stilbenes and Seizures

Resveratrol (RESV; 3,5,4'-tri-hydroxy stilbene), a naturally occurring phytoalexin, is found at a high concentration in the skin of red grapes and red wine. RESV mediates a wide-range of biological activities, which comprise an increased life span, anti-ischemic, anti-cancer, antiviral, anti-aging and anti-inflammatory properties. Studies in several animal prototypes of brain injury suggest that RESV is an effective neuroprotective compound. Ability to enter the brain after a peripheral administration and no adverse effects on the brain or body are other features that are appealing for using this compound as a therapy for brain injury or neurodegenerative diseases. The goal of this review is to discuss the promise of RESV for treating acute seizures, preventing the acute seizure or status epilepticus induced development of chronic epilepsy, and easing the chronic epilepsy typified by spontaneous recurrent seizures and cognitive dysfunction. First, the various beneficial effects of RESV on the normal brain are discussed to provide a rationale for considering RESV treatment in the management of acute seizures and epilepsy. Next, the detrimental effects of acute seizures or status epilepticus on the hippocampus and the implications of post-status epilepticus changes in the hippocampus towards the occurrence of chronic epilepsy and cognitive dysfunction are summarized. The final segment evaluates studies that have used RESV as a neuroprotective compound against seizures, and proposes studies that are critically needed prior to the clinical application of RESV as a prophylaxis against the development of chronic epilepsy and cognitive dysfunction after an episode of status epilepticus or head injury.

Topics: Animals; Epilepsy; Hippocampus; Humans; Resveratrol; Seizures; Status Epilepticus; Stilbenes

Epilepsy is a common neurological disorder which affects 50 million people worldwide. Patients with epilepsy may present cognitive deficits and psychological impairment. Currently, 30% of patients fail to respond to any available antiseizure drug, and a significant number of patients do not well tolerate the offered treatments. Then, it is necessary to find out alternatives for controlling epileptic seizures. Studies have shown that despite its neuroprotective effects, resveratrol shows poor anticonvulsant properties. Resveratrol analog, piceatannol, possesses higher biological activity than resveratrol and could be an alternative to control seizure. Thus, the present study investigated the effects of resveratrol and piceatannol in pentylenetetrazole-induced seizures in adult zebrafish (Danio rerio). Only the experimental positive control (diazepam) showed anticonvulsant effect in this study. In addition, no behavioral changes were observed 24 h after seizure occurrence. Finally, the expression of genes related to neuronal activity (c-fos), neurogenesis (p70S6Ka and p70S6Kb), inflammatory response (interleukin 1β), and cell apoptosis (caspase-3) did not change by pentylenetetrazole-induced seizures. Therefore, we failed to observe any anticonvulsant and neuroprotective potential of resveratrol and piceatannol in adult zebrafish. However, resveratrol and piceatannol benefits in epilepsy are not discharged, and more studies are necessary.

Topics: Animals; Anticonvulsants; Caspase 3; Diazepam; Epilepsy; Interleukin-1beta; Neuroprotective Agents; Pentylenetetrazole; Resveratrol; Seizures; Stilbenes; Zebrafish

Pterostilbene (PTE), a natural dimethylated analog of resveratrol, possesses numerous health-beneficial properties. The ability of PTE to cross the blood-brain barrier raised the possibility that this compound may modulate central nervous system functions, including seizure activity. The aim of our study was to investigate the activity of PTE in the larval zebrafish pentylenetetrazole (PTZ) seizure assay and three acute seizure tests in mice, i.e., in the maximal electroshock seizure threshold (MEST), 6 Hz-induced psychomotor seizure threshold and intravenous (iv) PTZ tests. Additionally, potential antidepressant activity of PTE was estimated in the forced swim test in mice. The chimney test was used to determine the influence of PTE on motor coordination in mice, while its influence on neuromuscular strength was assessed in the grip strength test in mice. Locomotor activity was determined to verify the results from the forced swim test. PTE revealed an evident anticonvulsant effect both in zebrafish larvae (10 µM; 2 h-incubation) and mice (at doses of 100 and 200 mg/kg, intraperitoneally) but it did not exhibit antidepressant potential in the forced swim test. Furthermore, it did not cause any statistically significant changes in motor coordination, neuromuscular strength and locomotor activity in mice. In conclusion, our present findings demonstrate for the first time the anticonvulsant potential of PTE. The aforementioned results suggest that it might be employed in epilepsy treatment, however, further precise studies are required to verify its activity in other experimental seizure and epilepsy models and its precise mechanism of action should be determined.

Topics: Animals; Anticonvulsants; Antidepressive Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Electroshock; Mice; Muscle Strength; Pentylenetetrazole; Seizures; Stilbenes; Zebrafish

Pterostilbene (PTE), a natural analog of resveratrol, is available both as a diet ingredient and a dietary supplement. The present study was undertaken to assess the effect of PTE on the activity of antiepileptic drugs in the acute seizure tests in mice, i.e., the intravenous pentetrazole (iv PTZ) seizure threshold, maximal electroshock (MES), and 6 Hz-induced psychomotor seizure tests. Our study revealed that PTE enhanced the anticonvulsant effect of clonazepam but did not change the activity of tiagabine in the iv PTZ test. In the MES test, PTE increased the effect of carbamazepine but did not affect the protective properties of topiramate, while in the 6-Hz test, we noted a significant enhancement of the activity of oxcarbazepine, but there were no changes in the activity of valproate. Interactions of PTE with carbamazepine and oxcarbazepine were pharmacokinetic, which was determined by the increase of concentration of these antiepileptic drugs both in the serum and brain. In contrast, interactions between PTE and clonazepam were pharmacodynamic since there were no changes in the concentration of clonazepam. Combined treatment with carbamazepine and PTE significantly attenuated muscular strength (estimated in the grip strength test) but did not change motor coordination (assessed in the chimney test) in mice. Other studied antiepileptic drugs and their combinations with PTE did not change these parameters. Further studies are required to evaluate the influence of PTE on the activity of anticonvulsant drugs to estimate the safety of using PTE by patients with epilepsy.

Topics: Animals; Anticonvulsants; Brain Chemistry; Convulsants; Dose-Response Relationship, Drug; Electroshock; Male; Mice; Pentylenetetrazole; Psychomotor Performance; Resveratrol; Seizures; Stilbenes

There is an urge to identify new molecules which can modulate process of epileptogenesis, since currently available drugs act symptomatically and one-third of the patients remain refractory to the disease. Hence, the present study was conducted to evaluate the effects of Resveratrol (RESV) on epileptogenesis in pentylenetetrazole (PTZ)-induced kindling in mice.. Swiss albino mice were administered RESV (10, 20 and 40 mg/kg,p.o) in acute study. On the seventh day animals were subjected to various neurological and neurobehavioral tests viz, Increasing Current Electroshock Test (ICES), PTZ-induced seizures, passive avoidance response, and elevated plus maze test. For the development of kindling PTZ was administered in a dose of 25 mg/kg, i.p. on every alternate day and RESV in all the three doses was administered daily. Seizure score was continuously monitored till the development of kindling and cognition tests were performed in the end of the study. The animals were sacrificed and levels of inflammatory biomarkers viz., IL-1β, interleukin-1 receptor antagonist (IL1-Ra), IL-6, and TNF-α were assessed in the hippocampus and cortex of the kindled animals.. RESV in all three doses increased the seizure threshold to hind limb extension in the ICES test. RESV in all the tested doses suppressed the development of kindling and reduced the levels of IL-1β, IL1-Ra, IL-6, and TNF-α in kindled mice.. RESV suppressed the development of kindling in mice and decreased the levels of inflammatory biomarkers in their hippocampus. RESV modified brain inflammation during epileptogenesis and found to possess nootropic activity in the kindled mice.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Anticonvulsants; Antioxidants; Avoidance Learning; Cerebral Cortex; Convulsants; Dietary Supplements; Encephalitis; Female; Hippocampus; Inflammation Mediators; Kindling, Neurologic; Male; Maze Learning; Mice; Neurons; Neuroprotective Agents; Pentylenetetrazole; Random Allocation; Resveratrol; Seizures; Stilbenes

Resveratrol (3,4',5-stilbenetriol) is a natural product having diverse anti-inflammatory and antioxidant properties. The compound has a wide spectrum of pharmacological and metabolic activity, including cardioprotective, neuroprotective, anticarcinogenic and anti-aging effects reported in numerous studies. Some reports also suggest potential anticonvulsant properties of resveratrol. In the present study, we used in mice three different seizure models which are routinely applied in preclinical drug discovery. The protective effects of resveratrol were evaluated in the pentylenetetrazole (PTZ), maximal electroshock (MES) and 6-Hz electrical seizure models. Resveratrol (up to 300mg/kg) administered ip (5-60min pre-treatment time) remained without any protective activity against seizures induced in these models. There was only a trend towards a delay in seizure latency, which reached statistical significance after treatment with resveratrol (100mg/kg; 15min) in case of tonic convulsions induced by PTZ. Phenobarbital (PHB, ip, 45min), used as a reference compound, displayed a clear-cut and dose-dependent protection against seizures in all the models. The ED50 values obtained with PHB were as follows: 7.3mg/kg (PTZ model), 13.3mg/kg (MES model) and 29.7mg/kg (6-Hz model). The present data demonstrate that an acute treatment with resveratrol does not provide any significant protection in three seizure models which collectively are able to detect anticonvulsants with diverse mechanisms of action. However, it cannot be excluded that chronic treatment with resveratrol may offer some protection in these or other seizure models.

Topics: Animals; Anticonvulsants; Antioxidants; Disease Models, Animal; Dose-Response Relationship, Drug; Electroshock; Male; Mice; Pentylenetetrazole; Resveratrol; Seizures; Stilbenes; Treatment Failure

Antiepileptic drug therapy, though beneficial for restraining seizures, cannot thwart status epilepticus (SE) induced neurodegeneration or down-stream detrimental changes. We investigated the efficacy of resveratrol (RESV) for preventing SE-induced neurodegeneration, abnormal neurogenesis, oxidative stress and inflammation in the hippocampus. We induced SE in young rats and treated with either vehicle or RESV, commencing an hour after SE induction and continuing every hour for three-hours on SE day and twice daily thereafter for 3 days. Seizures were terminated in both groups two-hours after SE with a diazepam injection. In contrast to the vehicle-treated group, the hippocampus of animals receiving RESV during and after SE presented no loss of glutamatergic neurons in hippocampal cell layers, diminished loss of inhibitory interneurons expressing parvalbumin, somatostatin and neuropeptide Y in the dentate gyrus, reduced aberrant neurogenesis with preservation of reelin + interneurons, lowered concentration of oxidative stress byproduct malondialdehyde and pro-inflammatory cytokine tumor necrosis factor-alpha, normalized expression of oxidative stress responsive genes and diminished numbers of activated microglia. Thus, 4 days of RESV treatment after SE is efficacious for thwarting glutamatergic neuron degeneration, alleviating interneuron loss and abnormal neurogenesis, and suppressing oxidative stress and inflammation. These results have implications for restraining SE-induced chronic temporal lobe epilepsy.

Topics: Animals; Behavior, Animal; Cell Adhesion Molecules, Neuronal; Cell Death; Cognition; Extracellular Matrix Proteins; GABAergic Neurons; Gene Expression Regulation; Hippocampus; Inflammation; Interneurons; Longevity; Male; Microglia; Nerve Degeneration; Nerve Tissue Proteins; Neurogenesis; Neuropeptide Y; Oxidative Stress; Parvalbumins; Rats, Inbred F344; Reelin Protein; Resveratrol; Seizures; Serine Endopeptidases; Somatostatin; Status Epilepticus; Stilbenes; Tumor Necrosis Factor-alpha

Resveratrol is a polyphone chemical found in a number of plant species, including peanuts and grapes, but with significant amounts in red wine. In normal plant physiology, Resveratrol is produced as a defensive response to injury or parasitic attacks. Resveratrol has diverse biological properties and actions with potential clinical applications, including anti-inflammatory, antioxidant, anti proliferative, and neuroprotective effects.. The aim of the present study was to explore the effect and mechanism of Resveratrol in Pentylenetetrazole (PTZ) induced kindling in rats.. In a PTZ kindled Wistar rat model, different doses of Resveratrol (25mg/kg, 50mg/kg and 75 mg/kg) were administered orally 30 min before the PTZ injection. The PTZ injection was given on alternate day till the animal became fully kindled or till 10 weeks. The following parameters were compared between control and various experimental groups: the course of kindling, stages of seizures, histopathological scoring of hippocampus, antioxidant parameters, DNA fragmentation and caspase-3 expression in the hippocampus, and neuron-specific enolase in the blood. One way ANOVA followed by Bonferroni post hoc analysis and Fischer's Exact test were used for statistical analyses.. In the present study, Resveratrol showed dose-dependent anti-seizure effect. Resveratrol (75 mg/kg) significantly increased the latency to myoclonic jerks, clinic seizures as well as generalized tonic-clinic seizures, improved the seizure score and decreased the number of myoclonic jerks. PTZ induced kindling caused a significant neuronal injury, oxidative stress and apoptosis which were reversed by pretreatment with Resveratrol in a dose-dependent manner.. Our study suggests that Resveratrol has a potential antiepileptogenic effect on PTZ-induced kindling in rats. The possible underlying mechanisms of Resveratrol as an antiepileptic agent may be due to its antioxidative property and neuroprotective effect.

Topics: Animals; Anticonvulsants; Antioxidants; Caspase 3; Convulsants; Hippocampus; Kindling, Neurologic; Lipid Peroxidation; Male; Oxidative Stress; Pentylenetetrazole; Phosphopyruvate Hydratase; Rats; Resveratrol; Seizures; Stilbenes

The synergic effect of regular exercise and resveratrol, a polyphenolic compound with potent antioxidant activity, was investigated against kainate-induced seizures and oxidative stress in mice. After 6 weeks of swimming training, the total body weight decreased and the blood concentration of lactate stabilized statistically in comparison with the sedentary mice, indicate that the training program increased the aerobic resistance of mice. Kainate (30 mg/kg) evoked seizure activity 5 min after injection, and seizure activity was measured seizure rating scores every 5 min up to 2 h. As previously well known experiments, regular exercise and resveratrol (40 mg/kg, daily supplementation for 6 weeks) have an inhibitory effect on kainate-induced seizure activity and oxidative stress. In particularly, a synergistic cooperation of regular exercise and resveratrol was observed in seizure activity, mortality and oxidative stress especially in SOD activity. These results suggest that regular exercise along with an anti-convulsant agent such as resveratrol could be a more efficient method for the prevention of seizure development than exercise alone.

Topics: Anaerobic Threshold; Animals; Antioxidants; Body Weight; Catalase; Kainic Acid; Lactic Acid; Male; Mice; Mice, Inbred ICR; Oxidative Stress; Physical Conditioning, Animal; Resveratrol; Seizures; Stilbenes; Superoxide Dismutase; Swimming

Resveratrol (Res) is a phytoalexin produced naturally by several plants, which has multi functional effects such as neuroprotection, anti-inflammatory, and anti-cancer. The present study was to evaluate a possible anti-epileptic effect of Res against kainate-induced temporal lobe epilepsy (TLE) in rat. We performed behavior monitoring, intracranial electroencepholography (IEEG) recording, histological analysis, and Western blotting to evaluate the anti-epilepsy effect of Res in kainate-induced epileptic rats. Res decreased the frequency of spontaneous seizures and inhibited the epileptiform discharges. Moreover, Res could protect neurons against kainate-induced neuronal cell death in CA1 and CA3a regions and depressed mossy fiber sprouting, which are general histological characteristics both in TLE patients and animal models. Western blot revealed that the expression level of kainate receptors (KARs) in hippocampus was reduced in Res-administrated rats compared to that in epileptic ones. These results suggest that Res is a potent anti-epilepsy agent, which protects against epileptogenesis and progression of the kainate-induced TLE animal.

Topics: Animals; Anticonvulsants; Behavior, Animal; Blotting, Western; Cell Death; Electroencephalography; Epilepsy, Temporal Lobe; Excitatory Amino Acid Agonists; In Vitro Techniques; Kainic Acid; Male; Mossy Fibers, Hippocampal; Neurons; Rats; Rats, Wistar; Receptors, Kainic Acid; Resveratrol; Seizures; Stilbenes

The effect of trans-resveratrol (resveratrol), a polyphenolic compound with potent antioxidant activity, was investigated against pentylenetetrazole (PTZ) induced seizures in rats. Resveratrol (20, 40, and 80 mg/kg i.p.) administered 20 min prior to convulsive challenge with PTZ (60 mg/kg i.p.) dose dependently reduced the percent incidence of generalized tonic-clonic convulsions. Resveratrol (40 mg/kg) also potentiated the effect of sodium valproate (150 mg/kg) and diazepam (2 mg/kg) against PTZ-induced seizures. Since adenosine, an endogenous anticonvulsant, has been demonstrated to modulate the action of various antiepileptics, experiments were also carried out to determine whether an adenosinergic mechanism is involved in the anticonvulsant action of resveratrol. When a subanticonvulsant dose of adenosine (500 mg/kg) was administered together with resveratrol, a significant reduction in the percent incidence of generalized tonic-clonic convulsions was observed. Moreover, the nonspecific adenosine receptor antagonist theophylline (50 mg/kg i.p.) significantly reversed the resveratrol-induced protection, whereas the specific adenosine A2 receptor antagonist 3,7-dimethyl-1-propargylxanthine (1 mg/kg i.p.) could not reverse the resveratrol-induced protection. The findings of the present study suggest an antiepileptic potential of resveratrol and that an adenosinergic mechanism may play a role in its anticonvulsant activity.

Topics: Adenosine; Animals; Anticonvulsants; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Injections, Intraperitoneal; Male; Pentylenetetrazole; Purinergic P1 Receptor Antagonists; Rats; Rats, Wistar; Resveratrol; Seizures; Stilbenes; Theophylline

The present study was carried out to investigate the effect of trans-resveratrol, a potent antioxidant, against FeCl3-induced posttraumatic seizures. Male Wistar rats weighing 200-250 g were implanted with epidural electrodes and allowed to recover After the recording of baseline EEG. FeCl3 (5 microl, 100 mM) was administered intracortically over a period of 5 min and EEG was monitored for 2 h. Subsequently, rats were sacrificed for the estimation of oxidative stress markers, ie., malondialdehyde (MDA) and glutathione in whole brain tissue. A sham group was run parallel with saline (pH adjusted) and similar protocol for EEG recording and estimation of oxidative stress markers was followed FeCl3-treated animals exhibited epileptiform EEG changes thigh amplitude sharp waves of increased frequency and polyspikes) within 15 min, which continued throughout the period of observation. The level of MDA was found to be significantly elevated, whereas insignificant change was observed in the level of glutathione. trans-Resveratrol (20 and 40 mg/kg ip.) administered 30 min before FeCl3 injection delayed the onset of the appearance of epileptiform EEG changes. The brain MDA levels were also significantly reduced in the trans-resveratrol-treated animals as compared to the vehicle-treated FeCl3-injected rats. The findings show the protective effect of trans-resveratrol in the FeCl3-induced seizure model of posttraumatic seizures.

Topics: Animals; Antioxidants; Brain; Chlorides; Electroencephalography; Epilepsy, Post-Traumatic; Female; Ferric Compounds; Free Radicals; Glutathione; Injections, Intraventricular; Lipid Peroxidation; Male; Malondialdehyde; Rats; Rats, Wistar; Resveratrol; Seizures; Stilbenes

A series of substituted (omega- aminoalkoxy )stilbene derivatives has been synthesized and screened for anticonvulsant activity. The effect of structural modification of these molecules on the activities has been systematically examined. Potent anticonvulsant activity was displayed by 2-[4-(4-methyl-1 piperazinyl)butoxy]stilbene (20) and some 2-[4-(3-alkoxy-1-piperidino)butoxy]stilbene derivatives (21, 37, 38, and 40), as determined by maximal electroshock seizure (MES) and pentylenetetrazol-induced convulsion tests in mice. Compound 21 exhibited more potent anti-MES activity than diphenylhydantoin and carbamazepine in further pharmacological tests in rats, and its therapeutic index was superior to those of two antiepileptic drugs.

Topics: Animals; Anticonvulsants; Biological Assay; Drug Evaluation, Preclinical; Electroshock; Indicators and Reagents; Male; Mice; Mice, Inbred Strains; Pentylenetetrazole; Rats; Rats, Inbred Strains; Seizures; Stilbenes; Structure-Activity Relationship

Topics: Anesthetics, Local; Animals; Anticonvulsants; Cinnamates; Electroshock; Female; Guinea Pigs; Male; Mice; Pyrans; Seizures; Stilbenes; Styrenes

Topics: Amphetamine; Amphetamines; Analgesics; Analgesics, Non-Narcotic; Antipyretics; Behavior, Animal; Blood Glucose; Body Temperature; Central Nervous System; Coumarins; Electroshock; Fluorescent Dyes; Hypnotics and Sedatives; Injections, Intraperitoneal; Mice; Neurochemistry; Pharmacology; Pyrazoles; Rabbits; Rats; Research; Respiration; Seizures; Stilbenes; Strychnine; Toxicology