal; Levetiracetam; Male; Neuroprotective Agents; Piracetam; Rats; Rats, Sprague-Dawley; Rats, Wistar

The library of 27 new 1-(4-phenylpiperazin-1-yl)- or 1-(morpholin-4-yl)-(2,5-dioxopyrrolidin-1-yl)propanamides and (2,5-dioxopyrrolidin-1-yl)butanamides as potential new hybrid anticonvulsant agents was synthesized. These hybrid molecules join the chemical fragments of well-known antiepileptic drugs (AEDs) such as ethosuximide, levetiracetam, and lacosamide. Compounds 5, 10, 11, and 24 displayed the broad spectra of activity across the preclinical seizure models, namely, the maximal electroshock (MES) test, the subcutaneous pentylenetetrazole (scPTZ) test, and the six-hertz (6 Hz) model of pharmacoresistant limbic seizures. The highest protection was demonstrated by 11 (ED50 MES = 88.4 mg/kg, ED50 scPTZ = 59.9 mg/kg, ED50 6 Hz = 21.0 mg/kg). This molecule did not impair the motor coordination of animals in the chimney test even at high doses (TD50 > 1500 mg/kg), yielding superb protective indexes (PI MES > 16.97, PI PTZ > 25.04, PI 6 Hz > 71.43). As a result, 11 displayed distinctly better safety profile than clinically relevant AEDs ethosuximide, lacosamide, or valproic acid.

Topics: Animals; Anticonvulsants; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Design; Electroshock; HEK293 Cells; Humans; Mice; Models, Molecular; Molecular Structure; Motor Activity; Piperazines; Seizures; Structure-Activity Relationship; Succinimides

Long-term prophylactic treatment with levetiracetam (LEV) has multiple neuroprotective effects in a traumatic brain injury (TBI) rat model. Although a rational time-frame of seizure prophylactic treatment with LEV for after TBI is not well established, clinical prophylaxis with LEV often includes treatment duration similar to clinical treatment guidelines with Phenytoin. Thus, this study investigated the effects of abbreviated LEV treatment on behavioural function and histological evidence of neuroprotection.. Pre-clinical trial of abbreviated LEV dosing in an experimental model of TBI Methods: After either controlled cortical impact (CCI) injury or sham surgery, rats received three 50 mg kg(-1) doses over 24 hours or vehicle. After injury/sham surgery, beam performance, spatial learning, contusion volume size and hippocampal neuron survival were assessed.. Abbreviated LEV did not improve motor or cognitive performance after TBI. Further, abbreviated LEV did not improve hippocampal neuron sparing or contusion volumes compared with vehicle controls.. Together with previous work assessing daily LEV treatment, these results suggest that longer-term therapy may be required to confer beneficial effects within these domains. These findings may guide (1) future experimental studies assessing minimal effective dosing for neuroprotection and anti-epileptogenesis and (2) treatment guideline updates for seizure prophylaxis post-TBI.

Topics: Animals; Brain Injuries; Contusions; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Hippocampus; Levetiracetam; Male; Neurons; Neuroprotective Agents; Phenytoin; Piracetam; Random Allocation; Rats; Rats, Sprague-Dawley; Seizures; Spatial Learning; Treatment Outcome

Despite more than 20 clinically approved antiepileptic drugs (AEDs), there remains a substantial unmet clinical need for patients with refractory (AED-resistant) epilepsy. Animal models of refractory epilepsy are needed for at least two goals; (1) better understanding of the mechanisms underlying resistance to AEDs, and (2) development of more efficacious AEDs for patients with refractory seizures. It is only incompletely understood why two patients with seemingly identical types of epilepsy and seizures may respond differently to the same AED. Prompted by this well-known clinical phenomenon, we previously evaluated whether epileptic rats respond differently to AEDs and discovered AED responsive and resistant animals in the same models. In the present study, we used the same approach for the widely used intrahippocampal kainate mouse model of mesial temporal lobe epilepsy. In a first step, we examined anti-seizure effects of 6 AEDs on spontaneous recurrent focal electrographic seizures and secondarily generalized convulsive seizures in epileptic mice, showing that the focal nonconvulsive seizures were resistant to carbamazepine and phenytoin, whereas valproate and levetiracetam exerted moderate and phenobarbital and diazepam marked anti-seizure effects. All AEDs seemed to suppress generalized convulsive seizures. Next we investigated the inter-individual variation in the anti-seizure effects of these AEDs and, in case of focal seizures, found responders and nonresponders to all AEDs except carbamazepine. Most nonresponders were resistant to more than one AED. Our data further validate the intrahippocampal kainate mouse model as a model of difficult-to-treat focal seizures that can be used to investigate the determinants of AED efficacy.

Topics: Animals; Anticonvulsants; Carbamazepine; Diazepam; Disease Models, Animal; Drug Resistance; Electrodes, Implanted; Electroencephalography; Epilepsy, Temporal Lobe; Female; Hippocampus; Kainic Acid; Levetiracetam; Mice; Phenobarbital; Phenytoin; Piracetam; Seizures; Valproic Acid

The 6 Hz model of focal seizures has been increasingly used to identify anticonvulsant compounds with potential activity against therapy-resistant epilepsy, but the protective response to anticonvulsants in this model could be dependent on experimental conditions and selection of mouse strains.. Seizure thresholds in the 6 Hz model were compared in CF-1, NMRI, and C57Bl/6J male mice with two different electrical stimulators (Ugo Basile 5780 and Grass S48). Dose-response curves for phenytoin and levetiracetam were generated in the three strains at 32 and 44 mA current intensities using both devices. Plasma and brain exposure to the two drugs were measured in all three strains.. CF-1 mice had the lowest seizure threshold and responded to phenytoin at 32 mA stimulation intensity, but not at 44 mA. NMRI and C57Bl/6J mice had nearly identical threshold values, but NMRI mice responded well to phenytoin at 32 mA and showed limited responsiveness to this drug at 44 mA, whereas C57Bl/6J mice were nearly completely resistant to phenytoin. Furthermore, levetiracetam showed limited efficacy and low potency in CF-1 and C57Bl/6J mice, particularly at 44 mA, whereas in NMRI mice the drug showed much higher potency in all experimental conditions. No obvious difference in the pharmacokinetics of both phenytoin and levetiracetam was detected between the mouse strains that would have explained these unexpected variations in potency. We have also found that the protective effects of both drugs may be influenced by the device type.. Collectively these observations clearly indicate that treatment resistance of 6 Hz seizures should be interpreted with strain and experimental conditions in mind. Furthermore, it is important to note that strain differences, much like human genetic differences, may explain why some mice and patients respond to a given treatment and others do not.

Topics: Animals; Anticonvulsants; Disease Models, Animal; Electroshock; Levetiracetam; Male; Mice; Phenytoin; Piracetam; Psychomotor Performance; Seizures; Treatment Outcome

To investigate the antiepileptic and protective effects of intravenous levetiracetam (iv LEV) in the rhesus monkey model of acute status epilepticus (SE).. Thirty minutes before intraperitoneal induction of SE by Coriaria lactone (CL), rhesus monkeys were treated with LEV (15 or 150 mg/kg) delivered intravenously as a single bolus. CL dose and epileptic behavior were recorded. Electroencephalography (EEG) was performed before and during the experiment. All rhesus monkeys were killed after 1-month video monitoring and processed for pathological investigation of neuronal injury, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining, and glial fibrillary acidic protein (GFAP) staining.. No animal exhibited spontaneous seizures during 1-month video monitoring. Development of acute SE was significantly inhibited in the group given 150 mg/kg LEV, compared with controls and the 15 mg/kg LEV group. Delayed latency, reduction of SE duration, decreased cumulative time of tonic convulsions, slight severity of SE, and a high CL induction dose were observed in the high LEV dose group (p<0.05). The EEG showed less frequent epileptic discharges in the group administered with 150 mg/kg LEV. Hematoxylin and eosin (H&E) staining, ultrastructural examination, TUNEL and GFAP staining revealed serious damage, including neuron loss, swollen mitochondrion, and strong positivity for TUNEL in the hippocampus and thalamus of controls, whereas moderate damage in the group administered with 15 mg/kg LEV, and very mild damage in the 150 mg/kg LEV group. Gliosis was found in the hippocampus of controls, not in the LEV groups and normal rhesus monkey.. The study supports the antiepileptic and protective effect of pretreatment with intravenous LEV in rhesus monkey model with SE.

Topics: Administration, Intravenous; Animals; Anticonvulsants; Disease Models, Animal; Humans; Lactones; Levetiracetam; Macaca mulatta; Male; Neurons; Piracetam; Status Epilepticus

Mesial temporal lobe epilepsy (MTLE) is the most prevalent type of partial epileptic disorders. In this study, we have analyzed the impact of levetiracetam (LEV) in the pilocarpine model of MTLE.. Sprague-Dawley rats (n=19) were injected with pilocarpine (380 mg/kg, i.p.) to induce a status epilepticus. Twelve animals were used as controls and seven were treated with LEV. They were implanted with bipolar electrodes in the CA3 subfield of the hippocampus, entorhinal cortex (EC), dentate gyrus (DG) and subiculum and EEG-video monitored continuously from day 4 to day 14 after SE.. Only 29% of LEV-treated animals had seizures compared to all controls following a latent period that was similar in duration. Seizure rates were lower in LEV-treated animals. In LEV-treated animals without seizures, lower interictal spike rates were found in all regions compared to controls. Analysis of interictal high-frequency oscillations (HFO s) revealed that LEV-treated animals without seizures had lower rates of interictal spikes with ripples (80-200 Hz) in CA3, EC and subiculum (p<0.01), whereas rates of interictal spikes with fast ripples (250-500 Hz) were significantly lower in CA3 and subiculum, compared to controls.. Our findings indicate that the anti-ictogenic properties of LEV are mirrored by decreases of interictal spike rate in temporal lobe regions, and are accompanied by subregion-specific decreases of HFO occurrence in CA3 and subiculum. Overall, this evidence suggest that LEV may inhibit neural network activity in regions that are known to play important roles in MTLE.

Topics: Animals; Anticonvulsants; Disease Models, Animal; Electrodes, Implanted; Electroencephalography; Epilepsy, Temporal Lobe; Hippocampus; Levetiracetam; Male; Periodicity; Pilocarpine; Piracetam; Rats, Sprague-Dawley; Seizures; Treatment Outcome; Video Recording

Levetiracetam is an antiepileptic drug with analgesic efficacy shown in pain models and small clinical trials. Sumatriptan is used in acute migraine treatment. Caffeine is widely consumed in some beverages/foods and is also an adjuvant in analgesic formulations. We examined the effects of systemic levetiracetam, sumatriptan, and caffeine and their interactions in 2-component combinations in the rat orofacial formalin test, a model of trigeminal pain.. Rats received a subcutaneous injection of formalin solution into the perinasal area, and the total time spent in nociceptive behavior (face rubbing) was quantified. The antinociceptive effect of drugs/drug combinations was assessed 1 hour after per os administration. The type of interaction between levetiracetam/sumatriptan and caffeine was examined by comparing the effects of a fixed, effective dose of levetiracetam/sumatriptan alone with the effects of the same dose applied with increasing, subeffective doses of caffeine. The type of interaction between levetiracetam and sumatriptan was determined by isobolographic analysis.. Levetiracetam (1-50 mg/kg) and sumatriptan (0.5-5 mg/kg) produced significant and dose-dependent antinociceptive effects in both phases of the orofacial formalin test (P ≤ 0.001). Caffeine (7.5-100 mg/kg) produced significant antinociception in the second phase of the test (P = 0.04). Caffeine (1-7.5 mg/kg) significantly reduced the antinociceptive effects of levetiracetam (25 mg/kg) (first phase P = 0.002, second phase P < 0.001) and sumatriptan (2.5 mg/kg) (first phase P = 0.014, second phase P = 0.027); dose-dependent inhibition was observed in the second phase. Levetiracetam and sumatriptan exerted an additive interaction in the second phase of the orofacial formalin test.. Results indicate that levetiracetam may be useful for treatment of pain in the trigeminal region. Dietary caffeine might decrease the effects of levetiracetam and sumatriptan; this needs to be considered in clinical settings. A levetiracetam-sumatriptan combination could also be useful in trigeminal pain treatment. Its efficacy and adverse effects should be examined clinically.

Topics: Analgesics; Animals; Behavior, Animal; Caffeine; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Facial Neuralgia; Facial Pain; Formaldehyde; Levetiracetam; Male; Motor Activity; Nociception; Piracetam; Rats, Wistar; Sumatriptan; Time Factors; Trigeminal Nerve Diseases

Emerging data suggest an important relationship between sleep and Alzheimer's disease (AD), but how poor sleep promotes the development of AD remains unclear.. Here, using a Drosophila model of AD, we provide evidence suggesting that changes in neuronal excitability underlie the effects of sleep loss on AD pathogenesis. β-amyloid (Aβ) accumulation leads to reduced and fragmented sleep, while chronic sleep deprivation increases Aβ burden. Moreover, enhancing sleep reduces Aβ deposition. Increasing neuronal excitability phenocopies the effects of reducing sleep on Aβ, and decreasing neuronal activity blocks the elevated Aβ accumulation induced by sleep deprivation. At the single neuron level, we find that chronic sleep deprivation, as well as Aβ expression, enhances intrinsic neuronal excitability. Importantly, these data reveal that sleep loss exacerbates Aβ-induced hyperexcitability and suggest that defects in specific K(+) currents underlie the hyperexcitability caused by sleep loss and Aβ expression. Finally, we show that feeding levetiracetam, an anti-epileptic medication, to Aβ-expressing flies suppresses neuronal excitability and significantly prolongs their lifespan.. Our findings directly link sleep loss to changes in neuronal excitability and Aβ accumulation and further suggest that neuronal hyperexcitability is an important mediator of Aβ toxicity. Taken together, these data provide a mechanistic framework for a positive feedback loop, whereby sleep loss and neuronal excitation accelerate the accumulation of Aβ, a key pathogenic step in the development of AD.

Topics: Action Potentials; Alzheimer Disease; Amyloid beta-Peptides; Animals; Animals, Genetically Modified; Anticonvulsants; Disease Models, Animal; Drosophila melanogaster; Humans; Levetiracetam; Neurons; Peptide Fragments; Piracetam; Sleep; Sleep Deprivation

The management of status epilepticus (SE) is important to prevent mortality and the development of post-SE symptomatic epilepsy. Acquired epilepsy after an initial brain insult by SE can be experimentally reproduced in the murine model of SE induced by pilocarpine. In the present study, we evaluated the possibility of treatment with a high-dose of levetiracetam in this model. Repeated treatment with high-dose levetiracetam after termination of SE by diazepam significantly prevented the incidence of spontaneous recurrent seizures and mortality for at least 28 days. To determine the brain alterations after SE, magnetic resonance imaging was performed. Both T2-weighted imaging and diffusion-weighted imaging showed changes in the limbic regions. These changes in the limbic regions demonstrated the development of cytotoxic edema three hours after SE, followed by the development of vasogenic edema two days after SE. In the pilocarpine-SE model, the incidence of spontaneous recurrent seizures after SE was strongly associated with neuronal damage within a few hours to days after SE by the development of vasogenic edema via the breakdown of the blood-brain barrier in the limbic regions. High-dose levetiracetam significantly suppressed the parameters in the limbic areas. These data indicate that repeated treatment with high-dose levetiracetam for at least two days after SE termination by diazepam is important for controlling the neuronal damage by preventing brain edema. Therefore, these findings suggest that early treatment with high-dose levetiracetam after SE termination by diazepam may protect against adverse sequelae via the inhibition of neurotoxicity induced by brain edema events.

Topics: Animals; Anticonvulsants; Brain Edema; Cell Death; Disease Models, Animal; Levetiracetam; Magnetic Resonance Imaging; Male; Mice; Mice, Inbred ICR; Muscarinic Agonists; Neurons; Pilocarpine; Piracetam; Status Epilepticus; Time Factors

Treatment-resistant seizures affect about a third of patients suffering from epilepsy. To fulfill the need for new medications targeting treatment-resistant seizures, a number of rodent models offer the opportunity to assess a variety of potential treatment approaches. The use of such models, however, has proven to be time-consuming and labor-intensive. In this study, we performed pharmacological characterization of the allylglycine (AG) seizure model, a simple in vivo model for which we demonstrated a high level of treatment resistance. (d,l)-Allylglycine inhibits glutamic acid decarboxylase (GAD) - the key enzyme in γ-aminobutyric acid (GABA) biosynthesis - leading to GABA depletion, seizures, and neuronal damage. We performed a side-by-side comparison of mouse and zebrafish acute AG treatments including biochemical, electrographic, and behavioral assessments. Interestingly, seizure progression rate and GABA depletion kinetics were comparable in both species. Five mechanistically diverse antiepileptic drugs (AEDs) were used. Three out of the five AEDs (levetiracetam, phenytoin, and topiramate) showed only a limited protective effect (mainly mortality delay) at doses close to the TD50 (dose inducing motor impairment in 50% of animals) in mice. The two remaining AEDs (diazepam and sodium valproate) displayed protective activity against AG-induced seizures. Experiments performed in zebrafish larvae revealed behavioral AED activity profiles highly analogous to those obtained in mice. Having demonstrated cross-species similarities and limited efficacy of tested AEDs, we propose the use of AG in zebrafish as a convenient and high-throughput model of treatment-resistant seizures.

Topics: Allylglycine; Animals; Anticonvulsants; Diazepam; Disease Models, Animal; Fructose; Levetiracetam; Male; Mice; Phenytoin; Piracetam; Seizures; Topiramate; Treatment Outcome; Valproic Acid; Zebrafish

TO determine neuroprotective properties of levetiracetam and simvastatin using rats with pilocaroine-induced epilepsy.. Epileptic rat models were randomly divided into 4 groups, each being exposed to saline, simvastatin, levetiracetam, or levetiracetam + simvastatin. Brain tissues of the rats were examined. Nissl staining was used to determine pilocarpine-induced neuronal loss in CA1 and CA3 of hippocampus. Western blot was used to detect calpain-1 expression of hippocampus.. Severe cell death was found 24 h after seizures, with a level significantly higher than the controls. Compared with the saline-treated cells, simvastatin did not decrease severe cell death (P>0.05), but levetiracetam and levetiracetam+simvastatin decreased severe cell death 24 h after seizures (P<0.05). No significant differences were found between those treated with levetiracetam and those with levetiracetam+simvastatin. Compared with controls, overexpressed calpain-1 was found in the rats 24 h after seizures, which indicates that calpain-1 may be involved in the pathophysiological mechanisms of epilepsy. Compared with those treated with pilocarpine + saline, simvastatin, levetiracetam and levetiracetam + simvastatin reduced the level of calpain-1 24 h after seizures (P<0.05).. Levetiracetam, not simvastatin, possesses neuroprotective properties, through changing calpain-1 expression levels. But levetiracetam plus simvastatin treatment does not have advantages over the choice of monotherapy. Simvastain does not possess neuroprotective properties at the early stage of epilepsy.

Topics: Animals; Calpain; Disease Models, Animal; Epilepsy; Hippocampus; Levetiracetam; Pilocarpine; Piracetam; Rats; Seizures; Simvastatin

Several factors may influence the efficacy of antiepileptic drugs (AEDs) in patients with epilepsy, and treatment resistance could be related to genetics, neuronal network alterations, and modification of drug transporters or targets. Consequently, preclinical models used for the identification of potential new, more efficacious AEDs should reflect at least a few of these factors. Previous studies indicate that induction of status epilepticus (SE) may alter drug efficacy and that this effect could be long-lasting. In this context, we wanted to assess the protective effects of mechanistically diverse AEDs in mice subjected to pilocarpine-induced SE in another seizure model. We first determined seizure thresholds in mice subjected to pilocarpine-induced SE in the 6-Hz model, 2 weeks and 8 weeks following SE. We then evaluated the protective effects of mechanistically diverse AEDs in post-SE and control animals. No major differences in 6-Hz seizure susceptibility were observed between control groups, while the seizure threshold of pilocarpine mice at 8 weeks after SE was higher than at 2 weeks and higher than in control groups. Treatment with AEDs revealed major differences in drug response depending on their mechanism of action. Diazepam produced a dose-dependent protection against 6-Hz seizures in control and pilocarpine mice, both at 2 weeks and 8 weeks after SE, but with a more pronounced increase in potency in post-SE animals at 2 weeks. Levetiracetam induced a potent and dose-dependent protection in pilocarpine mice, 2 weeks after SE, while its protective effects were observed only at much higher doses in control mice. Its potency decreased in post-SE mice at 8 weeks and was very limited (30% protection at the highest tested dose) in the control group. Carbamazepine induced a dose-dependent protection at 2 weeks in control mice but only limited effect (50% at the highest tested dose) in pilocarpine mice. Its efficacy deeply decreased in post-SE mice at 8 weeks after SE. Perampanel and phenytoin showed almost comparable protective effects in all groups of mice. These experiments confirm that prior SE may have an impact on both potency and efficacy of AEDs and indicate that this effect may be dependent on the underlying epileptogenic processes. This article is part of a Special Issue entitled "Status Epilepticus".

Topics: Animals; Anticonvulsants; Carbamazepine; Diazepam; Disease Models, Animal; Levetiracetam; Male; Mice; Phenytoin; Pilocarpine; Piracetam; Seizures; Status Epilepticus; Treatment Outcome

The six hertz (6 Hz) refractory seizure model is considered an indispensable chain of the Anticonvulsant Screening Project. We here describe an adapted protocol using the intracerebroventricular (i.c.v.) delivery route, which will allow researchers to perform targetvalidation or proof-of-principle studies using promising compounds with unknown or limited blood-brain barrier permeability (e.g. neuropeptides and peptidomimetics) in this model. Seizures were induced by single application of a current intensity of 49 mA to i.c.v.-implanted NMRI mice using an ECT Unit 57800 Ugo Basile stimulator. By applying these key parameters, c-Fos immunohistochemistry revealed the recruitment of the dentate gyrus, ratifying this model as a valuable tool for testing i.c.v. administered compounds against therapy-resistant seizures. This finding was further strengthened, since i.c.v. administration of levetiracetam suppressed 6 Hz-evoked seizure severity but sodium phenytoin did not. We also propose to use "seizure duration" as an alternative, accurate parameter to express the results within this model.

Topics: Animals; Anticonvulsants; Blood-Brain Barrier; Capillary Permeability; Catheters, Indwelling; Cornea; Dentate Gyrus; Disease Models, Animal; Electric Stimulation; Immunohistochemistry; Injections, Intraventricular; Levetiracetam; Mice; Phenytoin; Piracetam; Proto-Oncogene Proteins c-fos; Seizures

A treatment regimen consisting of HI-6, levetiracetam, and procyclidine (termed the triple regimen) has previously been shown to work as a universal therapy against soman poisoning in rats, since it has capacities to function as both prophylactic and therapeutic measure. The purpose of the present study was to examine whether the triple regimen may have antidotal efficacy against intoxication by other classical nerve agents than soman. The treatment was given 1 and 5 min after exposure to a supralethal dose of nerve agents, and the results showed that the triple regimen successfully prevented or terminated seizures and preserved the lives of rats exposed to 5×LD50 of soman, sarin, cyclosarin, or VX, but solely 3×LD50 of tabun was managed by this regimen. To meet the particular antidotal requirements of tabun, the triple regimen was reinforced with obidoxime and was made to a quadruple regimen that effectively treated rats intoxicated by 5×LD50 of tabun. The rats recovered very well and the majority gained pre-exposure body weight within 7 days. Neuropathology was seen in all groups regardless of whether the rats seized or not. The most extensive damage was produced by sarin and cyclosarin. Differentiation between the nerve agents' potency to cause lesions was probably seen because the efficacious treatments ensured survival of supralethal poisoning. A combination of 2 oximes and 2 anticonvulsants may be a prerequisite to counteract effectively high levels of poisoning by any classical nerve agent.

Topics: Animals; Anticonvulsants; Antidotes; Body Weight; Brain; Disease Models, Animal; Dose-Response Relationship, Drug; Electroencephalography; Lethal Dose 50; Levetiracetam; Male; Nerve Agents; Organophosphate Poisoning; Organophosphates; Organophosphorus Compounds; Organothiophosphorus Compounds; Oximes; Piracetam; Procyclidine; Pyridinium Compounds; Rats; Rats, Wistar; Seizures; Soman

To elucidate the mechanisms that regulate p-glycoprotein (PGP) expression and function in pharmacoresistant epilepsy, we investigated the effect of an ETB receptor antagonist (BQ788) and a p38 mitogen-activated protein kinase (p38MAPK) inhibitor (SB202190) on intractable seizures in chronic epileptic rats.. Lithium-pilocarpine-induced chronic epileptic rats were used in the present study. Animals were given levetiracetam (LEV), LEV + SB202190, LEV + BQ788, SB202190 or BQ788 over a 3-day period using an osmotic pump. Seizure activity was recorded by video-EEG monitoring with 2h of recording per day at the same time of day. We also performed western blot after EEG analysis.. Compared to control animals, PGP, ETB receptor and p38MAPK expression was increased in the hippocampus of epileptic animals. Neither SB202190 nor BQ788 affected the spontaneous seizure activity in epileptic rats. Three of ten rats were responders and achieved complete seizure control or significant reduction in seizure activity by LEV. In four of ten rats, seizure frequency was unaltered by LEV (non-responders). LEV + SB202190 reduced seizure duration, but not seizure frequency, in both responders and non-responders. LEV + BQ788 alleviated seizure frequency and seizure duration in both responders and non-responders. Compared to responders, PGP and ETB receptor expression was enhanced in the hippocampus of non-responders.. To the best of our knowledge, these findings are the first indications of the role of ETB receptor in pharmacoresistant epilepsy. Therefore, the present data suggest that the regulation of the ETB receptor-mediated signaling pathway may be important for identification of new therapeutic strategies for improving antiepileptic drug efficacy.

Topics: Animals; Anticonvulsants; Brain; Chronic Disease; Disease Models, Animal; Endothelin B Receptor Antagonists; Enzyme Inhibitors; Epilepsy; Imidazoles; Levetiracetam; Male; Oligopeptides; p38 Mitogen-Activated Protein Kinases; Piperidines; Piracetam; Pyridines; Rats, Sprague-Dawley; Receptor, Endothelin B; Seizures; Treatment Outcome

A series of fluorinated analogs of the potent investigative anticonvulsant agent (4S,8aS)-4-phenylperhydropyrrolo[1,2-a]pyrazine-2,6-dione 1 was prepared and characterized by IR, 1H, 13C NMR and mass spectral data. The compounds have been evaluated in the in vivo rodent models of epilepsy. They displayed high activity in the 'classical' maximal electroshock seizure (MES) and subcutaneous Metrazol (scMET) tests as well as in the 6Hz model of pharmacoresistant limbic seizures. The results showed that incorporating fluorine atoms into the phenyl ring of 1 can be beneficial for the anticonvulsant potency. The most promising meta-trifluoromethyl and meta-trifluoromethoxy derivatives (4S,8aS)-5h and (4S,8aS)-5l, respectively, displayed very broad spectra of activity across the preclinical seizure models.

Topics: Animals; Anticonvulsants; Disease Models, Animal; Dose-Response Relationship, Drug; Electroshock; Epilepsy; Halogenation; Hydrocarbons, Fluorinated; Male; Mice; Molecular Structure; Pentylenetetrazole; Pilocarpine; Pyrazines; Pyrroles; Rats; Rats, Sprague-Dawley; Seizures; Structure-Activity Relationship

The natural compounds carvacrol and thymol completely prevented seizures in the 6 Hz, 32 mA partial seizure model. Carvacrol and thymol, both exhibited an ED₅₀ = 35.8 mg/kg, ip and yielded protective indices of 5.3 and 3.4, respectively. At 44 mA current intensity, carvacrol and thymol exhibited ED₅₀s of 88.82 mg/kg (PI = 2.15) and 73.0 mg/kg (PI = 1.65), respectively. Thymol, but not carvacrol showed partial inhibitory activity in the maximal electroshock (MES), sc Metrazol (scMET) and Corneal-kindled models. These results suggest that carvacrol and thymol are more efficacious anticonvulsants than suggested by their lower efficacies in the conventional MES and scMET tests.

Topics: Animals; Anticonvulsants; Cymenes; Disease Models, Animal; Monoterpenes; Phenols; Psychomotor Performance; Seizures; Thymol

The β-lactam antibiotic ceftriaxone stimulates glutamate transporter GLT-1 expression and is effective in neuropathic and visceral pain models. This study examined the effects of ceftriaxone and its interactions with different analgesics (ibuprofen, celecoxib, paracetamol, and levetiracetam) in somatic and visceral pain models in rodents.. The effects of ceftriaxone (intraperitoneally/intraplantarly), analgesics (orally), and their combinations were examined in the carrageenan-induced paw inflammatory hyperalgesia model in rats (n = 6-12) and in the acetic acid-induced writhing test in mice (n = 6-10). The type of interaction between ceftriaxone and analgesics was determined by isobolographic analysis.. Pretreatment with intraperitoneally administered ceftriaxone (10-200 mg/kg per day) for 7 days produced a significant dose-dependent antihyperalgesia in the somatic inflammatory model. Acute administration of ceftriaxone, via either intraperitoneal (10-200 mg/kg) or intraplantar (0.05-0.2 mg per paw) routes, produced a significant and dose-dependent but less efficacious antihyperalgesia. In the visceral pain model, significant dose-dependent antinociception of ceftriaxone (25-200 mg/kg per day) was observed only after the 7-day pretreatment. Isobolographic analysis in the inflammatory hyperalgesia model revealed approximately 10-fold reduction of doses of both drugs in all examined combinations. In the visceral nociception model, more than 7- and 17-fold reduction of doses of both drugs was observed in combinations of ceftriaxone with ibuprofen/paracetamol and celecoxib/levetiracetam, respectively.. Ceftriaxone exerts antihyperalgesia/antinociception in both somatic and visceral inflammatory pain. Its efficacy is higher after a 7-day pretreatment than after acute administration. The two-drug combinations of ceftriaxone and the nonsteroidal analgesics/levetiracetam have synergistic interactions in both pain models. These results suggest that ceftriaxone, particularly in combinations with ibuprofen, celecoxib, paracetamol, or levetiracetam, may provide useful approach to the clinical treatment of inflammation-related pain.

Topics: Acetaminophen; Analgesics; Analgesics, Non-Narcotic; Animals; Anti-Bacterial Agents; Ceftriaxone; Celecoxib; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Hyperalgesia; Ibuprofen; Inflammation; Levetiracetam; Male; Pain; Piracetam; Pyrazoles; Rats; Rats, Wistar; Sulfonamides

The aim of the presented study was to characterize the anticonvulsant effects of levetiracetam in combination with various antiepileptic drugs (carbamazepine, phenytoin, topiramate and vigabatrin) in the mouse 6Hz psychomotor seizure model. Limbic (psychomotor) seizure activity was evoked in albino Swiss mice by a current (32mA, 6Hz, 3s stimulus duration) delivered via ocular electrodes; type II isobolographic analysis was used to characterize the consequent anticonvulsant interactions between the various drug combinations for fixed-ratios of 1:1, 1:2, 1:5 and 1:10. With type II isobolographic analysis, the combinations of levetiracetam with carbamazepine and phenytoin for the fixed-ratios of 1:5 and 1:10 were supra-additive (synergistic; P<0.01) in terms of seizure suppression, while the combinations for the fixed-ratios of 1:1 and 1:2 were additive. Levetiracetam combined with topiramate and vigabatrin for the fixed-ratio of 1:10 exerted supra-additive interaction (P<0.05), and simultaneously, the two-drug combinations for the fixed-ratios of 1:1, 1:2 and 1:5 produced additive interaction in the mouse 6Hz psychomotor seizure model. The combinations of levetiracetam with carbamazepine and phenytoin for the fixed-ratios of 1:5 and 1:10, as well as the combinations of levetiracetam with topiramate and vigabatrin for the fixed-ratio of 1:10 appear to be particularly favorable combinations exerting supra-additive interaction in the mouse 6Hz psychomotor seizure model. Finally, it may be concluded that because of the synergistic interactions between levetiracetam and carbamazepine, phenytoin, topiramate and vigabatrin, the combinations might be useful in clinical practice.

Topics: Animals; Anticonvulsants; Avoidance Learning; Carbamazepine; Disease Models, Animal; Drug Combinations; Drug Interactions; Fructose; Hand Strength; Levetiracetam; Male; Mice; Phenytoin; Piracetam; Psychomotor Performance; Seizures; Topiramate; Vigabatrin

Corticosteroids are extensively used in treatment of many diseases. In neurosurgery practice, dexamethasone (DEX) is commonly used particularly in cerebral edema secondary to brain tumors, head trauma, and central nervous system infections. There are some uncertainties surrounding the secure use of DEX in patients with epilepsy or seizures induced by diseases of the central nervous system such as head trauma and brain tumors. Despite its extensive use, the effect of DEX on epileptiform activity is unclear. In this study the effect of DEX on epileptiform activity was investigated in rats. The effects of 1, 3, and 10mg/kg DEX on epileptiform activity was compared with effects of antiepileptic drugs commonly employed in treatment of epilepsy, namely phenytoin (PHT) 50mg/kg and levetiracetam (LEV) 50mg/kg that were administered intraperitoneally for 1 week. All groups were administered intracortical penicillin (500IU) to induce epileptiform activity. DEX at the doses of 3mg/kg and 10mg/kg significantly reduced spike frequencies compared to the initial values. In conclusion, we think that DEX can effectively decrease the epileptiform activity.

Topics: Animals; Anticonvulsants; Brain; Dexamethasone; Disease Models, Animal; Dose-Response Relationship, Drug; Electroencephalography; Epilepsy; Glucocorticoids; Levetiracetam; Male; Penicillins; Phenytoin; Piracetam; Rats; Rats, Wistar; Time Factors; Treatment Outcome

Hypoxic-ischemic encephalopathy (HIE) resulting from perinatal asphyxia often leads to severe neurologic impairment or even death. There is a need to advance therapy for infants with HIE, for example to combine hypothermia with pharmacological treatment strategies. Levetiracetam (LEV) is approved for clinical administration to infants older than 4 weeks of age and is also used off-label in neonates. Furthermore, LEV was shown to be neuroprotective in adult animal models of brain injury.. The aim of this study was to evaluate the neuroprotective potential of LEV in vitro using primary hippocampal neurons, and in vivo using an established model of neonatal hypoxic-ischemic brain injury.. LEV treatment per se did not induce neurotoxicity in the developing rodent brain. Following oxygen glucose deprivation, we observed some, although not a significant, increase in cell death after LEV treatment. In vivo, LEV was administered under normothermic and hypothermic conditions following hypoxic-ischemic brain damage. LEV administration significantly increased brain injury under normothermic conditions. Compared to the normothermia-treated group, in the hypothermia group LEV administration did not increase hypoxic-ischemic brain injury.. This study demonstrates that LEV treatment increases neonatal hypoxic-ischemic brain injury. Administration of LEV in the acute phase of the injury might interfere with the balanced activation and inactivation of excitatory and inhibitory receptors in the developing brain. The neurotoxic effect of LEV in the injured newborn brain might further suggest an agonistic effect of LEV on the GABAergic system. Hypothermia treatment attenuates glutamate release following hypoxic-ischemic brain injury and might therefore limit the potentially deleterious effects of LEV. As a consequence, our findings do not necessarily rule out a potentially beneficial effect, but argue for cautious use of LEV in newborn infants with pre-existing brain injury.

Topics: Animals; Apoptosis Inducing Factor; Caspase 3; Cell Count; Cell Death; Cells, Cultured; Cerebral Cortex; Disease Models, Animal; Dose-Response Relationship, Drug; Embryo, Mammalian; Gene Expression Regulation; Glucose; Hippocampus; Hypothermia, Induced; Hypoxia; Hypoxia-Ischemia, Brain; Levetiracetam; Mice; Neurons; Neuroprotective Agents; Piracetam

Quercetin is one of the most widely occurring flavonoid which is also often present in plants as glycosidic form - rutin. These compounds are ingredients of plant diet and are also present in numerous pharmaceutical preparations and diet supplements which are taken by patients suffering from epilepsy and treating with antiepileptic drugs (AEDs). Influence of these compounds on central nervous system-related effects was proved both in experimental and clinical studies. Their influence on anxiety, depression, memory processes and convulsant activity was reported. The aim of the present study was to investigate the effect of quercetin and rutin in some models of seizures, i.e., in the model of psychomotor seizures induced by 6Hz stimulation, in the maximal electroshock seizure threshold and intravenous pentylenetetrazole tests in mice. We also examined a possible mechanism of anticonvulsant activity of quercetin and its influence on action of two AEDs, i.e., valproic acid and levetiracetam, in the 6Hz seizure test. Our results revealed only a weak anticonvulsant potential of the studied flavonoids because they showed anticonvulsant action at doses from 10 to 200mg/kg only in the 6Hz test and did not change seizure thresholds in the remaining tests. Moreover, anticonvulsant action of the studied flavonoids was short-term, noted only at pretreatment time ranging between 30 and 60min. The highest anticonvulsant activity of quercetin was correlated with its high plasma and brain concentration, which was revealed in a pharmacokinetic study. We did not note changes in the anticonvulsant action of the used AEDs combined with quercetin in the model of psychomotor seizures in mice. Neither quercetin and rutin nor combinations of quercetin with the studied AEDs produced any significant impairments of motor coordination (assessed in the chimney test), muscular strength (investigated in the grip-strength test) and long-term memory (evaluated in the passive avoidance test) in mice. The results of the present study suggest that quercetin and rutin have only weak and short-term anticonvulsant potential. These flavonoids seem to be safe for patients with epilepsy because they neither changed activity of the studied AEDs nor produced any adverse effects.

Topics: Animals; Anticonvulsants; Brain; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Electric Stimulation; Levetiracetam; Male; Memory, Long-Term; Mice; Muscle Strength; Pentylenetetrazole; Piracetam; Psychomotor Performance; Quercetin; Rutin; Seizures; Time Factors; Valproic Acid

The aim of this study was to investigate the effects of levetiracetam (LEV) on penicillin-induced epileptiform activity in rats. Penicillin was applied intracerebroventricularly (icv) at a dose of 500 IU to induce epileptiform activity. LEV was given intraperitoneally (ip) at doses of 20, 40, 80 mg/kg before penicillin injection. This agent reduced epileptiform activity by decreasing spike frequencies. The mean spike frequencies decreased significantly in all the LEV treated groups. There was no significant change in the spike amplitudes of the LEV groups compared with the control group. 40 mg/kg of LEV was determined as the most effective dose on reducing epileptiform activity. The results of this study suggest that LEV is an effective antiepileptic agent in penicillin-induced epilepsy.

Topics: Animals; Anticonvulsants; Brain; Disease Models, Animal; Dose-Response Relationship, Drug; Electroencephalography; Epilepsy; Female; Levetiracetam; Penicillins; Piracetam; Rats, Wistar

Hypertension and heart failure belong to common comorbid conditions with epilepsy so drug interactions between antiepileptics and cardiovascular drugs are possible in clinical practice. The aim of this study was to evaluate the effects of angiotensin AT1 receptor antagonists (losartan potassium and candesartan cilexetil), angiotensin-converting enzyme (ACE) inhibitors (captopril and perindopril arginine) and diuretics (hydrochlorothiazide and ethacrynic acid) on the anticonvulsant activity of levetiracetam (LEV) in mice.. The protective action of LEV was examined in the maximal electroshock seizure threshold test. Drugs were administered intraperitoneally (ip). Additionally, combinations of cardiovascular drugs with LEV were tested for adverse effects in the passive avoidance task and the chimney test.. Losartan potassium (50mg/kg), candesartan cilexetil (8mg/kg), captopril (50mg/kg), hydrochlorothiazide (100mg/kg) and ethacrynic acid (100mg/kg) did not affect the anticonvulsant activity of LEV. Perindopril arginine (10mg/kg) raised the convulsive threshold for LEV administered at doses of 100, 300 and 500mg/kg. This interaction could be pharmacodynamic in nature because the brain concentration of LEV remained unchanged by perindopril. The adverse effects of the combined treatment with LEV and cardiovascular drugs were not observed in the passive avoidance task or the chimney test.. Although experimental data can be hardly extrapolated to clinical practice, it is suggested that perindopril arginine may positively influence the anticonvulsant action of LEV in epileptic patients. The use of losartan potassium, candesartan cilexetil, captopril, hydrochlorothiazide or ethacrynic acid in patients treated with LEV seems neutral regarding its anticonvulsant activity.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Anticonvulsants; Avoidance Learning; Cardiovascular Agents; Disease Models, Animal; Diuretics; Dose-Response Relationship, Drug; Drug Interactions; Electroshock; Injections, Intraperitoneal; Levetiracetam; Mice; Piracetam; Seizures

The synthesis and anticonvulsant properties of new N-Mannich bases of 3-phenyl- (9a-d), 3-(2-chlorophenyl)- (10a-d), 3-(3-chlorophenyl)- (11a-d) and 3-(4-chlorophenyl)-pyrrolidine-2,5-diones (12a-d) were described. The key synthetic strategies involve the formation of 3-substituted pyrrolidine-2,5-diones (5-8), and then aminoalkylation reaction (Mannich-type) with formaldehyde and corresponding secondary amines, which let to obtain the final compounds 9a-d, 10a-d, 11a-d and 12a-d in good yields. Initial anticonvulsant screening was performed in mice (ip) using the maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizures tests. The most effective compounds in mice were tested after oral administration in rats. The acute neurological toxicity was determined applying the minimal motor impairment rotarod test. The in vivo results revealed that numerous compounds were effective especially in the MES test (model of human tonic-clonic seizures). The most active in the MES seizures in rats was 1-[(4-benzyl-1-piperidyl)methyl]-3-(2-chlorophenyl)pyrrolidine-2,5-dione (10c) which showed ED50 value of 37.64mg/kg. It should be stressed that this molecule along with 9a, 9d and 10d showed protection in the psychomotor seizure test (6-Hz), which is known as an animal model of therapy-resistant epilepsy. Furthermore compounds 9a, 9d and 10d were also tested in the pilocarpine-induced status prevention (PISP) test to assess their potential effectiveness in status epilepticus. For the most promising molecule 9d an influence on human CYP3A4 isoform of P-450 cytochrome was studied in vitro.

Topics: Administration, Oral; Animals; Anticonvulsants; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Disease Models, Animal; Drug Design; Electroshock; Humans; Male; Mannich Bases; Mice; Microsomes, Liver; Motor Activity; Pentylenetetrazole; Protein Binding; Pyrrolidines; Rats; Rats, Sprague-Dawley; Seizures; Structure-Activity Relationship

Emerging evidence suggests that elevated hippocampal activation may be important for disrupting cognitive functions in aged subjects as well as patients with Alzheimer's disease (AD). Therefore, reducing deleterious overactivity of the hippocampus may have therapeutic benefits. This study was designed to compare the effects of levetiracetam, an antiepileptic drug, on memory deficits associated with normal aging and AD in mouse models. Pretraining administration of levetiracetam ameliorated memory impairments of aged C57BL/6 mice (17-20months of age) in the contextual fear conditioning paradigm. Acute levetiracetam immediately after training was also efficacious in rescuing contextual memory decline in aged mice, whereas administration at a later posttraining interval (3h) had no effect. These results suggest that suppressing overexcitation with acute levetiracetam around the time of acquisition or early consolidation may be sufficient to reverse memory decline associated with aging. In contrast, pretraining administration of levetiracetam was not able to rescue memory deficits in 5XFAD transgenic mice harboring amyloid plaque pathologies at moderate (6-8months old) or massive (12-15months old) levels, differentiating between normal aging- and AD-related memory impairments in the responsiveness to acute levetiracetam treatment.

Topics: Aging; Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Conditioning, Operant; Disease Models, Animal; Fear; Female; Levetiracetam; Male; Memory; Memory Disorders; Mice; Mice, Transgenic; Nootropic Agents; Piracetam

Levetiracetam has been reported to be well tolerated and effective in status epilepticus (SE) refractory to benzodiazepine. Because of little preclinical or clinical data concerning the outcomes of LEV in SE-induced neuronal death and vasogenic edema, we investigated the effect of LEV on SE-induced injury in comparison to diazepam (DZP), and valproate (VPA).. Two hours after pilocarpine-induced SE, rats were given one of the following drugs; (1) DZP, (2) LEV, (3) VPA, (4) DZP+LEV, (5) DZP+VPA, and (6) DZP+oxiracetam. Three-four days after SE, neuronal damage and vasogenic edema were evaluated by Fluoro-Jade B (FJB) staining and serum-protein extravasation, respectively.. LEV (≥50 mg/kg) was effective to protect neuronal damage from SE in comparison to DZP and VPA. LEV as an add-on drug with DZP could not alleviate neuronal damage as compared to LEV alone. VPA (≥100 mg/kg) was effective to protect neuronal damage from SE, as compared to DZP. VPA as an add-on drug with DZP reduced neuronal damage, as compared to DZP alone.. These findings suggest that LEV may negatively interact with DZP, and be more effective to prevent SE-induced neuronal death as a first line drug than as a second line therapy after BDZ treatment.

Topics: Animals; Behavior, Animal; Cell Death; Diazepam; Disease Models, Animal; Drug Therapy, Combination; Fluoresceins; Hippocampus; Levetiracetam; Neurons; Pilocarpine; Piracetam; Rats; Rats, Sprague-Dawley; Status Epilepticus; Valproic Acid

Epilepsy modeling is essential for understanding the basic mechanisms of the epileptic process. The Genetic Audiogenic Seizure Hamster (GASH:Sal) exhibits generalized tonic-clonic seizures of genetic origin in response to sound stimulation and is currently being validated as a reliable model of epilepsy. Here, we performed a pharmacological and neuroethological study using well-known and widely used antiepileptic drugs (AEDs), including phenobarbital (PB), valproic acid (VPA), and levetiracetam (LEV). The intraperitoneal administration of PB (5-20mg/kg) and VPA (100-300mg/kg) produced a dose-dependent decrease in GASH:Sal audiogenic seizure severity scores. The administration of LEV (30-100mg/kg) did not produce a clear effect. Phenobarbital showed a short plasmatic life and had a high antiepileptic effect starting at 10mg/kg that was accompanied by ataxia. Valproic acid acted only at high concentrations and was the AED with the most ataxic effects. Levetiracetam at all doses also produced sedation and ataxia side effects. We conclude that the GASH:Sal is a reliable genetic model of epilepsy suitable to evaluate AEDs.

Topics: Acoustic Stimulation; Animals; Anticonvulsants; Behavior, Animal; Chromatography, High Pressure Liquid; Cricetinae; Disease Models, Animal; Dose-Response Relationship, Drug; Epilepsy, Reflex; Homeodomain Proteins; Levetiracetam; Locomotion; Male; Mass Spectrometry; Phenobarbital; Piracetam; Time Factors; Transcription Factors; Valproic Acid

The antiepileptic drug Levetiracetam (Lev) has neuroprotective properties in experimental stroke, cerebral hemorrhage and neurotrauma. In these conditions, non-convulsive seizures (NCSs) propagate from the core of the focal lesion into perilesional tissue, enlarging the damaged area and promoting epileptogenesis. Here, we explore whether Lev neuroprotective effect is accompanied by changes in NCS generation or propagation. In particular, we performed continuous EEG recordings before and after the permanent occlusion of the middle cerebral artery (pMCAO) in rats that received Lev (100 mg/kg) or its vehicle immediately before surgery. Both in Lev-treated and in control rats, EEG activity was suppressed after pMCAO. In control but not in Lev-treated rats, EEG activity reappeared approximately 30-45 min after pMCAO. It initially consisted in single spikes and, then, evolved into spike-and-wave and polyspike-and-wave discharges. In Lev-treated rats, only rare spike events were observed and the EEG power was significantly smaller than in controls. Approximately 24 hours after pMCAO, EEG activity increased in Lev-treated rats because of the appearance of polyspike events whose power was, however, significantly smaller than in controls. In rats sacrificed 24 hours after pMCAO, the ischemic lesion was approximately 50% smaller in Lev-treated than in control rats. A similar neuroprotection was observed in rats sacrificed 72 hours after pMCAO. In conclusion, in rats subjected to pMCAO, a single Lev injection suppresses NCS occurrence for at least 24 hours. This electrophysiological effect could explain the long lasting reduction of ischemic brain damage caused by this drug.

Topics: Animals; Anticonvulsants; Disease Models, Animal; Electroencephalography; Infarction, Middle Cerebral Artery; Levetiracetam; Male; Neuroprotective Agents; Piracetam; Rats; Seizures; Time Factors

The zebrafish model is an attractive candidate for screening of developmental toxicity during early drug development. Antiepileptic drugs (AEDs) arouse concern for the risk of teratogenicity, but the data are limited. In this study, we evaluated the teratogenic potential of seven AEDs (carbamazepine (CBZ), ethosuximide (ETX), valproic acid (VPN), lamotrigine (LMT), lacosamide (LCM), levetiracetam (LVT), and topiramate (TPM)) in the zebrafish model. Zebrafish embryos were exposed to AEDs from initiation of gastrula (5.25 hours post-fertilization (hpf)) to termination of hatching (72 hpf) which mimic the mammalian teratogenic experimental design. The lethality and teratogenic index (TI) of AEDs were determined and the TI values of each drug were compared with the US FDA human pregnancy categories. Zebrafish model was useful screening model for teratogenic potential of antiepilepsy drugs and was in concordance with in vivo mammalian data and human clinical data.

Topics: Acetamides; Animals; Anticonvulsants; Carbamazepine; Disease Models, Animal; Ethosuximide; Female; Fructose; Humans; Lacosamide; Lamotrigine; Levetiracetam; Piracetam; Pregnancy; Teratogenesis; Topiramate; Triazines; United States; Valproic Acid; Zebrafish

Approximately one-third of people with epilepsy receive insufficient benefit from currently available anticonvulsant medication, and some evidence suggests that this may be due to a lack of effective penetration into brain parenchyma. The current study investigated the ability of biodegradable polymer implants loaded with levetiracetam to ameliorate seizures following implantation above the motor cortex in the tetanus toxin model of temporal lobe epilepsy in rats. The implants led to significantly shorter seizures and a trend towards fewer seizures for up to 1 week. The results of this study indicate that drug-eluting polymer implants represent a promising evolving treatment option for intractable epilepsy. Future research is warranted to investigate issues of device longevity and implantation site.

Topics: Absorbable Implants; Animals; Anticonvulsants; Disease Models, Animal; Drug Delivery Systems; Electroencephalography; Epilepsy, Temporal Lobe; Lactic Acid; Levetiracetam; Male; Neurotoxins; Piracetam; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Rats; Rats, Sprague-Dawley; Tetanus Toxin; Time Factors

The aim of this study was to characterize the anticonvulsant effects of pregabalin in combination with four second-generation antiepileptic drugs (i.e., gabapentin, levetiracetam, tiagabine, and vigabatrin) in the mouse maximal electroshock (MES)-induced seizure model by using the type II isobolographic analysis. Tonic hind limb extension (seizure activity) was evoked in adult male albino Swiss mice by a current (sine-wave, 25 mA, 500 V, 50 Hz, 0.2 s stimulus duration) delivered via auricular electrodes. The combination of pregabalin with gabapentin at the fixed-ratio of 1:1 was supra-additive (synergistic) in terms of seizure suppression while the combinations at the fixed-ratios of 2:1 and 4:1 were additive in the mouse MES model. Similarly, the combination of pregabalin with tiagabine at the fixed-ratio of 25:1 was supra-additive, whereas the combinations at the fixed-ratios of 100:1 and 50:1 were additive in the mouse MES model. Pregabalin with levetiracetam and vigabatrin at the fixed-ratios of 1:1, 2:1 and 4:1 were additive in this seizure model. The combinations of pregabalin with gabapentin (1:1) and pregabalin with tiagabine (25:1) appear to be favorable combinations exerting supra-additive interaction in suppressing MES-induced seizures. Pregabalin in combination with levetiracetam and vigabatrin appears to be neutral producing only additivity in the mouse MES model.

Topics: Amines; Animals; Anticonvulsants; Avoidance Learning; Confidence Intervals; Cyclohexanecarboxylic Acids; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Electroshock; Gabapentin; gamma-Aminobutyric Acid; Hand Strength; Levetiracetam; Male; Mice; Motor Activity; Piracetam; Pregabalin; Seizures; Vigabatrin

Mutations of the leucine-rich glioma-inactivated 1 (LGI1) gene cause an autosomal dominant partial epilepsy with auditory features also known as autosomal-dominant lateral temporal lobe epilepsy. LGI1 is also the main antigen present in sera and cerebrospinal fluids of patients with limbic encephalitis and seizures, highlighting its importance in a spectrum of epileptic disorders. LGI1 encodes a neuronal secreted protein, whose brain function is still poorly understood. Here, we generated, by ENU (N-ethyl-N-nitrosourea) mutagenesis, Lgi1-mutant rats carrying a missense mutation (L385R). We found that the L385R mutation prevents the secretion of Lgi1 protein by COS7 transfected cells. However, the L385R-Lgi1 protein was found at low levels in the brains and cultured neurons of Lgi1-mutant rats, suggesting that mutant protein may be destabilized in vivo. Studies on the behavioral phenotype and intracranial electroencephalographic signals from Lgi1-mutant rats recalled several features of the human genetic disorder. We show that homozygous Lgi1-mutant rats (Lgi1(L385R/L385R)) generated early-onset spontaneous epileptic seizures from P10 and died prematurely. Heterozygous Lgi1-mutant rats (Lgi1(+/L385R)) were more susceptible to sound-induced, generalized tonic-clonic seizures than control rats. Audiogenic seizures were suppressed by antiepileptic drugs such as carbamazepine, phenytoin and levetiracetam, which are commonly used to treat partial seizures, but not by the prototypic absence seizure drug, ethosuximide. Our findings provide the first rat model with a missense mutation in Lgi1 gene, an original model complementary to knockout mice. This study revealed that LGI1 disease-causing missense mutations might cause a depletion of the protein in neurons, and not only a failure of Lgi1 secretion.

Topics: Amino Acid Sequence; Animals; Anticonvulsants; Brain; Carbamazepine; Cells, Cultured; Chlorocebus aethiops; COS Cells; Disease Models, Animal; Electroencephalography; Epilepsies, Partial; Epilepsy; Epilepsy, Reflex; Ethosuximide; Heterozygote; Homozygote; Humans; Intercellular Signaling Peptides and Proteins; Levetiracetam; Molecular Sequence Data; Mutation, Missense; Neurons; Phenytoin; Piracetam; Proteins; Rats, Mutant Strains

Levetiracetam (LEV) is an established anticonvulsant with numerous mechanisms of action. Apart from its anti-epileptic effects, recent experimental studies suggest anti-inflammatory properties via modulation of interleukin (IL)-1β and transforming-growth-factor (TGF)-β1. However, its anti-inflammatory properties have not yet been examined in an autoimmune inflammatory disease of the central nervous system (CNS). We investigated LEV anti-inflammatory properties in experimental autoimmune encephalomyelitis, an established mouse model of multiple sclerosis. FACS analyses, ELISA, histology and rt-PCR experiments were done to explore potential anti-inflammatory effects. In line with prior studies, we demonstrate that LEV modulates both the relative gene expression and secretion of IL-1β and TGF-1β. However, these changes were not sufficient to alter the disease course or histological parameters. Additionally, LEV showed no effects on the absolute number of different immune cell subsets. In summary, LEV showed only minor anti-inflammatory effects not sufficient to ameliorate disease course in an autoimmune inflammatory disease of CNS.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cells, Cultured; Disease Models, Animal; Disease Progression; Encephalomyelitis, Autoimmune, Experimental; Female; Gene Expression Regulation; Immunomodulation; Interleukin-1beta; Levetiracetam; Mice; Mice, Inbred C57BL; Multiple Sclerosis; Myelin-Oligodendrocyte Glycoprotein; Neuroglia; Peptide Fragments; Piracetam; Transforming Growth Factor beta1

Topics: Alzheimer Disease; Animals; Antibodies, Monoclonal, Humanized; Anticonvulsants; Clinical Trials as Topic; Disease Models, Animal; Humans; Levetiracetam; Mice; Piracetam

Many recent researches have confirmed the effectiveness of antiepileptic drugs in preventing alcohol dependency, whereas our previous study showed that repeated treatment with topiramate, a new antiepileptic drug, was effective in increasing the plasma levels of beta-endorphin (an endogenous opioid peptide) in rats. It is well documented that in humans a genetic deficit of beta-endorphin is often associated with alcohol addiction as alcohol consumption elevates the level of this peptide. The aim of the present study is multifaceted: to investigate the effect of repeated treatment of levetiracetam (50 or 100mg/kg b.w., twice daily) on voluntary alcohol intake in alcohol preferring rats (Warsaw High Preferring; WHP) and to assess changes in plasma beta-endorphin levels while alcohol is available and when it is not available for an extended period of time. We observed a noticeable increase in the levels of beta-endorphin in rats with free access to alcohol whether in a prolonged levetiracetam-treated or vehicle-treated group. However, in the levetiracetam group, a voluntary intake of alcohol diminished in comparison with both the pretreatment period and in comparison with the vehicle-treated rats. A similar increase in the plasma beta-endorphin levels was observed in levetiracetam-treated rats that did not have access to ethanol. This finding lets us to believe that levetiracetam may be a promising medication in treatment of alcohol dependency as its application leads to the increase in the beta-endorphin concentration and ultimately results in reducing deficiency of this peptide.

Topics: Alcohol Drinking; Alcoholism; Animals; Anticonvulsants; beta-Endorphin; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Ethanol; Female; Humans; Levetiracetam; Piracetam; Rats; Rats, Inbred Strains; Self Administration; Substance Withdrawal Syndrome

Results from studies based on microinfusions into seizure controlling brain sites (area tempestas, medial septum, perirhinal cortex, posterior piriform cortex) have shown that procyclidine, muscimol, caramiphen, and NBQX, but not ketamine, exert anticonvulsant effects against soman-induced seizures. The purpose of the present study was to examine whether levetiracetam (Keppra(®)) may enhance the anticonvulsant potency of the above drugs to become optimally effective when used systemically. Levetiracetam has a unique profile in preclinical models of epilepsy and has been shown to increase the potency of other antiepileptic drugs. The rats were pretreated with pyridostigmine (0.1mg/kg) to enhance survival and received anticonvulsants 20 min after onset of seizures evoked by soman (1.15 × LD(50)). The results showed that no single drug was able to terminate seizure activity. However, when levetiracetam (LEV; 50mg/kg) was combined with either procyclidine (PCD; 10mg/kg) or caramiphen (CMP; 10mg/kg) complete cessation of seizures was achieved, but the nicotinic antagonist mecamylamine was needed to induce full motor rest in some rats. In a subsequent experiment, rats were pretreated with HI-6 (125 mg/kg) to enhance survival and treatment started 40 min following seizure onset of a soman dose of 1.6 × LD(50). LEV (50mg/kg) combined with either PCD (20mg/kg) or CMP (20mg/kg) terminated seizure activity, but the survival rate was considerably higher for LEV+PCD than LEV+CMP. Both therapies could also save the lives of rats that were about to die 5-10 min after seizure onset. Thus, the combination of LEV and PCD or CMP may make up a model of a future autoinjector being effective regardless of the time of application.

Topics: Animals; Anticonvulsants; Antidotes; Chemical Warfare Agents; Cholinesterase Inhibitors; Cholinesterase Reactivators; Cyclopentanes; Disease Models, Animal; Drug Therapy, Combination; Lethal Dose 50; Levetiracetam; Male; Motor Activity; Muscimol; Nicotinic Antagonists; Piracetam; Procyclidine; Quinoxalines; Rats; Rats, Wistar; Reaction Time; Seizures; Soman; Time Factors

Tolerance to drug treatment is a serious problem in the treatment of epilepsy. We previously showed that tolerance to levetiracetam (LEV) developed within 4 days after the start of the treatment in a rat model for spontaneous seizures after electrically induced status epilepticus. In the current study we tested whether the development of tolerance to LEV could be prevented by alternating between LEV and valproate (VPA) treatment.. Before starting the alternating therapy with LEV and VPA (3 day LEV-3 day VPA, two cycles), we assessed the efficacy of VPA monotherapy by administering VPA to chronic epileptic rats via osmotic minipumps during 7 days. The anticonvulsive effects were determined by continuous video-EEG (electroencephalography) monitoring, and the concentration of VPA and LEV was measured in plasma using gas chromatography.. VPA significantly suppressed spontaneous seizures in chronic epileptic rats for 5 days. Hereafter, seizure frequency increased to pretreatment values despite adequate VPA blood levels. Seizure duration was reduced for 6 days during treatment. Seizure severity was reduced throughout the 7-day treatment period. Alternating treatment of LEV and VPA did not prevent development of tolerance; however, seizures were suppressed significantly longer compared to VPA and LEV monotherapy.. Because alternating treatment with LEV and VPA led to a prolonged effective seizure control in the animal model, it would be worthwhile to explore the possibilities of using an alternating treatment protocol in pharmacoresistant patients in whom an effective treatment is hampered by tolerance to antiepileptic drugs.

Topics: Animals; Anticonvulsants; Dentate Gyrus; Disease Models, Animal; Drug Administration Schedule; Drug Resistance; Drug Tolerance; Electric Stimulation; Electroencephalography; Epilepsy; Epilepsy, Temporal Lobe; Humans; Levetiracetam; Male; Piracetam; Rats; Rats, Sprague-Dawley; Status Epilepticus; Treatment Outcome; Valproic Acid

In order to clarify the seizure susceptibility of Noda epileptic rat (NER) and the antiepileptic effects of levetiracetam (LEV), we performed electrical hippocampal kindling in NERs compared with Wistar rats (experiment 1), and hippocampal kindling in NERs with LEV administration (experiment 2). In experiment 1, electrical stimulation was administered to the right dorsal hippocampus of NERs and Wistar rats once per day. In experiment 2, NERs were randomly assigned to group L (LEV administration) and C (saline administration). Following daily administration of LEV (240 mg/kg, i.p.) to group L and saline to group C, hippocampal kindling was performed from the 5th day of consecutive LEV or saline administration. As a result of experiment 1, all NERs exhibited stage 5 (falling) or stage 6 seizure (running/jumping, subsequent seizure) from the first electrical stimulation. In experiment 2, LEV suppressed development of hippocampal kindling, increased the afterdischarge threshold of the hippocampus and inhibited stage 6 seizures in NER. Although LEV prolonged the afterdischarge duration at the first stage 5 seizure significantly, there was a tendency to prolong the latency to generalization by LEV. These findings indicate that NER is susceptible not only to limbic seizures but also to brainstem seizures. Furthermore, LEV may have inhibitory effects not only on the hippocampus but also on other neuronal pathways to secondary generalization in this rat model.

Topics: Animals; Anticonvulsants; Brain Stem; Disease Models, Animal; Disease Progression; Drug Administration Schedule; Electric Stimulation; Epilepsy; Functional Laterality; Genetic Predisposition to Disease; Hippocampus; Kindling, Neurologic; Levetiracetam; Male; Neural Inhibition; Neural Pathways; Piracetam; Rats; Rats, Mutant Strains; Rats, Wistar; Treatment Outcome

Epilepsy is a heterogeneous syndrome characterized by recurrent, spontaneous seizures; continuous medication is, therefore, necessary, even after the seizures have long been suppressed with antiepileptic drug (AED) treatments. The most disturbing issue is the inability of AEDs to provide a persistent cure, because these compounds generally suppress the occurrence of epileptic seizures without necessarily having antiepileptogenic properties. The aim of our experiments was to determine, in the WAG/Rij model of absence epilepsy, if early long-term treatment with some established antiabsence drugs might prevent the development of seizures, and whether such an effect could be sustained.. WAG/Rij rats were treated for ∼3.5 months (starting at 1.5 months of age, before seizure onset) with either ethosuximide (ETH; drug of choice for absence epilepsy) or levetiracetam (LEV; a broad-spectrum AED with antiabsence and antiepileptogenic properties).. We have demonstrated that both drugs are able to reduce the development of absence seizures, exhibiting antiepileptogenic effects in this specific animal model.. These findings suggest that absence epilepsy in this strain of rats very likely follows an epileptogenic process during life and that early therapeutic intervention is possible, thereby opening a new area of research for absence epilepsy and AED treatment strategies.

Topics: Age Factors; Analysis of Variance; Animals; Anticonvulsants; Chromatography, High Pressure Liquid; Disease Models, Animal; Epilepsy, Absence; Ethosuximide; Levetiracetam; Male; Piracetam; Rats; Rats, Mutant Strains; Time Factors

Excess neural activity in the CA3 region of the hippocampus has been linked to memory impairment in aged rats. We tested whether interventions aimed at reducing this excess activity would improve memory performance. Aged (24 to 28 months old) male Long-Evans rats were characterized in a spatial memory task known to depend on the functional integrity of the hippocampus, such that aged rats with identified memory impairment were used in a series of experiments. Overexpression of the inhibitory neuropeptide Y 13-36 in the CA3 via adeno-associated viral transduction was found to improve hippocampal-dependent long-term memory in aged rats, which had been characterized with impairment. Subsequent experiments with two commonly used antiepileptic agents, sodium valproate and levetiracetam, similarly produced dose-dependent memory improvement in such aged rats. Improved spatial memory with low doses of these agents was observed in both appetitve and aversive spatial tasks. The benefits of these different modalities of treatment are consistent with the concept that excess activity in the CA3 region of the hippocampus is a dysfunctional condition that may have a key role underlying age-related impairment in hippocampal-dependent memory processes. Because increased hippocampal activation occurs in age-related memory impairment in humans as observed in functional neuroimaging, the current findings also suggest that low doses of certain antiepileptic drugs in cognitively impaired elderly humans may have therapeutic potential and point to novel targets for this indication.

Topics: Age Factors; Aging; Animals; Anticonvulsants; CA3 Region, Hippocampal; Cognition Disorders; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Combinations; Levetiracetam; Male; Maze Learning; Neuropeptide Y; Peptide Fragments; Piracetam; Rats; Rats, Long-Evans; Space Perception; Transduction, Genetic; Valproic Acid

Topics: Acetamides; Animals; Anticonvulsants; Disease Models, Animal; Indoles; Levetiracetam; Ligands; Membrane Glycoproteins; Mice; Nerve Tissue Proteins; Piracetam; Pyrrolidinones; Rats; Seizures; Synaptic Vesicles

The amygdala-kindled rat is a model for human temporal lobe epilepsy and activity-dependent synaptic plasticity. Hippocampal RNA isolated from amygdala-kindled rats at different kindling stages was analyzed to identify kindling-induced genes. Furthermore, effects of the anti-epileptic drug levetiracetam on kindling-induced gene expression were examined.. Cyclooxygenase-2 (Cox-2), Protocadherin-8 (Pcdh8) and TGF-beta-inducible early response gene-1 (TIEG1) were identified and verified as differentially expressed transcripts in the hippocampus of kindled rats by in situ hybridization and quantitative RT-PCR. In addition, we identified a panel of 16 additional transcripts which included Arc, Egr3/Pilot, Homer1a, Ania-3, MMP9, Narp, c-fos, NGF, BDNF, NT-3, Synaptopodin, Pim1 kinase, TNF-alpha, RGS2, Egr2/krox-20 and beta-A activin that were differentially expressed in the hippocampus of amygdala-kindled rats. The list consists of many synaptic plasticity-related immediate early genes (IEGs) as well as some late response genes encoding transcription factors, neurotrophic factors and proteins that are known to regulate synaptic remodelling. In the hippocampus, induction of IEG expression was dependent on the afterdischarge (AD) duration. Levetiracetam, 40 mg/kg, suppressed the development of kindling measured as severity of seizures and AD duration. In addition, single animal profiling also showed that levetiracetam attenuated the observed kindling-induced IEG expression; an effect that paralleled the anti-epileptic effect of the drug on AD duration.. The present study provides mRNA expression data that suggest that levetiracetam attenuates expression of genes known to regulate synaptic remodelling. In the kindled rat, levetiracetam does so by shortening the AD duration thereby reducing the seizure-induced changes in mRNA expression in the hippocampus.

Topics: Amygdala; Animals; Anticonvulsants; Disease Models, Animal; Electric Stimulation; Epilepsy, Temporal Lobe; Gene Expression; Genes, Immediate-Early; Hippocampus; Levetiracetam; Male; Neuronal Plasticity; Piracetam; Rats; Rats, Wistar; RNA, Messenger; Seizures; Synapses; Synaptic Transmission; Time Factors

Levetiracetam (LEV) is a unique antiepileptic drug that preferentially interacts with synaptic vesicle protein 2A (SV2A). To evaluate the antiepileptogenic action of LEV, we studied its effects on the development and acquisition of pentylenetetrazole (PTZ) kindling and compared them to those of sodium valproate (VPA). Anticonvulsive actions of LEV in PTZ-kindled animals were also determined. LEV did not affect PTZ seizures in naïve animals even at high doses (approximately 300 mg/kg, i.p.). However, combined treatment of LEV (30 and 100 mg/kg, i.p.) with PTZ significantly suppressed the development and acquisition of PTZ kindling. In addition, LEV at relatively low doses (3-30 mg/kg, i.p.) inhibited PTZ-evoked seizures in fully kindled animals. In contrast to LEV, VPA at sub-anticonvulsive doses (30 and 100 mg/kg, i.p.) failed to prevent the development of PTZ kindling and its anticonvulsive potency was similar in PTZ-kindled and naïve mice. The present study shows that LEV contrasts VPA by preventing the development of PTZ kindling and inhibiting seizures selectively in kindled animals.

Topics: Animals; Anticonvulsants; Convulsants; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Injections, Intraperitoneal; Kindling, Neurologic; Levetiracetam; Male; Mice; Mice, Inbred Strains; Pentylenetetrazole; Piracetam; Seizures; Treatment Outcome; Valproic Acid

Electroencephalographic (EEG) seizures and behavioral convulsions begin to appear spontaneously a few weeks after chemoconvulsant-induced status epilepticus (SE) and thereafter become more intense. This indicates the progressive development of a long-lasting epileptic focus. In addition, chemoconvulsant-induced SE increases neuronal proliferation in the dentate subgranular zone (SGZ) and ectopic migration of newborn neurons into the dentate hilus of adult animals. These seizure-induced newborn neurons, especially ectopic granule cells in the dentate hilus, are believed to facilitate the development of epileptic foci in animal models of temporal lobe epilepsy. In the present study, we examined the effects of a novel antiepileptic drug, levetiracetam, on the appearance of spontaneous EEG seizures and on the generation of newborn neurons, especially of ectopic granule cells in the dentate hilus, following kainate-induced SE. Levetiracetam treatment for 25 days, initiated 24 hours after induction of kainate-induced SE, significantly decreased the mean duration of spontaneous EEG seizures 58 days later. Levetiracetam treatment also prevented an SE-induced increase in the number of ectopic granule cells observed 58 days after kainate administration by suppressing neuronal proliferation in the dentate SGZ and abnormal migration of newborn neurons from the dentate SGZ to the hilus. These results are in accord with a previous report that an antimitotic agent that reduced the number of newborn neurons significantly decreased the frequency of spontaneous convulsions 1 month after pilocarpine-induced SE. This evidence from the kainate model of temporal lobe epilepsy suggests that levetiracetam may exert antiepileptogenic effects through the suppression of seizure-induced neurogenesis.

Topics: Animals; Animals, Newborn; Bromodeoxyuridine; Dentate Gyrus; Disease Models, Animal; Electroencephalography; Homeodomain Proteins; Immunohistochemistry; Kainic Acid; Levetiracetam; Neurons; Nootropic Agents; Piracetam; Rats; Seizures; Status Epilepticus; Tetanus Toxin; Time Factors; Tumor Suppressor Proteins

Levetiracetam, a novel antiepileptic drug, has recently been shown to have antinociceptive effects in various animal models of pain. The purpose of this study was to investigate the antihyperalgesic effect of levetiracetam and its mechanism of action, by examining the involvement of GABAergic, opioidergic, 5-hydroxytryptaminergic (5-HTergic) and adrenergic systems in its effect, in a rat model of inflammatory pain.. Rats were intraplantarly injected with the pro-inflammatory compound carrageenan. A paw pressure test was used to determine: (i) the effect of levetiracetam on carrageenan-induced hyperalgesia; and (ii) the effects of bicuculline (selective GABA(A) receptor antagonist), naloxone (non-selective opioid receptor antagonist), methysergide (non-selective 5-HT receptor antagonist) and yohimbine (selective alpha(2)-adrenoceptor antagonist) on the antihyperalgesic action of levetiracetam.. Levetiracetam (10-200 mg.kg(-1); p.o.) significantly reduced, in a dose-dependent manner, the inflammatory hyperalgesia induced by carrageenan. The antihyperalgesic effect of levetiracetam was significantly decreased after administration of bicuculline (0.5-2 mg.kg(-1); i.p.), naloxone (1-3 mg.kg(-1); i.p.), methysergide (0.25-1 mg.kg(-1); i.p.) and yohimbine (1-3 mg.kg(-1); i.p.).. These results show that levetiracetam produced antihyperalgesia which is at least in part mediated by GABA(A), opioid, 5-HT and alpha(2)-adrenergic receptors, in an inflammatory model of pain. The efficacy of levetiracetam in this animal model of inflammatory pain suggests that it could be a potentially important agent for treating inflammatory pain conditions in humans.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Carrageenan; Disease Models, Animal; Hyperalgesia; Levetiracetam; Male; Narcotic Antagonists; Pain; Piracetam; Rats; Rats, Wistar; Receptors, Adrenergic, alpha-2; Receptors, GABA-A; Receptors, Opioid; Receptors, Serotonin

Synapsins (SynI, SynII, SynIII) are a multigene family of synaptic vesicle (SV) phosphoproteins implicated in the regulation of synaptic transmission and plasticity. Synapsin I, II, I/II and I/II/III knockout mice are epileptic and SYN1/2 genes have been identified as major epilepsy susceptibility genes in humans. We analyzed cortico-hippocampal epileptiform activity induced by 4-aminopyridine (4AP) in acute slices from presymptomatic (3-weeks-old) and symptomatic (1-year-old) Syn I/II/III triple knockout (TKO) mice and aged-matched triple wild type (TWT) controls and assessed the effect of the SV-targeted antiepileptic drug (AED) levetiracetam (LEV) in reverting the epileptic phenotype. Both fast and slow interictal (I-IC) and ictal (IC) events were observed in both genotypes. The incidence of fast I-IC events was higher in presymptomatic TKO slices, while frequency and latency of I-IC events were similar in both genotypes. The major age and genotype effects were observed in IC activity, that was much more pronounced in 3-weeks-old TKO and persisted with age, while it disappeared from 1-year-old TWT slices. LEV virtually suppressed fast I-IC and IC discharges from 3-weeks-old TWT slices, while it only increased the latency of fast I-IC and IC activity in TKO slices. Analysis of I-IC events in patch-clamped CA1 pyramidal neurons revealed that LEV increased the inhibitory/excitatory ratio of I-IC activity in both genotypes. The lower LEV potency in TKO slices of both ages was associated with a decreased expression of SV2A, a SV protein acting as LEV receptor, in cortex and hippocampus. The results demonstrate that deletion of Syn genes is associated with a higher propensity to 4AP-induced epileptic paroxysms that precedes the onset of epilepsy and consolidates with age. LEV ameliorates such hyper excitability by enhancing the inhibition/excitation ratio, although the effect is hindered in TKO slices which exhibit a concomitant decrease in the levels of the LEV receptor SV2A.

Topics: 4-Aminopyridine; Aging; Analysis of Variance; Animals; Anticonvulsants; Cerebral Cortex; Disease Models, Animal; Drug Interactions; Electrodes; Epilepsy, Tonic-Clonic; Evoked Potentials; Gene Expression Regulation; Hippocampus; In Vitro Techniques; Levetiracetam; Membrane Glycoproteins; Membrane Potentials; Mice; Mice, Inbred C57BL; Mice, Knockout; Nerve Tissue Proteins; Neurons; Patch-Clamp Techniques; Piracetam; Potassium Channel Blockers; Synapsins; Synaptophysin

Levetiracetam (LEV) is known to inhibit convulsive seizures and is clinically used for treating both partial and generalized seizures. The study was performed to determine whether LEV possesses an inhibitory effect on absence seizures in a novel genetic animal model of absence epilepsy, Groggy (GRY) rats. Single injections of LEV at doses ranging from 20 to 160 mg/kg i.p. markedly inhibited absence seizures in GRY rats. The anti-absence action of LEV was potent and the cumulative duration of spike and wave discharges (SWD) in GRY rats was almost completely suppressed even at 20 mg/kg (i.p.). When the time-course of the inhibitory action of LEV (80 mg/kg i.p.) was examined up to 24 h after the treatment, the appearance of SWD was suppressed for over 6 h after injection of LEV in contrast to the action of sodium valproate (200 mg/kg i.p.) which had a very short effect (< 2 h). The maximum level of blood concentration of LEV was attained within 2 h after administration, and the drug disappeared from the blood in 24 h with T(¹/₂) of 2.7 h. These results revealed that LEV displays potent and relatively long-lasting inhibitory effects on absence seizures in GRY rats.

Topics: Animals; Anticonvulsants; Disease Models, Animal; Electroencephalography; Epilepsy, Absence; Levetiracetam; Piracetam; Rats; Rats, Mutant Strains; Rats, Wistar

The mechanisms underlying the changes in blood-brain barrier (BBB) integrity and the generation of seizures in childhood associated with preexisting brain lesions like cortical dysplasia (CD) are poorly understood. We investigated the effects of levetiracetam (LEV) on BBB integrity and the survival during hyperthermic seizures in rats with CD.. Pregnant rats were exposed to 145 cGy of gamma-irradiation on embryonic day 17. On postnatal day 28, hyperthermia-induced seizures were evoked in offspring with CD. To show the functional and morphological alterations in BBB integrity, quantitative analysis of sodium fluorescein (NaFlu) extravasation, immunohistochemistry and electron microscopy were performed.. Seizure scores and mortality rates were decreased by LEV during hyperthermia-induced seizures in rats with CD (P<0.01). Increased NaFlu extravasation into brain by hyperthermia-induced seizures in animals with CD was decreased by LEV (P<0.01). While glial fibrillary acidic protein (GFAP) immunoreactivity slightly increased in brain sections of animals with CD during hyperthermia-induced seizures, LEV led to GFAP immunoreactivity comparable to that of controls. Decreased occludin immunoreactivity and expression in CD plus hyperthermia-induced seizures was increased by LEV. Opening of tight junctions and abundance of pinocytotic vesicles representing ultrastructural evidences of BBB impairment and severe perivascular edema were observed in animals with CD exposed to hyperthermia-induced seizures and LEV treatment led to the attenuation of these findings.. These results indicate that LEV may present a novel approach for the protection of the BBB besides its antiepileptic impact on hyperthermic seizures in the setting of CD.

Topics: Animals; Anticonvulsants; Blood-Brain Barrier; Disease Models, Animal; Female; Fever; Fluorescein; Gamma Rays; Levetiracetam; Male; Malformations of Cortical Development; Microscopy, Electron; Piracetam; Pregnancy; Rats; Rats, Sprague-Dawley; Seizures; Tight Junctions

We previously showed that gene expression of synaptic vesicle protein 2A (SV2A), the binding site for the antiepileptic drug levetiracetam, is reduced during epileptogenesis in the rat. Since absence of SV2A has been associated with increased epileptogenicity, changes in expression of SV2A could have consequences for the progression of epilepsy. Therefore we investigated hippocampal SV2A protein expression of temporal lobe epilepsy (TLE) patients and in rats during epileptogenesis and in the chronic epileptic phase.. SV2A immunocytochemistry and Western blot analysis were performed on the hippocampus of autopsy controls, patients that died from status epilepticus (SE), and pharmacoresistant TLE patients. In addition, in epileptic rats, SV2A expression was determined after SE during the acute, latent, and chronic epileptic phase.. In control tissue, presynaptic SV2A was expressed in all hippocampal subfields, with strongest expression in mossy fiber terminals. SV2A positive puncta were distributed in a patchy pattern over the somata and dendrites of neurons. SV2A decreased throughout the hippocampus of TLE patients with hippocampal sclerosis (HS), compared to autopsy control, SE, and non-HS tissue. In most rats, SV2A was already decreased in the latent period especially in the inner molecular layer and stratum lucidum. Similarly as in humans, SV2A was also decreased throughout the hippocampus of chronic epileptic rats, specifically in rats with a progressive form of epilepsy.. These data support previous findings that reduced expression of SV2A could contribute to the increased epileptogenicity. Whether this affects the effectiveness of levetiracetam needs to be further investigated.

Topics: Adolescent; Adult; Animals; Anticonvulsants; Blotting, Western; Child; Disease Models, Animal; Epilepsy, Temporal Lobe; Female; Hippocampus; Humans; Infant; Levetiracetam; Male; Membrane Glycoproteins; Microscopy, Confocal; Middle Aged; Nerve Tissue Proteins; Piracetam; Rats; Sclerosis; Status Epilepticus; Young Adult

To characterize the interactions between levetiracetam and the antiepileptic drugs gabapentin, tiagabine, and vigabatrin in suppressing pentylenetetrazole-induced clonic seizures in mice, type II isobolographic analysis was used. Clonic seizures were evoked in Albino Swiss mice by subcutaneous injection of pentylenetetrazole at its CD(97)(98 mg/kg). Adverse-effect profiles with respect to motor performance, long-term memory and skeletal muscular strength were measured along with total brain antiepileptic drug concentrations. The combination of gabapentin with levetiracetam at the fixed-ratios of 2:1, 1:1, 1:2, and 1:4 were supra-additive (synergistic) in terms of seizure suppression whilst the combination at the fixed-ratio of 4:1 was additive. Tiagabine with levetiracetam and vigabatrin with levetiracetam at the fixed-ratios of 1:25, 1:50, 1:100, 1:200, and 1:400 and at 2:1, 3:1, 4:1, 6:1, 8:1, and 16:1 were additive, respectively. No acute adverse effects were observed. Measurement of total brain antiepileptic drug concentrations revealed that levetiracetam in combination with gabapentin at the fixed-ratio of 1:4 significantly elevated (21%) total brain gabapentin concentrations. In contrast, levetiracetam was without affect on tiagabine or vigabatrin concentrations and co-administration with gabapentin, tiagabine or vigabatrin had no effect on levetiracetam brain concentrations, indicating the pharmacodynamic nature of interaction between these antiepileptic drugs in the mouse pentylenetetrazole model. The combination of gabapentin with levetiracetam at the fixed-ratios of 2:1, 1:1, 1:2, and 1:4 appears to be particularly favorable combination exerting supra-additive interaction in suppressing pentylenetetrazole-induced seizures, although there is a pharmacokinetic contribution to the interaction between levetiracetam and gabapentin at the fixed-ratio of 1:4. Levetiracetam in combination with tiagabine and vigabatrin appear to be neutral combinations producing only additivity in the mouse pentylenetetrazole model.

Topics: Amines; Animals; Anticonvulsants; Brain; Cyclohexanecarboxylic Acids; Disease Models, Animal; Drug Interactions; Drug Synergism; Gabapentin; gamma-Aminobutyric Acid; Levetiracetam; Male; Mice; Nipecotic Acids; Pentylenetetrazole; Piracetam; Seizures; Tiagabine; Tissue Distribution; Vigabatrin

Synaptic vesicle protein 2A (SV2A) constitutes a distinct binding site for an antiepileptic drug levetiracetam (Keppra). In the present study we characterized SV2A (+/-) heterozygous mice in several seizure models and tested if the anticonvulsant efficacy of levetiracetam is reduced in these mice.. Seizure thresholds of male SV2A (+/-) mice and their wild-type littermates were assessed in pilocarpine (i.p.), kainic acid (s.c.), pentylenetetrazol (i.v.), 6-Hz and maximal electroshock models. Kindling development was compared in amygdala and corneal kindling models. Ex vivo binding of levetiracetam to SV2A was also performed.. Long-term electroencephalography (EEG) monitoring and behavioral observations of SV2A (+/-) mice did not reveal any spontaneous seizure activity. However, a reduced seizure threshold of SV2A (+/-) mice was observed in pilocarpine, kainic acid, pentylenetetrazol, and 6-Hz models, but not in maximal electroshock seizure model. Accelerated epileptogenesis development was also demonstrated in amygdala and corneal kindling models. Anticonvulsant efficacy of levetiracetam, defined as its ability to increase seizure threshold for 6 Hz electrical stimulation, was significantly reduced (approx. 50%) in the SV2A (+/-) mice, consistently with reduced binding to SV2A in these mice. In contrast, valproate produced the same anticonvulsant effect in both SV2A (+/+) and SV2A (+/-) mice.. The present results evidence that SV2A is involved in mediation of the in vivo anticonvulsant activity of levetiracetam, in accordance with its previously proposed mechanism of action. Furthermore, the present data also indicate that even partial SV2A deficiency may lead to increased seizure vulnerability and accelerated epileptogenesis.

Topics: Amygdala; Animals; Anticonvulsants; Binding Sites; Brain; Disease Models, Animal; Electroshock; Epilepsy; Kainic Acid; Kindling, Neurologic; Levetiracetam; Male; Membrane Glycoproteins; Mice; Mice, Knockout; Nerve Tissue Proteins; Pentylenetetrazole; Pharmacogenetics; Phenotype; Piracetam

The effects of nitric oxide-active drugs on the anticonvulsant action of the antiepileptic drug levetiracetam in an experimental model of partial complex seizures named maximal dentate gyrus activation were studied in rats. Levetiracetam was given alone or in combination with 7-nitroindazole, a preferential inhibitor of neuronal nitric oxide synthase, or with L: -arginine, the precursor of nitric oxide synthesis. The maximal dentate activation parameters were the time of latency and the durations of maximal dentate activation and afterdischarge responses. The administration of levetiracetam showed an anticonvulsant effect that was increased when given in combination with 7-nitroindazole. The co-administration of levetiracetam and L: -arginine, which is pro-convulsant, did not significantly modify all the parameters. The present results indicate that the acute administration of levetiracetam, at the lower effective dose, exerts an efficacious inhibitory effect on the severity of maximal dentate activation seizures. Levetiracetam-induced antiepileptic effect is significantly increased by the simultaneous inhibition of neuronal nitric oxide synthase.

Topics: Animals; Anticonvulsants; Arginine; Dentate Gyrus; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Combinations; Drug Interactions; Enzyme Inhibitors; Epilepsy, Complex Partial; Indazoles; Levetiracetam; Male; Nitric Oxide; Nitric Oxide Synthase Type I; Piracetam; Rats; Rats, Wistar

The aim of this study was to characterize the anticonvulsant effects of levetiracetam (LEV) in combination with the various antiepileptic drugs (clonazepam [CZP], oxcarbazepine [OXC], phenobarbital [PB], tiagabine [TGB], and valproate [VPA]), in the mouse 6 Hz psychomotor seizure model. Limbic (psychomotor) seizure activity was evoked in albino Swiss mice by a current (32 mA, 6 Hz, 3s stimulus duration) delivered via ocular electrodes and isobolographic analysis for parallel and non-parallel dose-response effects was used to characterize the consequent anticonvulsant interactions between the various drug combinations. Potential concurrent adverse-effect profiles of interactions between LEV and CZP, OXC, PB, TGB, and VPA at the fixed-ratio of 1:1 were evaluated in the chimney (motor performance), passive avoidance (long-term memory), and grip-strength (muscular strength) tests. LEV administered singly was associated with a dose-response relationship curve (DRRC) that was parallel to that for CZP and non-parallel to that for OXC, PB, TGB and VPA. With isobolography for parallel DRRCs, the combination of LEV with CZP at three fixed-ratios of 1:3, 1:1 and 3:1 was additive in nature. With isobolography for non-parallel DRRCs the combinations of LEV with OXC, TGB and VPA at the fixed-ratio of 1:1 were also additive. In contrast, the isobolography for non-parallel DRRCs revealed that the interaction for the combination of LEV with PB at the fixed-ratio of 1:1 was supra-additive (synergistic). None of the combinations were associated with any concurrent adverse effects with regards to motor coordination, long-term memory or muscular strength. LEV is associated with favorable anticonvulsant synergism with PB and is additive with regards to CZP, OXC, TGB and VPA in the mouse 6 Hz psychomotor seizure model.

Topics: Animals; Anticonvulsants; Clonazepam; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Drug Synergism; Drug Therapy, Combination; Electroshock; Epilepsy; Levetiracetam; Male; Mice; Phenobarbital; Piracetam; Psychomotor Performance; Valproic Acid

This study was designed so as to characterize the interactions between levetiracetam (LEV) and the conventional antiepileptic drugs (AEDs) clonazepam (CZP), ethosuximide (ETS), phenobarbital (PB), and valproate (VPA) in suppressing pentylenetetrazole (PTZ)-induced clonic seizures in mice by use of type II isobolographic analysis. Adverse-effect profiles of the drugs in combination were determined and brain AED concentrations were measured. The combinations of VPA and ETS with LEV at the fixed-ratio of 1:2, CZP with LEV (1:20,000), and PB with LEV (1:20) were supra-additive (synergistic) in suppressing seizures. In contrast, VPA and ETS with LEV (1:1, 2:1, and 4:1), CZP with LEV (1:1000, 1:5000, and 1:10,000), and PB with LEV (1:1, 1:5, and 1:10) were additive. No adverse effects were observed. ETS significantly reduced brain LEV concentrations but no other pharmacokinetic changes were observed. The combinations of CZP with LEV (1:20,000); VPA and ETS with LEV (1:2); and PB with LEV (1:20) appear to be favorable combinations exerting supra-additive interactions in suppressing PTZ-induced seizures.

Topics: Animals; Anticonvulsants; Clonazepam; Convulsants; Disease Models, Animal; Drug Interactions; Drug Therapy, Combination; Ethosuximide; Levetiracetam; Male; Mice; Pentylenetetrazole; Phenobarbital; Piracetam; Seizures; Valproic Acid

Chemical modifications of dimiracetam, a bicyclic analogue of the nootropic drug piracetam, afforded a small set of novel derivatives that were investigated in in vivo models of neuropathic pain. Compounds 5, 7 and 8 displayed a very promising antihyperalgesic profile in rat models of neuropathic pain induced by both chronic constriction injury of the sciatic nerve and streptozotocin. The compounds completely reverted the reduction of pain threshold evaluated by the paw pressure test. Importantly these derivatives did not induce any behavioural impairment as evaluated by the rotarod test. These results suggest that compounds 5, 7 and 8 might represent novel and well-tolerated therapeutic agents for the relief of neuropathic pain.

Topics: Animals; Behavior, Animal; Disease Models, Animal; Imidazoles; Neuralgia; Pain Threshold; Pyrroles; Rats; Structure-Activity Relationship

Understanding the molecular mechanisms underlying epilepsy is crucial to designing novel therapeutic regimens. This report focuses on alterations in the secretory machinery responsible for neurotransmitter (NT) release. Soluble N-ethylmaleimide sensitive factor (NSF) attachment protein receptor (SNARE) complexes mediate the fusion of synaptic vesicle and active zone membranes, thus mediating NT secretion. SNARE regulators control where and when SNARE complexes are formed. Previous studies showed an asymmetric accumulation of 7S SNARE complexes (7SC) in the ipsilateral hippocampus of kindled animals. The present studies probe the persistence of 7SC accumulation and the effect of the anticonvulsant, levetiracetam (LEV), on 7SC and SNARE regulators.. Quantitative Western blotting was used to monitor levels of 7SC and SNARE regulators in hippocampal synaptosomes from kindled animals both before and after LEV treatment.. The asymmetric accumulation of 7SC is present 1-year postamygdalar kindling. The synaptic vesicle protein, synaptic vesicle protein 2 (SV2), a primary LEV-binding protein, and the SNARE regulator Tomosyn increase, whereas NSF decreases in association with this accumulation. Treatment with LEV prevented kindling-induced accumulation of SV2, but did not affect the transient increase of Tomosyn or the long-term decrease NSF. LEV treatment retarded the electrical and behavioral concomitants of amygdalar kindling coincident with a decrease in accumulation of 7SC.. The ipsilateral hippocampal accumulation of SNARE complexes is an altered molecular process associated with kindling that appears permanent. Kindling epileptogenesis alters synaptosomal levels of the SNARE regulators: NSF, SV2, and Tomosyn. Concomitant treatment with LEV reverses the kindling-induced 7SC accumulation and increase of SV2.

Topics: Amygdala; Analysis of Variance; Animals; Anticonvulsants; Disease Models, Animal; Electric Stimulation; Gene Expression Regulation; Hippocampus; Kindling, Neurologic; Levetiracetam; Male; Membrane Glycoproteins; N-Ethylmaleimide-Sensitive Proteins; Nerve Tissue Proteins; Piracetam; R-SNARE Proteins; Rats; Rats, Sprague-Dawley; Seizures; SNARE Proteins; Time Factors

Levetiracetam, the alpha-ethyl analogue of the nootropic piracetam, is a widely used antiepileptic drug (AED) that provides protection against partial seizures and is also effective in the treatment of primary generalized seizure syndromes including juvenile myoclonic epilepsy. Levetiracetam was discovered in 1992 through screening in audiogenic seizure susceptible mice and, 3 years later, was reported to exhibit saturable, stereospecific binding in brain to a approximately 90 kDa protein, later identified as the ubiquitous synaptic vesicle glycoprotein SV2A. A large-scale screening effort to optimize binding affinity identified the 4-n-propyl analogue, brivaracetam, as having greater potency and a broadened spectrum of activity in animal seizure models. Recent phase II clinical trials demonstrating that brivaracetam is efficacious and well tolerated in the treatment of partial onset seizures have validated the strategy of the discovery programme. Brivaracetam is among the first clinically effective AEDs to be discovered by optimization of pharmacodynamic activity at a molecular target.

Topics: Animals; Anticonvulsants; Binding Sites; Disease Models, Animal; Drug Delivery Systems; Drug Design; Epilepsy; Humans; Levetiracetam; Piracetam

Previous examinations demonstrated antidystonic effects of the synaptic vesicle protein 2A (SV2A) ligand levetiracetam in the dt(sz) mutant hamster, an animal model of paroxysmal non-kinesiogenic dyskinesia in which dystonic episodes can be induced by stress. In the present study, we examined the effects of the two new, high affinity SV2A ligands, brivaracetam and seletracetam, in comparison to levetiracetam on the severity of dystonia in mutant hamsters. Seletracetam (50 and 75 mg/kg i.p.) and brivaracetam (75 mg/kg i.p.) reduced the severity of dystonia to a comparable extent as levetiracetam (50 and 75 mg/kg i.p.). These data confirm the therapeutic potential of these pyrrolidone derivatives for the treatment of paroxysmal dystonia.

Topics: Animals; Cricetinae; Disease Models, Animal; Dose-Response Relationship, Drug; Dystonia; Humans; Levetiracetam; Ligands; Membrane Glycoproteins; Nerve Tissue Proteins; Piracetam; Pyrrolidinones; Severity of Illness Index

Preemptive versus therapeutic effects of levetiracetam were investigated in a model of postoperative incisional pain in rats.. Levetiracetam (250, 500, and 1000 mg/kg intraperitoneal (i.p.) or morphine (5 mg/kg i.p.) was administered either 1 h before (preemptive administration) or 1 h after (therapeutic administration) incisional surgery to the hind paw of rats. The effects of levetiracetam were evaluated based on thermal hyperalgesia measured by the plantar test.. All preoperatively treated levetiracetam groups showed a significant, dose dependent, increase in paw withdrawal latency. However, post-incisional administration of levetiracetam produced no antihyperalgesic effect at any dose or at any time. In contrast, post-incisional administration of morphine reduced thermal hyperalgesia, while preemptive administration of morphine did not produce any significant antihyperalgesic effects.. The present results suggest that levetiracetam might possess preemptive analgesic activity.

Topics: Analgesics; Analysis of Variance; Animals; Anticonvulsants; Disease Models, Animal; Dose-Response Relationship, Drug; Levetiracetam; Male; Morphine; Pain, Postoperative; Piracetam; Premedication; Preoperative Care; Random Allocation; Rats; Rats, Wistar; Statistics, Nonparametric; Treatment Outcome

Pharmacoresistance is a major problem in the treatment of epilepsy. We showed previously that pharmacoresistance, at least partially, is due to an up-regulation of the multidrug transporter (MDT) P-glycoprotein (P-gp): inhibition of P-gp improves seizure control in phenytoin-treated epileptic rats (poststatus epilepticus rat model for temporal lobe epilepsy). Since it has been suggested that levetiracetam (LEV) is no substrate for MDTs, we hypothesized that LEV would more adequately control seizures in this rat model.. Chronic epileptic rats were treated repeatedly with LEV (2-week interval; different dosages) via continuous infusion using osmotic minipumps, 5-6 months after electrically induced status epilepticus. The anticonvulsive effects were determined by video-EEG monitoring and the concentration of LEV was measured in plasma and brain homogenates using gas chromatography.. LEV adequately entered the epileptic brain and dose-dependently suppressed spontaneous seizures in chronic epileptic rats for 3-4 days. Hereafter, seizure frequency increased, while LEV plasma levels did not change. Seizure behavior was less severe throughout the whole treatment. LEV did not affect seizure duration. After a withdrawal period of 2 weeks all rats initially responded again to LEV.. The initial seizure control by LEV supports the observation that LEV is not impeded by MDTs. However, the failure to control seizures for a longer period of time indicates the development of tolerance to this drug. This poses another problem in the treatment of this kind of epilepsy. Whether tolerance may be prevented by intermittent administration of LEV should be further investigated.

Topics: Animals; Anticonvulsants; Chromatography, Gas; Chronic Disease; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Tolerance; Electrodes, Implanted; Electroencephalography; Epilepsy, Temporal Lobe; Infusion Pumps; Levetiracetam; Male; Phenytoin; Piracetam; Rats; Rats, Sprague-Dawley; Temporal Lobe; Videotape Recording

Hypoxia-inducible transcription factor-1 (HIF-1) is critically involved in adaptive endogenous mechanisms to hypoxic brain injury by transcriptional activation of specific target genes that restore oxygen supply. Exogenously, neuroprotective properties of levetiracetam (LEV) have been suggested in experimental cerebral ischemia and epilepsy. We aimed to elucidate 1) effects of acute hypoxic distress on HIF-1 and vasoactive target genes, and 2) effects of LEV on HIF-1-regulated mechanisms in the brain at early developmental stages. To this end, we studied the impact of hypoxia in the presence or absence of LEV on the O2-dependent HIF-1alpha subunit as well as on VEGF and iNOS in the developing brain of normoxic and hypoxic mice. C57BL/6 mice (P0, P7) were treated with saline or LEV (i.p.; 50 mg/kg) 1 h before exposure to either normoxia (21% O2; N) or hypoxia (8% O2 of 6 h; H) without reoxygenation. HIF-1alpha was analyzed by Western blot and immunohistochemistry and mRNA levels were quantified by TaqMan RT-PCR. Hypoxia led to prominent accumulation of cerebral HIF-1alpha protein in cortical neurons and glial cells and significant up-regulation of VEGF mRNA at P0 (N, 0.018+/-0.002, vs. H, 0.031+/-0.003, n=6; p<0.05) and P7 (N, 0.096+/-0.032, vs. H, 0.873+/-0.069, n=7; p<0.001). Interestingly, we detected a significant decrease of iNOS mRNA levels in hypoxic brains. LEV treatment did not alter HIF-1alpha accumulation either in normoxic or hypoxic brains (P0, P7). Moreover, significant changes of VEGF and NOS mRNA levels did not occur with the exception that hypoxia-induced decreased iNOS levels were not observed in P0 brains. We conclude that acute systemic hypoxia differentially affects expression of HIF-1-regulated vasoactive factors in the newborn mouse brain. Of clinical importance, LEV treatment did not alter crucial HIF-1-regulated neuroprotective mechanisms.

Topics: Age Factors; Analysis of Variance; Animals; Animals, Newborn; Brain; Disease Models, Animal; Gene Expression Regulation, Developmental; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Levetiracetam; Mice; Mice, Inbred C57BL; Nerve Tissue Proteins; Nitric Oxide Synthase Type II; Nootropic Agents; Piracetam; Vascular Endothelial Growth Factor A

Despite important advances in available knowledge, management of neuropathic pain remains incomplete, and results from experimental and clinical studies indicate that some anticonvulsants show promise for treating neuropathic pain. The aim of this study was to assess the antinociceptive efficacy of levetiracetam (LEV, ucb L059) in a mice model for painful diabetic neuropathy using the in vivo nociceptive behavioral 'hot-plate test.'. The hot-plate test consisted of placing individual mice (adult male Balb/C) on the hot plate at 50+/-0.1 degrees C and timing the delay for the first hind paw lift (nociceptive threshold). After obtaining control values, diabetes was induced by injection of streptozotocin [200 mg/kg intraperitoneally (i.p.)] and 2 weeks after induction of diabetes (serum glucose > or =400 mg/dL) LEV was administered i.p. and hot-plate tests were repeated. Pain threshold values were determined and analyzed by Kruskal-Wallis one-way analysis of variance (ANOVA) followed by a pairwise comparison using a Dunnett's t-test on the ranked data.. LEV (60, 300 and 900 mg/kg) had no significant effect on the nociceptive threshold in normal mice (n=8 for each dose, P>0.05). There were significant decreases in pain threshold latency in diabetic mice compared with the normal healthy group and these were significantly and dose-dependently restored by much lower doses of LEV (20, 100 and 200 mg/kg) in a reversible manner.. Results obtained from the in vivo behavioral test lend support to the validation of the promising therapeutic potential of the novel antiepileptic agent LEV in the treatment of neuropathic pain.

Topics: Analgesics; Animals; Anticonvulsants; Behavior, Animal; Diabetic Neuropathies; Disease Models, Animal; Dose-Response Relationship, Drug; Hot Temperature; Levetiracetam; Male; Mice; Mice, Inbred BALB C; Pain; Pain Measurement; Piracetam; Time Factors; Treatment Outcome

Screening of 12,000 compounds for binding affinity to the synaptic vesicle protein 2A (SV2A), identified a high-affinity pyrrolidone derivative, brivaracetam (ucb 34714). This study examined its pharmacological profile in various in vitro and in vivo models of seizures and epilepsy, to evaluate its potential as a new antiepileptic drug.. The effects of brivaracetam and levetiracetam on epileptiform activity and seizure expression were examined in rat hippocampal slices, corneally kindled mice, audiogenic seizure-susceptible mice, maximal electroshock and pentylenetetrazol seizures in mice, hippocampal-kindled rats, amygdala-kindled rats and genetic absence epilepsy rats.. Brivaracetam and levetiracetam reduced epileptiform responses in rat hippocampal slices, brivaracetam being most potent. Brivaracetam also differed from levetiracetam by its ability to protect against seizures in normal mice induced by a maximal electroshock or maximal dose of pentylenetetrazol. In corneally kindled mice and hippocampal-kindled rats, brivaracetam induced potent protection against secondarily generalized motor seizures and showed anti-kindling properties superior to levetiracetam. In amygdala-kindled rats, brivaracetam induced a significant suppression in motor-seizure severity and, contrary to levetiracetam, reduced the after-discharge at a higher dose. Audiogenic seizure-susceptible mice were protected more potently against the expression of clonic convulsions by brivaracetam than by levetiracetam. Brivaracetam induced a more complete suppression of spontaneous spike-and-wave discharges in genetic absence epilepsy rats than levetiracetam.. Brivaracetam has higher potency and efficacy than levetiracetam as an anti-seizure and anti-epileptogenic agent in various experimental models of epilepsy, and a wide therapeutic index.

Topics: Animals; Anticonvulsants; Disease Models, Animal; Electroshock; Epilepsy; Hippocampus; Levetiracetam; Ligands; Male; Membrane Glycoproteins; Mice; Nerve Tissue Proteins; Piracetam; Pyrrolidinones; Rats; Rats, Sprague-Dawley; Seizures

Status epilepticus (SE) is often followed by severe cognitive impairment, including memory impairment. Previous studies have shown that SE is associated with impairment of single cells in the hippocampus that fire action potentials when the animal is in a specific location in space, the so-called place cells, and that place cell function correlates well with performance in tasks of visual-spatial memory. Place cell patterns therefore appear to be an excellent measure of spatial memory and may serve as a tool to assess seizure-induced impairment in memory. In this study we determined the relationship between visual-spatial memory and place cell function following SE. In addition, we determined if levetiracetam (LEV), an antiepileptic drug with a novel mechanism of action, can improve cognitive function and place cell firing patterns when administered following SE. SE was induced in adult male rats which were then randomized to post-SE treatment with LEV or normal saline (NS) treatment for 14 days. Non-SE control rats also were randomized to LEV or NS. Following discontinuation of LEV rats were tested for visual-spatial memory in the Morris water-maze and then underwent unit recording in the CA1 region of the hippocampus. Brains were then evaluated for cell loss and mossy fiber sprouting. SE was associated with severely impaired performance in the water-maze with SE rats demonstrating no learning over four days of testing. Paralleling this memory deficit was a marked disturbance in firing patterns of pyramidal neurons in CA1. Non-SE rats learned quickly over four days of water-maze testing and had normal pyramidal cell firing patterns. LEV had no major effects on water-maze performance or place cell function. Histopathological examination of the brains showed severe cell loss in CA1 in all of the SE rats with lesser degrees of injury in CA3 and the hilus. LEV treatment resulted in less histological damage in the hippocampus but had no effect on visual-spatial function or place cell physiology in either control or SE rats.

Topics: Animals; Anticonvulsants; Behavior, Animal; Cell Death; Disease Models, Animal; Electroencephalography; Hippocampus; Levetiracetam; Male; Maze Learning; Memory Disorders; Pilocarpine; Piracetam; Random Allocation; Rats; Rats, Sprague-Dawley; Status Epilepticus; Swimming; Water

Neuronal death and dysfunction occur after status epilepticus (SE), and is associated with mitochondrial enzyme damage. We previously showed, using the rat perforant pathway stimulation model, that levetiracetam administration (LEV; 1000 mg/kg intraperitoneal) during established SE reduces seizure severity and prevents mitochondrial dysfunction. We now show that administration of the same dose of LEV after 5h SE, does not protect from mitochondrial dysfunction.

Topics: Animals; Anticonvulsants; Disease Models, Animal; Electric Stimulation; Electroencephalography; Levetiracetam; Mitochondria; Neuroprotective Agents; Piracetam; Rats; Rats, Sprague-Dawley; Status Epilepticus; Time Factors

Polytherapy with two or more antiepileptic drugs (AEDs) is generally required for approximately 30% of patients with epilepsy, who do not respond satisfactorily to monotherapy. The potential usefulness of AED combinations, producing synergistic anticonvulsant efficacy and minimal adverse effects, is therefore of significant importance. The present study sought to ascertain the potential usefulness of levetiracetam (LEV) and felbamate (FBM) in combination in the mouse maximal electroshock (MES)-induced seizure model.. The anticonvulsant interaction profile between LEV and FBM in the mouse MES-induced seizure model was determined using type II isobolographic analysis. Acute adverse effects (motor performance) were ascertained by use of the chimney test. LEV and FBM brain concentrations were measured by HPLC in order to determine any pharmacokinetic contribution to the observed antiseizure effect.. LEV in combination with FBM, at the fixed ratios of 1:2, 1:1, 2:1, and 4:1, were supraadditive, whereas at the fixed ratio of 1:4, additivity was observed in the mouse MES model. Furthermore, none of the investigated combinations altered motor performance in the chimney test. Brain FBM concentrations were unaffected by concomitant LEV administration. In contrast, FBM significantly increased LEV brain concentrations.. LEV in combination with FBM was associated with pharmacodynamic supraadditivity in the MES test. However, this anticonvulsant supraadditivity was associated with a concurrent increase in brain LEV concentrations indicating a pharmacokinetic contribution to the observed pharmacodynamic interaction between LEV and FBM.

Topics: Animals; Anticonvulsants; Behavior, Animal; Brain; Chromatography, High Pressure Liquid; Disease Models, Animal; Drug Synergism; Electroshock; Epilepsy; Felbamate; Humans; Levetiracetam; Male; Mice; Motor Activity; Phenylcarbamates; Piracetam; Propylene Glycols; Seizures

Levetiracetam (LEV) is a structurally novel antiepileptic drug (AED) which has demonstrated a broad spectrum of anticonvulsant activities both in experimental and clinical studies. Previous experiments in the kindling model suggested that LEV, in addition to its seizure-suppressing activity, may possess antiepileptogenic or disease-modifying activity. In the present study, we evaluated this possibility by using a rat model in which epilepsy with spontaneous recurrent seizures (SRS), behavioral alterations, and hippocampal damages develop after a status epilepticus (SE) induced by sustained electrical stimulation of the basal amygdala. Two experimental protocols were used. In the first protocol, LEV treatment was started 24h after onset of electrical amygdala stimulation without prior termination of the SE. In the second protocol, the SE was interrupted after 4h by diazepam, immediately followed by onset of treatment with LEV. Treatment with LEV was continued for 8 weeks (experiment #1) or 5 weeks (experiment #2) after SE, using continuous drug administration via osmotic minipumps. The occurrence of SRS was recorded during and after treatment. In addition, the rats were tested in a battery of behavioral tests, including the elevated-plus maze and the Morris water maze. Finally, the brains of the animals were analyzed for histological lesions in the hippocampal formation. With the experimental protocols chosen for these experiments, LEV did not exert antiepileptogenic or neuroprotective activity. Furthermore, the behavioral alterations, e.g., behavioral hyperexcitability and learning deficits, in epileptic rats were not affected by treatment with LEV after SE. These data do not support the idea that administration of LEV after SE prevents or reduces the long-term alterations developing after such brain insult in rats.

Topics: Amygdala; Analysis of Variance; Animals; Anticonvulsants; Behavior, Animal; Brain Damage, Chronic; Diazepam; Disease Models, Animal; Drug Administration Schedule; Electric Stimulation; Exploratory Behavior; Female; Hippocampus; Hyperkinesis; Levetiracetam; Maze Learning; Piracetam; Rats; Rats, Sprague-Dawley; Status Epilepticus; Swimming; Time Factors

In the present study, we evaluated the anti-seizure and anti-myoclonic activity of levetiracetam and brivaracetam in an established rat model of cardiac arrest-induced post-hypoxic myoclonus. We found that brivaracetam (0.3 mg/kg, the minimal effective dose) was more potent than levetiracetam (3 mg/kg, the minimal effective dose) against post-hypoxic seizures. The anti-seizure activity of both compounds occurred 30 min following intraperitoneal (i.p.) administration and was maintained over the entire 150 min post-dose observation period. Both brivaracetam and levetiracetam significantly reduced auditory stimulated post-hypoxic myoclonus from a dose 0.3 mg/kg. At that dose, the anti-myoclonic activity of brivaracetam was already maximal whereas it continued to increase in a dose-relation manner with levetiracetam, suggesting that brivaracetam is a more potent agent. The onset and the duration of anti-myoclonic activity of both compounds were similar. These findings demonstrate that brivaracetam possesses more potent anti-seizure and anti-myoclonic activity than levetiracetam in an established rat model of cardiac arrest-induced post-hypoxic myoclonus.

Topics: Animals; Anticonvulsants; Disease Models, Animal; Dose-Response Relationship, Drug; Epilepsies, Myoclonic; Heart Arrest; Hypoxia; Levetiracetam; Piracetam; Pyrrolidinones; Rats; Rats, Sprague-Dawley; Seizures

Approximately 30% of patients with epilepsy do not experience satisfactory seizure control with antiepileptic drug (AED) monotherapy and often require polytherapy. The potential usefulness of AED combinations, in terms of efficacy and adverse effects, is therefore of major importance. The present study sought to identify potentially useful AED combinations with levetiracetam (LEV) METHODS: With isobolographic analysis, the mouse maximal electroshock (MES)-induced seizure model was investigated with regard to the anticonvulsant effects of carbamazepine (CBZ), phenytoin, phenobarbital (PB), valproate, lamotrigine, topiramate (TPM), and oxcarbazepine (OXC), administered singly and in combination with LEV. Acute adverse effects were ascertained by use of the chimney test evaluating motor performance and the step-through passive-avoidance task assessing long-term memory. Brain AED concentrations were determined to ascertain any pharmacokinetic contribution to the observed antiseizure effect.. LEV in combination with TPM, at the fixed ratios of 1:2, 1:1, 2:1, and 4:1, was supraadditive (synergistic) in the MES test. Likewise, the combination of LEV with CBZ (at the fixed ratio of 16:1) and LEV with OXC (8:1 and 16:1) were supraadditive. In contrast, all other LEV/AED combinations displayed additivity. Furthermore, none of the investigated LEV/AED combinations altered motor performance and long-term memory. LEV brain concentrations were unaffected by concomitant AED administration, and LEV had no significant effect on brain concentrations of concomitant AEDs.. These preclinical data would suggest that LEV in combination with TPM is associated with beneficial anticonvulsant pharmacodynamic interactions. Similar, but less profound effects were seen with OXC and CBZ.

Topics: Animals; Anticonvulsants; Behavior, Animal; Brain; Carbamazepine; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Electroshock; Epilepsy; Humans; Levetiracetam; Male; Memory; Mice; Motor Activity; Oxcarbazepine; Piracetam; Seizures

To assess the anticonvulsant activity of the novel antiepileptic drug, levetiracetam (LEV) in a model of self-sustaining limbic status epilepticus, and to measure the consequence of LEV treatment on the pattern of mitochondrial dysfunction known to occur after status epilepticus (SE).. The rat perforant pathway was stimulated for 2 h to induce self-sustaining status epilepticus (SSSE). Stimulated rats were assigned to one of three treatment groups, receiving intraperitoneal injections of saline, 200 mg/kg LEV, or 1,000 mg/kg LEV, 15 min into SSSE and at 3 times over the next 44-h period. All animals received diazepam after 3-h SSSE to terminate seizures. Forty-four hours later, the hippocampi were extracted and prepared for electrochemical high-performance liquid chromatography (HPLC), to measure reduced glutathione levels, and for spectrophotometric assays to measure activities of mitochondrial enzymes (aconitase, alpha-ketoglutarate dehydrogenase, citrate synthase, complex I, and complex II/III). These parameters were compared between treatment groups and with sham-operated rats.. LEV administration did not terminate seizures or have any significant effect on spike frequency, although rats that received 1,000 mg/kg LEV did exhibit improved behavioral seizure parameters. Significant biochemical changes occurred in saline-treated stimulated rats compared with shams: with reductions in glutathione, alpha-ketoglutarate dehydrogenase, aconitase, citrate synthase, and complex I activities. Complex II/III activities were unchanged throughout. Rats that received 1,000 mg/kg LEV had significantly improved biochemical parameters, in many instances, comparable to sham control levels.. Despite continuing seizures, administration of LEV (1,000 mg/kg) protects against mitochondrial dysfunction, indicating that in addition to its antiepileptic actions, LEV may have neuroprotective effects.

Topics: Aconitate Hydratase; Animals; Anticonvulsants; Chromatography, High Pressure Liquid; Citrate (si)-Synthase; Disease Models, Animal; Dose-Response Relationship, Drug; Electric Stimulation; Electroencephalography; Epilepsy; Glutathione; Hippocampus; Levetiracetam; Male; Mitochondria; Mitochondrial Diseases; Neurons; Neuroprotective Agents; Perforant Pathway; Piracetam; Rats; Rats, Sprague-Dawley; Status Epilepticus

To study the effect of the antiepileptic drug levetiracetam (LEV) on the patterns of intrinsic optical signals (IOSs) generated by slices of the somatosensory cortex obtained from 3- and 6-month-old WAG/Rij and age-matched, nonepileptic control (NEC) rats.. WAG/Rij and NEC animals were anesthetized with enfluorane and decapitated. Brains were quickly removed, and neocortical slices were cut coronally with a vibratome, transferred to a submerged tissue chamber, and superfused with oxygenated artificial cerebrospinal fluid (aCSF). Slices were illuminated with a dark-field condensor and examined with a x2.5 objective; images were processed with a real time digital video image-enhancement system. Images were acquired before (background) and during electrical stimulation with a temporal resolution of 10 images/s and were displayed in pseudocolors. Extracellular stimuli (200 micros; <4 V) were delivered through bipolar stainless steel electrodes placed in the white matter.. IOSs recorded in NEC slices bathed in control aCSF became less intense and of reduced size with age (p < 0.05); this trend was not seen in WAG/Rij slices. Age-dependent decreases in IOS intensity and area size were also seen in NEC slices superfused with aCSF containing the convulsant 4-aminopyridine (4-AP, 5 microM); in contrast, significant increases in both parameters occurred with age in 4-AP-treated WAG/Rij slices (p < 0.05). Under any of these conditions, the IOS intensity and area size slices were larger in WAG/Rij than in NEC slices. LEV (50-500 microM) application to WAG/Rij slices caused dose-dependent IOS reductions that were evident both in control and in 4-AP-containing aCSF and were more pronounced in 6-month-old tissue.. These data demonstrate age-dependent IOS modifications in NEC and WAG/Rij rat slices and identify a clear pattern of hyperexcitability that occurs in 6-month-old WAG/Rij neocortical tissue, an age when absence seizures occur in all animals. The ability of LEV to reduce these patterns of network hyperexcitability supports the potential use of this new antiepileptic drug in primary generalized epileptic disorders.

Topics: 4-Aminopyridine; Age Factors; Animals; Anticonvulsants; Disease Models, Animal; Electric Stimulation; Electrodes, Implanted; Epilepsy, Absence; Image Enhancement; In Vitro Techniques; Levetiracetam; Models, Genetic; Neocortex; Oscillometry; Piracetam; Rats; Rats, Inbred Strains; Rats, Wistar; Signal Processing, Computer-Assisted; Somatosensory Cortex; Videotape Recording

Owing to their activation by increased intracellular Ca(2+) levels following burst firing, and the resultant hyperpolarisation and dampening of neuronal excitability, the small-conductance Ca(2+)-activated K(+) (SK(Ca)) channels have been proposed as a potential target for novel antiepileptic drugs. Indeed, the channel activator 1-ethyl-2-benzimidazolinone (1-EBIO) has been shown to reduce epileptiform activity in vitro. Accordingly, this study has investigated the therapeutic potential of 1-EBIO using a range of in vivo seizure models, and assessed the adverse effect liability with the rotarod and locomotor activity paradigms. To aid benchmarking of 1-EBIO's therapeutic and adverse effect potential, it was tested alongside two currently marketed antiepileptic drugs, phenytoin and levetiracetam. 1-EBIO was found to be effective at reducing seizure incidence in mice following maximal electroshock (ED(50) 36.0 mg/kg) as well as increasing the threshold to electrically- and pentylenetetrazole-induced seizures (TID(10)s 7.3 and 21.5 mg/kg, respectively). However, results from the mouse rotarod test revealed a strong adverse effect potential within the therapeutic dose range (ID(50) 35.6 mg/kg), implying a significantly inferior therapeutic index with respect to the comparator compounds. These results, therefore, support the in vitro data detailing 1-EBIO's reduction of epileptiform activity. However, the use of in vivo models has revealed a significant adverse effect potential within the therapeutic dose range. Nevertheless, given the multiplicity of SK(Ca) channel subunits and that 1-EBIO has been shown to enhance additional, non-SK(Ca) carried currents, these findings do not preclude the possibility that more selective enhancers of SK(Ca) function could prove to be effective as antiepileptic medications.

Topics: Animals; Anticonvulsants; Benzimidazoles; Disease Models, Animal; Dose-Response Relationship, Drug; Electroshock; Levetiracetam; Male; Mice; Motor Activity; Pentylenetetrazole; Phenytoin; Pilocarpine; Piracetam; Seizures; Sensory Thresholds; Small-Conductance Calcium-Activated Potassium Channels

Prophylactic treatment with antiepileptic drugs is common practice following subarachnoid hemorrhage (SAH) and traumatic brain injury. However, commonly used antiepileptic drugs have multiple drug interactions, require frequent monitoring of serum levels, and are associated with adverse effects that may prompt discontinuation. In the current study, we test the hypothesis that levetiracetam, an anticonvulsant with favorable interaction and adverse event profiles, is neuroprotective in clinically relevant models of SAH and closed head injury (CHI).. A single intravenous dose of vehicle, low-dose (18 mg/kg), or high-dose (54 mg/kg) levetiracetam was administered intravenously followed CHI. Functional assessments were performed on a daily basis, and histological assessments performed at 24 hours. In a separate series of experiments, mice were randomized to receive intravenous administration of vehicle, low-dose, or high-dose levetiracetam every 12 hours for 3 days following SAH. Functional endpoints were assessed daily, followed by measurement of MCA luminal diameter on day 3.. A single dose of levetiracetam improved functional and histological outcomes after CHI. This effect appeared specific for levetiracetam and was not associated with fosphenytoin treatment. Treatment with levetiracetam also improved functional outcomes and reduced vasospasm following SAH.. Levetiracetam is neuroprotective in clinically relevant animal models of SAH and CHI. Levetiracetam may be a therapeutic alternative to phenytoin following acute brain injury in the clinical setting when seizure prophylaxis is indicated.

Topics: Animals; Disease Models, Animal; Drug Administration Schedule; Head Injuries, Closed; Injections, Intravenous; Levetiracetam; Male; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Piracetam; Random Allocation; Subarachnoid Hemorrhage; Time Factors; Vasospasm, Intracranial

Nefiracetam (NEF) is a novel pyrrolidone-type nootropic agent, and it has been reported to possess various pharmacologic effects as well as cognition-enhancing effects. The present study focused on the anticonvulsant effect of NEF and its potential for antiepileptic therapy.. The anticonvulsant properties of NEF were investigated in experimental seizure models of mice and rats, compared with levetiracetam (LEV) and other standard antiepileptic drugs [AEDs; zonisamide (ZNS), phenytoin (PHT), carbamazepine (CBZ), valproic acid (VPA), diazepam (DZP), and ethosuximide (ESM)]. With reference to standard programs for evaluating potential AEDs, the study included the traditional maximal electroshock seizure and subcutaneous chemoconvulsant (pentylenetetrazole, bicuculline, picrotoxin, strychnine, or N-methyl-D-aspartate) seizure tests and two threshold models (the increasing-current electroshock seizure test and intravenous pentylenetetrazole seizure threshold test). Neurotoxic activities were examined with the rotarod test and traction test.. NEF inhibited electroshock-induced seizures at nontoxic doses, whereas it had no effect on seizures chemically induced by pentylenetetrazole, bicuculline, picrotoxin, strychnine, or N-methyl-D-aspartate. The anticonvulsant spectrum of NEF paralleled that of ZNS, PHT, and CBZ. The anticonvulsant efficacy of NEF was comparable with that of ZNS and less potent than that of PHT, CBZ, and DZP. However, the safety margin of NEF was superior to that of ZNS, CBZ, VPA, and DZP. LEV showed only slight anticonvulsant effects in threshold models, and it was not effective in conventional screening models.. These results suggest that NEF has distinct anticonvulsant spectrum and mechanisms from those of LEV. NEF is an orally active and safe AED, and it possesses a potential for antiepileptic therapy.

Topics: Animals; Anticonvulsants; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Electroshock; Levetiracetam; Male; Mice; Nootropic Agents; Pentylenetetrazole; Piracetam; Pyrrolidinones; Rats; Rats, Wistar; Seizures

Levetiracetam (LEV) is a new antiepileptic drug effective as adjunctive therapy for partial seizures. It displays a unique pharmacological profile against experimental models of seizures, including pilocarpine-induced seizures in rodents. Aiming to clarify if anticonvulsant activity of LEV occurs due to cholinergic alterations, adult male mice received LEV injections before cholinergic agonists' administration. Pretreatment with LEV (30-200 mg/kg, i.p.) increased the latencies of seizures, but decreased status epilepticus and death on the seizure model induced by pilocarpine, 400 mg/kg, s.c. (P400). LEV (LEV200, 200 mg/kg, i.p.) pretreatment also reduced the intensity of tremors induced by oxotremorine (0.5 mg/kg, i.p). [3H]-N-methylscopolamine-binding assays in mice hippocampus showed that LEV200 pretreatment reverts the downregulation on muscarinic acetylcholine receptors (mAChR), induced by P400 administration, bringing back these density values to control ones (0.9% NaCl, i.p.). However, subtype-specific-binding assays revealed that P400- and LEV-alone treatments result in M1 and M2 subtypes decrease, respectively. The agonist-like behavior of LEV on the inhibitory M2 mAChR subtype, observed in this work, could contribute to explain the reduction on oxotremorine-induced tremors and the delay on pilocarpine-induced seizures, by an increase in the attenuation of neuronal activity mediated by the M1 receptors.

Topics: Animals; Anticonvulsants; Convulsants; Disease Models, Animal; Hippocampus; Levetiracetam; Male; Mice; Muscarinic Agonists; Oxotremorine; Pilocarpine; Piracetam; Receptors, Muscarinic; Seizures

The long-lasting antiseizure effects of levetiracetam (LEV) have been observed in the spontaneously epileptic rat (SER) that expresses both tonic and absence-like seizures. Furthermore, the antiepileptogenic effects of LEV in addition to antiseizure effects have been reported in the amygdala-kindling model in rats. This suggests that the long-lasting seizure protection of LEV may be at least partly due to its antiepileptogenic effects. Therefore this study aimed to differentiate the antiseizure and potential antiepileptogenic effects of LEV by administering LEV continuously to SERs before the appearance of any seizure expression.. LEV was administered to the SERs at 80 mg/kg/day (i.p.) from postnatal weeks 5 to 8. The period of observation for tonic convulsions was from postnatal week 5 to 13. Absence-like seizures were recorded by using conventional EEG in weeks 12 and 13.. After age 7-8 weeks, SERs exhibit spontaneous tonic convulsions. Development of tonic convulsions was significantly inhibited in the LEV group, compared with the control group, by the middle of week 9. A significant reduction of tonic convulsions also was observed in the LEV group until week 13 (5 weeks after termination of the administration). In week 12, the absence-like seizures were significantly lower in the LEV group, compared with the control group.. This study demonstrates a significant inhibition of seizures after prolonged treatment with LEV before the developmental expression of seizure activity in SERs. This effect is suggested to be due to an antiepileptogenic effect and not an antiseizure effect of LEV, because the half-life of the drug in plasma is short (2-3 h in rats) after single and long-term administration. Furthermore, the inhibition of seizure expression in SERs was still apparent 5 weeks after termination of LEV treatment. These results further suggest that LEV possesses not only antiseizure effects but also antiepileptogenic properties.

Topics: Animals; Animals, Newborn; Anticonvulsants; Disease Models, Animal; Drug Administration Schedule; Electrodes, Implanted; Electroencephalography; Epilepsy; Female; Frontal Lobe; Hippocampus; Injections, Intraperitoneal; Levetiracetam; Male; Piracetam; Rats; Rats, Mutant Strains; Seizures

Some evidence suggests that levetiracetam (LEV) possesses antiepileptogenic characteristics. The purpose of this study was to investigate the time course of seizure protection by LEV compared with that of phenytoin (PHT), phenobarbital (PB), valproate (VPA), and carbamazepine (CBZ) in the spontaneously epileptic rat (SER). The SER is a double mutant (tm/tm, zi/zi) showing both tonic convulsions and absence-like seizures.. The effect of single (40, 80, and 160 mg/kg, i.p.) and 5-day (80 mg/kg/day, i.p.) administration of LEV on tonic convulsions and absence-like seizures in SERs were studied. Tonic convulsions induced by blowing air onto the animal's head at 5-min intervals for 30 min and spontaneous absence-like seizures characterized by 5- to 7-Hz spike-wave-like complexes in the cortical and hippocampal EEG were recorded for 30 min. In the single-administration study, observations for seizure activity were performed once before and 3 times (45, 75, and 135 min) after drug administration. In the 5-day administration study, seizure observation was performed 4 times for 30 min (once before and 3 times after drug administration) during the 5-day drug-administration period, and continued once a day until 8 days after the final administration. The antiepileptic effects of 5-day administration of conventional AEDs (PHT, PB, VPA, and CBZ) were examined by using similar methods.. Tonic convulsions and absence-like seizures were inhibited by a single administration of LEV at 80 and 160 mg/kg, i.p., but not significantly at 40 mg/kg, i.p. When LEV was repeatedly administered at 80 mg/kg/day, i.p., for 5 days to SERs, the inhibitory effects on seizures increased with administration time. The number of tonic convulsions and absence-like seizures were significantly reduced to 39.1% and 38.4% compared with previous values, respectively, after 5-day LEV administration. Furthermore, significant inhibition of tonic convulsions was detected

Topics: Animals; Anticonvulsants; Behavior, Animal; Cerebral Cortex; Disease Models, Animal; Dose-Response Relationship, Drug; Electroencephalography; Epilepsy; Epilepsy, Absence; Epilepsy, Generalized; Female; Injections, Intraperitoneal; Levetiracetam; Male; Piracetam; Rats; Rats, Mutant Strains; Time Factors

Nefiracetam (NEF) is a novel pyrrolidonetype nootropic agent, and it has been reported to possess various pharmacologic effects as well as cognition-enhancing effects. The present study focused on the effects of NEF in amygdala-kindled seizures and its potential for antiepileptic therapy.. Effects of NEF on fully amygdala-kindled seizures and development of amygdala-kindled seizures were investigated in rats and compared with those of levetiracetam (LEV), a pyrrolidone-type antiepileptic drug (AED).. In fully amygdala-kindled rats, NEF (25, 50, and 100 mg/kg, p.o.) decreased afterdischarge induction, afterdischarge duration, seizure stage, and motor seizure duration in a dose-dependent manner. LEV (25, 50, and 100 mg/kg, p.o.) had no effects on afterdischarge induction and slightly decreased afterdischarge duration, whereas it markedly decreased seizure stage and motor seizure duration. In contrast to the results in fully amygdala-kindled rats, NEF (25 and 50 mg/kg/day, p.o.) had few or no effects on the development of amygdala-kindled seizures. As well as fully amygdala-kindled seizures, LEV (50 mg/kg/day, p.o.) markedly inhibited the development of behavioral seizures without reducing daily afterdischarge duration.. Although NEF possesses potent anticonvulsant effects on fully amygdala-kindled seizures, it has few or no effects on the development of amygdala-kindled seizures. LEV shows marked anticonvulsant effects on both phases of kindling. In fully amygdala-kindled rats, NEF inhibits both electroencephalographic and behavioral seizures, whereas LEV inhibits only behavioral seizures. This double dissociation suggests that NEF has a distinct anticonvulsant spectrum and mechanisms from those of LEV.

Topics: Administration, Oral; Amygdala; Animals; Anticonvulsants; Behavior, Animal; Disease Models, Animal; Electric Stimulation; Electrodes, Implanted; Electroencephalography; Epilepsy, Complex Partial; Humans; Kindling, Neurologic; Levetiracetam; Male; Nootropic Agents; Piracetam; Pyrrolidinones; Rats; Rats, Wistar; Seizures

Since its introduction into clinical practice in 1999, levetiracetam, the S enantiomer of piracetam, has rapidly found a secure place, initially in the therapy of partial onset seizures and subsequently in the treatment of idiopathic generalized epilepsies (IGE). It has many of the properties of an "ideal" antiepileptic drug, including rapid absorption, linear pharmokinetics, and sparse drug interactions. Tolerabiliy is generally excellent in both adults and children, although tiredness is a common dose-limiting adverse effect. Occasionally the drug can precipitate behavioral abnormalities, especially in patients with learning disability. There is a wide safety margin in overdose. In common with most antiepileptic drugs its mode of action remains uncertain. Levetiracetam binds to a specific site in the brain, influences intracellular calcium currents and reverses negative allosteric modulators of GABA- and glycine-gated currents in vitro. Its effectiveness has been demonstrated in animal models of epilepsy and in clinical trials of partial onset and IGE. Treatment of IGEs may be straightforward, with many patients demonstrating an excellent and robust response to valproate monotherapy. However, there remains a significant minority of patients for whom valproate is unsuitable, including those who experience unacceptable adverse effects (e.g., weight gain or hair loss) and women of childbearing age in whom the teratogenic potential of valproate is unacceptable. Therapeutic response to lamotrigine in this group is often disappointing, and many clinicians now are turning to the choice of levetiracetam. Efficacy in generalized tonic-clonic seizures and myoclonus is usually apparent and some patients experience improvement in typical absences. Experience of combinations of levetiracetam with other antiepileptic drugs is limited in IGE and the responses are largely anecdotal. In our hands, patients with refractory IGEs may respond to combinations of levetiracetam with valproate, lamotrigine, and phenobarbital, and adverse effects when they occur are usually limited to tiredness. Levetiracetam does not interact with the oral contraceptive pill, simplifying treatment in women of childbearing age. Although animal data look encouraging, questions over levetiracetam's teratogenic potential and overall safety in pregnancy will remain for many years to come.

Topics: Adult; Animals; Anticonvulsants; Child; Disease Models, Animal; Epilepsy, Generalized; Female; Humans; Levetiracetam; Piracetam; Treatment Outcome

Levetiracetam (LEV) (Keppra; UCB Pharma, Brussels, Belgium) has recently been reported to have antidyskinetic activity against levodopa (L-DOPA)-induced dyskinesia in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset and macaque models of Parkinson's disease. Amantadine is frequently used as adjunctive therapy for L-DOPA-induced dyskinesia, but adverse effects limit its clinical utility. The current study was designed to investigate whether LEV can potentiate the antidyskinetic action of amantadine. The antiparkinsonian and antidyskinetic effects of LEV (13 and 60 mg/kg) and amantadine (0.01, 0.03, 0.1, and 0.3 mg/kg), administered alone and in combination, were assessed in the MPTP-lesioned marmoset model of L-DOPA-induced dyskinesia (n = 12). LEV (60 mg/kg) and amantadine (0.3 mg/kg) administered alone significantly reduced l-DOPA-induced dyskinesia without compromising the antiparkinsonian action of l-DOPA. Lower doses were without any significant effects. The combination of LEV (60 mg/kg) and amantadine (0.01, 0.03, 0.1, and 0.3 mg/kg) significantly decreased dyskinesia severity, without compromising the antiparkinsonian action of L-DOPA, more efficaciously than LEV or amantadine monotherapy. These results support the concept that normalization of different pathophysiological mechanisms (i.e., altered synchronization between neurons and enhanced N-methyl-D-aspartate transmission) has a greater efficacy. Combined LEV/amantadine therapy might be useful as an adjunct to L-DOPA to treat dyskinetic side effects and to expand the population of Parkinson's disease patients who benefit from treatment with amantadine alone.

Topics: Amantadine; Animals; Anticonvulsants; Antiparkinson Agents; Callithrix; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Dyskinesias; Female; Levetiracetam; Levodopa; Male; MPTP Poisoning; Piracetam

A novel mechanism of action has recently been described for levetiracetam, a member of a new class of anticonvulsants. Levetiracetam binds selectively and with high affinity to a synaptic vesicle protein known as SV2A, thought to be involved with synaptic vesicle exocytosis and presynaptic neurotransmitter release.

Topics: Animals; Anticonvulsants; Disease Models, Animal; Exocytosis; Humans; Levetiracetam; Membrane Glycoproteins; Mice; Mice, Knockout; Nerve Tissue Proteins; Neurotransmitter Agents; Piracetam; Protein Binding; Seizures; Synaptic Transmission; Synaptic Vesicles

The purpose of this study was to assess, in rats, the antinociceptive effects of levetiracetam (i.p.), a novel antiepileptic drug, in acute pain tests and in two models of human neuropathic pain. Levetiracetam and carbamazepine contrasted morphine by an absence of effect in the tail flick and hot plate tests. In normal rats, carbamazepine failed to modify the vocalisation thresholds to paw pressure whereas levetiracetam slightly increased this threshold only at the highest dose (540 mg/kg) for 30 min. In the sciatic nerve with chronic constriction injury model, the highest dose of levetiracetam (540 mg/kg) and carbamazepine (30 mg/kg) reversed the hyperalgesia. In streptozocin-induced diabetic rats, levetiracetam dose-dependently increased the vocalization threshold from 17 to 120 mg/kg reaching a similar effect as 10 mg/kg of carbamazepine. These results indicate that levetiracetam induces an antihyperalgesic effect in two models of human neuropathic pain, suggesting a therapeutic potential in neuropathic pain patients.

Topics: Acute Disease; Analgesics; Animals; Carbamazepine; Chronic Disease; Constriction, Pathologic; Diabetes Mellitus, Experimental; Disease Models, Animal; Dose-Response Relationship, Drug; Humans; Hyperalgesia; Injections, Intraperitoneal; Levetiracetam; Male; Morphine; Pain; Pain Measurement; Peripheral Nervous System Diseases; Piracetam; Rats; Rats, Sprague-Dawley; Sciatic Nerve; Vocalization, Animal

The purpose of this study was to test the teratogenic potential of the antiepileptic drug (AED) levetiracetam (LEV), its major metabolite in humans, 2-pyrrolidone-N-butyric acid (PBA), and enantiomer, (R)-alpha-ethyl-oxo-pyrrolidine acetamide (REV), in a well-established mouse model.. All compounds were administered by intraperitoneal injections once daily to SWV/Fnn mice on gestational days 8-1/2 to 12-1/2. LEV was administered at doses of 600, 1,200, and 2,000 mg/kg/day, piracetam (PIR) and PBA, at 600 and 1,200 mg/kg/day, and REV, at 600 mg/kg/day. On gestational day 18(1/2), fetuses were examined for gross external malformations and prepared for skeletal analysis by using Alizarin Red S staining.. No significant gross external malformations were observed in any of the study groups. Fetal weights were significantly reduced in most study groups. Resorption rates were significantly increased only in the 2,000-mg/kg/day LEV group. The overall incidence of skeletal abnormalities and specifically of hypoplastic phalanges was significantly increased in both PBA treatments and in the intermediate 1,200-mg/kg/day LEV group. In contrast to that in humans, 24-h urinary excretion analysis in mice showed that 65-100% of the LEV doses were excreted unchanged, whereas only 4% was excreted as the metabolite PBA.. Results of this study demonstrate that both LEV and its major metabolite in humans, PBA, do not induce major structural malformations in developing SWV/Fnn embryos and suggest that they provide a margin of reproductive safety for the pregnant epileptic population when compared with other AEDs tested in this mouse model.

Topics: Animals; Butyrates; Disease Models, Animal; Female; Fetus; Levetiracetam; Mice; Piracetam; Pregnancy; Prenatal Exposure Delayed Effects; Pyrrolidines; Pyrrolidinones; Teratogens

Topics: Acetaminophen; Acetates; Amines; Analgesics; Animals; Cyclohexanecarboxylic Acids; Disease Models, Animal; Drug Delivery Systems; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Levetiracetam; Nitrates; Pain; Peripheral Nervous System Diseases; Piracetam; Pregabalin; Topiramate

Levetiracetam (LEV) is a new antiepileptic drug with a promising preclinical profile involving both anticonvulsant and antiepileptogenic effects in kindling models. The latter stimulated the present study to compare its neuroprotective properties with the potent and selective, non-competitive NMDA antagonist, MK-801, in the rat middle cerebral artery occlusion model. Twenty-four hours after a transient occlusion of 90 minutes the animals were sacrificed and infarct volume and lesion distribution were determined from stained coronal sections. LEV was administered by intraperitoneal (i.p.) bolus injections of 5.5, 11, 22 and 44 mg x kg(-1), 30 minutes before occlusion followed by a continuous 24 hour i.p. infusion of 1.25, 2.6, 5.1 and 10.2 mg x kg(-1) per hour, respectively. LEV administration did not alter body temperature but reduced the infarct volume by 33% (P< 0.05) at the highest dose tested. An i.p. bolus injection of 0.04, 0.12 and 0.4 mg x kg(-1) of MK-801 followed by continuous i.p. infusion of 0.036, 0.108 and 0.36 mg x kg(-1) per hour, reduced the infarct volume by 49, 51 and 74% (P< 0.05), respectively. However, only the highest dose of MK-801 induced a significant reduction in the infarct volume (P< 0.05) and this was associated with hypothermia. These results suggest that LEV possesses neuroprotective properties which may be relevant for its antiepileptogenic action.

Topics: Animals; Anticonvulsants; Arterial Occlusive Diseases; Body Temperature; Brain; Brain Ischemia; Cerebrovascular Circulation; Disease Models, Animal; Dizocilpine Maleate; Levetiracetam; Male; Middle Cerebral Artery; N-Methylaspartate; Neuroprotective Agents; Piracetam; Rats; Rats, Wistar

Levetiracetam (LEV) is an interesting novel antiepileptic drug with proven efficacy in both animal models and patients with partial epilepsy. To study whether the efficacy of the drug changes during chronic treatment, we evaluated the anticonvulsant activity of LEV during prolonged daily administration in amygdala-kindled rats.. On the basis of the anticonvulsant potency and duration of action after acute doses, LEV was administered in fully kindled rats three times daily at 108 mg/kg i.p. for 3 weeks. For the study of anticonvulsant efficacy, the afterdischarge threshold was determined before, during, and after the drug treatment period. To determine whether the pharmacokinetics of the drug change during prolonged treatment, LEV levels were repeatedly determined in plasma during the treatment period.. LEV markedly increased the afterdischarge threshold and decreased the seizure severity and duration after initial dosing, but a marked loss of anticonvulsant efficacy developed during chronic treatment. This loss of efficacy was not due to alterations in drug elimination, indicating the development of functional tolerance to LEV during repeated administration. After the termination of treatment, no withdrawal signs (e.g., changes in behavior, body temperature, body weight, or seizure threshold) were observed.. The data demonstrate that chronic administration of LEV leads to a significant reduction in anticonvulsant efficacy in the kindling model of temporal lobe epilepsy. Whether this experimental observation has clinical relevance must await monotherapy trials with long-term follow-up of patients who initially responded to LEV.

Topics: Amygdala; Animals; Anticonvulsants; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Tolerance; Epilepsy, Temporal Lobe; Female; Kindling, Neurologic; Levetiracetam; Piracetam; Rats; Rats, Wistar; Substance Withdrawal Syndrome

Epileptogenesis induced by electrical kindling of rats appears to be superior to the acute maximal electroshock seizure (MES) test in normal animals in predicting the efficacy and adverse effect potential of drugs in patients with partial epilepsy. Unfortunately, inclusion of such kindling models in primary screening is hampered by the laborious and expensive procedure of stimulation and recording with implanted brain electrodes. Furthermore the size of the rats excludes their use in initial testing where compound availability is often limited for the 'first batch synthesis'. The present study demonstrates that chronic electrical stimulation with corneal electrodes in mice can rapidly yield large numbers of kindled animals with a seizure phenomenology reflecting partial seizures in man. A pharmacological characterisation showed that corneally kindled mice can be used repeatedly for several drug experiments with reproducible results. The seizure protection and adverse effect potential obtained with proven antiepileptic drugs were similar to the effects observed in amygdala kindled rats and their corresponding clinical profile in partial epilepsy. Protection was obtained with vigabatrin and levetiracetam in this new model despite their lack of anticonvulsant activity in the acute MES test. Furthermore, in agreement with clinical findings with NMDA antagonists, MK-801 revealed more severe adverse effects in corneally kindled mice than in normal animals. These results suggest that corneal kindling of mice represents a sensitive and valid screening model for the identification of new therapies for partial epilepsy in man.

Topics: Amygdala; Animals; Anticonvulsants; Carbamazepine; Cornea; Disease Models, Animal; Dizocilpine Maleate; Drug Evaluation, Preclinical; Electric Stimulation; Electroshock; Epilepsies, Partial; gamma-Aminobutyric Acid; Kindling, Neurologic; Levetiracetam; Male; Mice; Piracetam; Rats; Rats, Sprague-Dawley; Reproducibility of Results; Retina; Seizures; Sensitivity and Specificity; Time Factors; Valproic Acid; Vigabatrin

The protective and adverse effect potentials of levetiracetam ((S)-alpha-ethyl-2-oxo-pyrrolidine acetamide) in rodent models of seizures and epilepsy were compared with the profile of several currently prescribed and newly developed antiepileptic drugs. Levetiracetam was devoid of anticonvulsant activity in the acute maximal electroshock seizure test and in the maximal pentylenetetrazol seizure test in mice (up to 540 mg/kg, i.p.) but exhibited potent protection against generalised epileptic seizures in electrically and pentylenetetrazol-kindled mice (ED50 values = 7 and 36 mg/kg, respectively, i.p.). This differs markedly from established and most new antiepileptic drugs which induce significant protection in both the acute seizure tests and the kindling models. Furthermore, levetiracetam was devoid of anticonvulsant activity in several maximal chemoconvulsive seizure tests although an interesting exception was the potent protection observed against secondarily generalised activity from focal seizures induced by pilocarpine in mice (ED50 value = 7 mg/kg, i.p.), pilocarpine and kainic acid in rats (minimum active dose = 17 and 54 mg/kg, respectively, i.p.). The protection afforded by levetiracetam on the threshold for methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM)-induced seizures persisted after chronic administration (17-170 mg/kg, i.p., twice daily/14 days) and levetiracetam did not lower the seizure threshold for the proconvulsant action of the inverse benzodiazepine receptor agonist, N-methyl-beta-carboline-3-carboxamide (FG 7142). The main metabolite of levetiracetam (ucb L057; (S)-alpha-ethyl-2-oxo-1-pyrrolidine acetic acid) was found to be inactive in sound-sensitive mice after acute administration of doses up to 548 mg/kg, i.p. Levetiracetam induced only minor behavioural alterations in both normal and amygdala-kindled rats (54-1700 mg/kg, i.p.) resulting in an unusually high safety margin between rotarod impairment and seizure suppression of 148 in corneally kindled mice and 235 in Genetic Absence Epilepsy Rats from Strasbourg. In comparison, existing antiepileptic drugs have ratios between 2 and 17 in the corneally kindled mouse model. These studies reveal a unique profile of levetiracetam in rodent models. Characteristics are a general lack of anticonvulsant activity against maximal, acute seizures and selective protection with a very high safety margin in genetic and kindled animals and against chemoconvulsants producing par

Topics: Amygdala; Animals; Anticonvulsants; Behavior, Animal; Carbolines; Convulsants; Diazepam; Disease Models, Animal; Electroconvulsive Therapy; Epilepsy; Excitatory Amino Acid Agonists; Flumazenil; GABA-A Receptor Antagonists; Kindling, Neurologic; Levetiracetam; Male; Mice; Pentylenetetrazole; Piracetam; Rats; Rats, Sprague-Dawley; Seizures