minocycline and Seizures

Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by a loss of the maternally inherited UBE3A; the paternal UBE3A is silenced in neurons by a mechanism involving an antisense transcript (UBE3A-AS). We reviewed the published information on clinical trials that have been completed as well as the publicly available information on ongoing trials of therapies for AS. Attempts at hypermethylating the maternal locus through dietary compounds were ineffective. The results of a clinical trial using minocycline as a matrix metalloproteinase-9 inhibitor were inconclusive; another clinical trial is underway. Findings from a clinical trial using L-dopa to alter phosphorylation of calcium/calmodulin-dependent kinase II are awaited. Topoisomerase inhibitors and antisense oligonucleotides are being developed to directly inhibit UBE3A-AS. Other strategies targeting specific pathways are briefly discussed. We also reviewed the medications that are currently used to treat seizures and sleep disturbances, which are two of the more debilitating manifestations of AS.

Topics: Angelman Syndrome; Animals; Clinical Trials as Topic; Disease Models, Animal; Gene Silencing; Levodopa; Mice; Minocycline; Oligoribonucleotides, Antisense; Seizures; Sleep Wake Disorders; Topoisomerase Inhibitors; Ubiquitin-Protein Ligases

Topics: Ampicillin; Bacterial Infections; Brain Edema; Child, Preschool; Chloramphenicol; Cloxacillin; Gentamicins; Haemophilus influenzae; Humans; Infant; Infant, Newborn; Injections, Spinal; Meningitis; Meningitis, Haemophilus; Meningitis, Meningococcal; Meningitis, Pneumococcal; Methicillin; Minocycline; Neisseria meningitidis; Penicillin G; Rifampin; Seizures; Shock; Streptococcus pneumoniae; Sulfonamides

Severe hypoxia induces seizures, which reduces ventilation and worsens the ictal state. It is a health threat to patients, particularly those with underlying hypoxic respiratory pathologies, which may be conducive to a sudden unexpected death in epilepsy (SUDEP). Recent studies provide evidence that brain microglia are involved with both respiratory and ictal processes. Here, we investigated the hypothesis that microglia could interact with hypoxia-induced seizures. To this end, we recorded electroencephalogram (EEG) and acute ventilatory responses to hypoxia (5% O

Topics: Animals; Brain; Hypoxia; Mice; Microglia; Minocycline; Seizures

Epilepsy is one of the most common neurological disorders, with individuals having an increased susceptibility of seizures in the first few years of life, making children at risk of developing a multitude of cognitive and behavioral comorbidities throughout development. The present study examined the role of PI3K/Akt/mTOR pathway activity and neuroinflammatory signaling in the development of autistic-like behavior following seizures in the neonatal period. Male and female C57BL/6J mice were administered 3 flurothyl seizures on postnatal (PD) 10, followed by administration of minocycline, the mTOR inhibitor rapamycin, or a combined treatment of both therapeutics. On PD12, isolation-induced ultrasonic vocalizations (USVs) of mice were examined to determine the impact of seizures and treatment on communicative behaviors, a component of the autistic-like phenotype. Seizures on PD10 increased the quantity of USVs in female mice and reduced the amount of complex call types emitted in males compared to controls. Inhibition of mTOR with rapamycin significantly reduced the quantity and duration of USVs in both sexes. Changes in USVs were associated with increases in mTOR and astrocyte levels in male mice, however, three PD10 seizures did not result in enhanced proinflammatory cytokine expression in either sex. Beyond inhibition of mTOR activity by rapamycin, both therapeutics did not demonstrate beneficial effects. These findings emphasize the importance of differences that may exist across preclinical seizure models, as three flurothyl seizures did not induce as drastic of changes in mTOR activity or inflammation as observed in other rodent models.

Topics: Animals; Convulsants; Disease Models, Animal; Epilepsy; Female; Flurothyl; Immunologic Factors; Male; Mice; Mice, Inbred C57BL; Minocycline; MTOR Inhibitors; Seizures; Sex Factors; Sirolimus; Vocalization, Animal

Topics: Acetaldehyde Dehydrogenase Inhibitors; Acidosis; Anti-Bacterial Agents; Brain; Chronic Disease; Clinical Deterioration; Consciousness Disorders; Diagnostic Errors; Disulfiram; Electroencephalography; Fatal Outcome; Humans; Inappropriate Prescribing; Lyme Disease; Magnetic Resonance Imaging; Male; Middle Aged; Minocycline; Patient Care; Respiration, Artificial; Seizures; Tinidazole

Acute cocaine intoxication is one of the important causes of admission to emergency department, especially in western countries. We aimed to compare the efficacies of tetracycline, minocycline, doxycycline in the prevention of seizures and deaths in mice due to cocaine intoxication.. In the study, a total of 120 balb-c male mice weighing 25-30 g were randomized into 4 groups as tetracycline 255 mg/kg, minocycline 170 mg/kg, doxycycline 157 mg/kg, 0.5 ml saline (placebo). The doses of tetracycline, minocycline and doxycycline are the calculated ED50 values. The mice in the groups received 93 mg/kg cocaine intraperitoneally 10 min after drug administration. The dose of cocaine is 50% of the lethal dose. After cocaine injection, all mice were observed for 30 min in terms of cocaine toxicity findings. Mortality rates, death times, seizure activities, and seizure onset times of the mice were clinically evaluated in an observational way.. There were significant differences among all the groups in terms of seizure and lethality (p < 0.001). The ratio of animals with seizures was significantly lower in the minocycline (73.3%), and doxycycline (73.3%) groups (all p = 0.040). The ratio of animals with lethality was significantly lower in the minocycline (23.3%) group compared with vehicle (p < 0.001).. In our acute cocaine intoxication model, minocycline was effective in terms of lethality and preventing seizures, doxycycline was effective in preventing seizures.

Topics: Animals; Anti-Bacterial Agents; Cocaine; Dose-Response Relationship, Drug; Doxycycline; Drug Overdose; Illicit Drugs; Male; Mice; Mice, Inbred BALB C; Minocycline; Random Allocation; Seizures; Tetracycline; Toxicity Tests; Treatment Outcome

Topics: Animals; Dose-Response Relationship, Drug; Lipopolysaccharides; Male; Mice; Minocycline; Mitochondria; NG-Nitroarginine Methyl Ester; Nitric Oxide; Seizures

Topics: Animals; Anticonvulsants; Arginine; Enzyme Inhibitors; Hippocampus; Male; Mice; Minocycline; Nitric Oxide; Nitric Oxide Synthase; Nitrites; Pentylenetetrazole; Receptors, N-Methyl-D-Aspartate; Seizures; Time Factors

The incidence of sudden unexpected death in epilepsy (SUDEP) is highest in people with chronic and drug-resistant epilepsy. Chronic spontaneous recurrent seizures cause cardiorespiratory autonomic dysfunctions. Pituitary adenylate cyclase-activating polypeptide (PACAP) is neuroprotective, whereas microglia produce both pro- and anti-inflammatory effects in the CNS. During acute seizures in rats, PACAP and microglia produce sympathoprotective effect at the intermediolateral cell column (IML), whereas their action on the presympathetic rostral ventrolateral medulla (RVLM) neurons mediates proarrhythmogenic changes. We evaluated the effect of PACAP and microglia at the IML on sympathetic nerve activity (SNA), cardiovascular reflex responses, and electrocardiographic changes in the post-status epilepticus (SE) model of acquired epilepsy, and control rats. Chronic spontaneous seizures in rats produced tachycardia with profound proarrhythmogenic effects (prolongation of QT interval). Antagonism of microglia, but not PACAP, significantly reduced the SNA and the corrected QT interval in post-SE rats. PACAP and microglia antagonists did not change baroreflex and peripheral or central chemoreflex responses with varied effect on somatosympathetic responses in post-SE and control rats. We did not notice changes in microglial morphology or changes in a number of M2 phenotype in epileptic nor control rats in the vicinity of RVLM neurons. Our findings establish that microglial activation, and not PACAP, at the IML accounts for higher SNA and proarrhythmogenic changes during chronic epilepsy in rats. This is the first experimental evidence to support a neurotoxic effect of microglia during chronic epilepsy, in contrast to their neuroprotective action during acute seizures.

Topics: Animals; Baroreflex; Blood Pressure; Chronic Disease; Epilepsy, Temporal Lobe; Male; Microglia; Minocycline; Neurons; Pituitary Adenylate Cyclase-Activating Polypeptide; Rats, Wistar; Seizures; Sympathetic Nervous System

The tetracycline antibiotic minocycline can exert strong anti-inflammatory, antioxidant, and antiapoptotic effects. There is cumulating evidence that epileptogenic brain insults trigger neuroinflammation and anti-inflammatory concepts can modulate the process of epileptogenesis. Based on the mechanisms of action discussed for minocycline, the compound is of interest for intervention studies as it can prevent the polarization of microglia into a pro-inflammatory state. Here, we assessed the efficacy of sub-chronic minocycline administration initiated immediately following an electrically-induced status epilepticus in rats. The treatment did not affect the development of spontaneous seizures. However, minocycline attenuated behavioral long-term consequences of status epilepticus with a reduction in hyperactivity and hyperlocomotion. Furthermore, the compound limited the spatial learning deficits observed in the post-status epilepticus model. The typical status epilepticus-induced neuronal cell loss was evident in the hippocampus and the piriform cortex. Minocycline exposure selectively protected neurons in the piriform cortex and the hilus, but not in the hippocampal pyramidal layer. In conclusion, the data argue against an antiepileptogenic effect of minocycline in adult rats. However, the findings suggest a disease-modifying impact of the tetracycline affecting the development of behavioral co-morbidities, as well as long-term consequences on spatial learning. In addition, minocycline administration resulted in a selective neuroprotective effect. Although strong anti-inflammatory effects have been proposed for minocycline, we could not verify these effects in our experimental model. Considering the multitude of mechanisms claimed to contribute to minocycline's effects, it is of interest to further explore the exact mechanisms underlying the beneficial effects in future studies.

Topics: Animals; Anticonvulsants; Behavior, Animal; Cerebral Cortex; Electric Stimulation; Female; Hippocampus; Maze Learning; Microglia; Minocycline; Motor Activity; Neurons; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Seizures; Status Epilepticus

Cardiovascular autonomic dysfunction in seizure is a major cause of sudden unexpected death in epilepsy. The catecholaminergic neurons in the rostral ventrolateral medulla (RVLM) maintain sympathetic vasomotor tone and blood pressure through their direct excitatory projections to the intermediolateral (IML) cell column. Glutamate, the principal excitatory neurotransmitter in brain, is increased in seizures. Pituitary adenylate cyclase activating polypeptide (PACAP) is an excitatory neuropeptide with neuroprotective properties, whereas microglia are key players in inflammatory responses in CNS. We investigated the roles of glutamate, PACAP, and microglia on RVLM catecholaminergic neurons during the cardiovascular responses to 2 mg/kg kainic acid (KA)-induced seizures in urethane anesthetized, male Sprague Dawley rats. Microinjection of the glutamate antagonist, kynurenic acid (50 nl; 100 mM) into RVLM, blocked the seizure-induced 43.2 ± 12.6% sympathoexcitation (p ≤ 0.05), and abolished the pressor responses, tachycardia, and QT interval prolongation. PACAP or microglia antagonists (50 nl) (PACAP(6-38), 15 pmol; minocycline 10 mg/ml) microinjected bilaterally into RVLM had no effect on seizure-induced sympathoexcitation, pressor responses, or tachycardia but abolished the prolongation of QT interval. The actions of PACAP or microglia on RVLM neurons do not cause sympathoexcitation, but they do elicit proarrhythmogenic changes. An immunohistochemical analysis in 2 and 10 mg/kg KA-induced seizure rats revealed that microglia surrounding catecholaminergic neurons are in a "surveillance" state with no change in the number of M2 microglia (anti-inflammatory). In conclusion, seizure-induced sympathoexcitation is caused by activation of glutamatergic receptors in RVLM that also cause proarrhythmogenic changes mediated by PACAP and microglia.. Sudden unexpected death in epilepsy is a major cause of death in epilepsy. Generally, seizures are accompanied by changes in brain function leading to uncontrolled nerve activity causing high blood pressure, rapid heart rate, and abnormal heart rhythm. Nevertheless, the brain chemicals causing these cardiovascular changes are unknown. Chemicals, such as glutamate and pituitary adenylate cyclase activating polypeptide, whose expression is increased after seizures, act on specific cardiovascular nuclei in the brain and influence the activity of the heart, and blood vessels. Microglia, which manage excitation in the brain, are commonly activated after seizure and produce pro- and/or anti-inflammatory factors. Hence, we aimed to determine the effects of blocking glutamate, pituitary adenylate cyclase activating polypeptide, and microglia in the RVLM and their contribution to cardiovascular autonomic dysfunction in seizure.

Topics: Animals; Calcium-Binding Proteins; Cardiovascular Abnormalities; Disease Models, Animal; Excitatory Amino Acid Antagonists; Gamma Rhythm; Kainic Acid; Male; Medulla Oblongata; Microfilament Proteins; Microglia; Minocycline; Peptide Fragments; Pituitary Adenylate Cyclase-Activating Polypeptide; Rats; Rats, Sprague-Dawley; Receptors, Glutamate; Seizures; Splanchnic Nerves; Tyrosine 3-Monooxygenase; Vagotomy

Alcohol use disorder (AUD) is a spectrum disorder characterized by mild to severe symptoms, including potential withdrawal signs upon cessation of consumption. Approximately five hundred thousand patients with AUD undergo clinically relevant episodes of withdrawal annually (New Engl J Med, 2003, 348, 1786). Recent evidence indicates potential for drugs that alter neuroimmune pathways as new AUD therapies. We have previously shown the immunomodulatory drugs, minocycline and tigecycline, were effective in reducing ethanol (EtOH) consumption in both the 2-bottle choice and drinking-in-the-dark paradigms. Here, we test the hypothesis that tigecycline, a tetracycline derivative, will reduce the severity of EtOH withdrawal symptoms in a common acute model of alcohol withdrawal (AWD) using a single anesthetic dose of EtOH in seizure sensitive DBA/2J (DBA) mice.. Naïve adult female and male DBA mice were given separate injections of 4 g/kg i.p. EtOH with vehicle or tigecycline (0, 20, 40, or 80 mg/kg i.p.). The 80 mg/kg dose was tested at 3 time points (0, 4, and 7 hours) post EtOH treatment. Handling-induced convulsions (HICs) were measured before and then over 12 hours following EtOH injection. HIC scores and areas under the curve were tabulated. In separate mice, blood EtOH concentrations (BECs) were measured at 2, 4, and 7 hours postinjection of 4 g/kg i.p. EtOH in mice treated with 0 and 80 mg/kg i.p. tigecycline.. AWD symptom onset, peak magnitude, and overall HIC severity were reduced by tigecycline drug treatment compared to controls. Tigecycline treatment was effective regardless of timing throughout AWD, with earlier treatment showing greater efficacy. Tigecycline showed a dose-responsive reduction in acute AWD convulsions, with no sex differences in efficacy. Importantly, tigecycline did not affect BECs over a time course of elimination.. Tigecycline effectively reduced AWD symptoms in DBA mice at all times and dosages tested, making it a promising lead compound for development of a novel pharmacotherapy for AWD. Further studies are needed to determine the mechanism of tigecycline action.

Topics: Animals; Dose-Response Relationship, Drug; Ethanol; Female; Male; Mice; Mice, Inbred DBA; Minocycline; Seizures; Substance Withdrawal Syndrome; Tigecycline

Mounting evidence suggests that brain inflammation mediated by glial cells may contribute to epileptogenesis. Minocycline is a second-generation tetracycline and has potent antiinflammatory effects independent of its antimicrobial action. The present study aimed to investigate whether minocycline could exert antiepileptogenic effects in a rat lithium-pilocarpine model of temporal lobe epilepsy. The temporal patterns of microglial and astrocytic activation were examined in the hippocampal CA1 and the adjacent cortex following pilocarpine-induced status epilepticus (SE). These findings displayed that SE caused acute and persistent activation of microglia and astrocytes. Based on these findings, Minocycline was administered once daily at 45 mg/kg for 14 days following SE. Six weeks after termination of minocycline treatment, spontaneous recurrent seizures (SRS) were recorded by continuous video monitoring. Minocycline inhibited the SE-induced microglial activation and the increased production of interleukin-1β and tumor necrosis factor-α in the hippocampal CA1 and the adjacent cortex, without affecting astrocytic activation. In addition, Minocycline prevented the SE-induced neuronal loss in the brain regions examined. Moreover, minocycline significantly reduced the frequency, duration, and severity of SRS during the two weeks monitoring period. These results demonstrated that minocycline could mitigate SE-induced brain inflammation and might exert disease-modifying effects in an animal model of temporal lobe epilepsy. These findings offer new insights into deciphering the molecular mechanisms of epileptogenesis and exploring a novel therapeutic strategy for prevention of epilepsy.

Topics: Animals; Anti-Inflammatory Agents; Anticonvulsants; Cerebral Cortex; Electroencephalography; Encephalitis; Epilepsy, Temporal Lobe; Hippocampus; Male; Minocycline; Neuroglia; Pilocarpine; Rats; Rats, Sprague-Dawley; Seizures; Status Epilepticus

Seizures are accompanied by cardiovascular changes that are a major cause of sudden unexpected death in epilepsy (SUDEP). Seizures activate inflammatory responses in the cardiovascular nuclei of the medulla oblongata and increase neuronal excitability. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide with autocrine and paracrine neuroprotective properties. Microglia are key players in inflammatory responses in the CNS. We sought to determine whether PACAP and microglia mitigate the adverse effects of seizure on cardiovascular function in a rat model of temporal lobe epilepsy. Kainic acid (KA)-induced seizures increased splanchnic sympathetic nerve activity by 97%, accompanied by increase in heart rate (HR) but not blood pressure (BP). Intrathecal infusion of the PACAP antagonist PACAP(6-38) or the microglia antagonists minocycline and doxycycline augmented sympathetic responses to KA-induced seizures. PACAP(6-38) caused a 161% increase, whereas minocycline and doxycycline caused a 225% and 215% increase, respectively. In intrathecal PACAP-antagonist-treated rats, both BP and HR increased, whereas after treatment with microglial antagonists, only BP was significantly increased compared with control. Our findings support the idea that PACAP and its action on microglia at the level of the spinal cord elicit cardioprotective effects during seizure. However, intrathecal PACAP did not show additive effects, suggesting that the agonist effect was at maximum. The protective effect of microglia may occur by adoption of an M2 phenotype and expression of factors such as TGF-β and IL-10 that promote neuronal quiescence. In summary, therapeutic interventions targeting PACAP and microglia could be a promising strategy for preventing SUDEP.

Topics: Animals; Arrhythmias, Cardiac; Blood Pressure; Doxycycline; Epilepsy, Temporal Lobe; Heart; Heart Rate; Male; Microglia; Minocycline; Peptide Fragments; Pituitary Adenylate Cyclase-Activating Polypeptide; Rats; Rats, Sprague-Dawley; Seizures; Spinal Cord; Sympathetic Nervous System

Inflammation is one of the mechanisms involved in seizure induction. In this study, the effect of minocycline, an anti-inflammatory drug, was investigated on kindling acquisition. Chemical kindling was induced by injection of a subthreshold dose of pentylenetetrazol (PTZ; 37.5 mg/kg) in mice on every other day. Two groups of animals received minocycline (25 mg/kg) at 1 h before or 1 h after PTZ injection. Following the last PTZ injection, the changes in gene expression of TNF-α receptor, γ2 subunit of GABAA receptor and NR2A subunit of NMDA receptor were assessed in the hippocampus and piriform cortex. Injection of minocycline before PTZ increased the latency to stage 4 seizure, and decreased the duration of stages 4 and 5 seizure. It also prevented the increase in the mRNA of NR2A subunit of NMDA receptor in the hippocampus and removed the PTZ-induced increase in mRNA of γ2 subunit of GABAA receptor in piriform cortex of PTZ kindled mice. Minocycline also prevented the increase in TNF-α receptor gene expression in both hippocampus and piriform cortex. Injection of minocycline after PTZ had no significant effect on measured parameters. Therefore, it can be concluded that minocycline may exert an anticonvulsant effect through preventing the increase in GABAA and NMDA receptor subunits. These effects are accompanied by a reduction in an important inflammation index, TNF-α receptor.

Topics: Animals; Anti-Inflammatory Agents; Anticonvulsants; Disease Models, Animal; Gene Expression; Hippocampus; Kindling, Neurologic; Male; Mice; Minocycline; Pentylenetetrazole; Piriform Cortex; Receptors, GABA-A; Receptors, N-Methyl-D-Aspartate; Receptors, Tumor Necrosis Factor; RNA, Messenger; Seizures

Minocycline is known as a chemical with neuroprotective, anti-inflammatory, and antimicrobial properties. In this study, the effects of minocycline on seizures induced by amygdala kindling in rats were studied.. Kindled Wistar rats were injected intraperitoneally with saline and, on the following day, with minocycline (50, 25, and 12.5mg/kg for the three groups (1-3), respectively). The animals in groups 1-3 had similar protocols. Groups 4 and 5 were given for the rotarod test and received 25 or 50mg/kg minocycline, respectively, without any kindling stimulation. The animals in groups 6 and 7 (seven each) received 25mg/kg minocycline or saline, respectively. All the injections were carried out 1h before kindling stimulation. Seizure parameters, including after discharge duration (ADD), stage 4 latency (S4L), stage 5 duration (S5D), and seizure duration (SD), were recorded and compared with those of the saline groups.. Minocycline (50mg/kg) significantly reduced ADD, 1/S4L, S5D, and SD (P<0.001, P<0.05, P<0.001, and P<0.001, respectively) in group 1. While the administration of 25mg/kg of minocycline decreased the ADD and S5D (P<0.05), in group 2. The injection of 12.5mg/kg resulted in decreased S5D (P<0.001) in group 3. The daily injection of minocycline (25mg/kg) significantly decreased ADD, S5D, and SD (P<0.001) in group 6.. The obtained results revealed that minocycline has anticonvulsant effect on seizures induced by amygdala kindling. Thus, it may be useful for epilepsy treatment.

Topics: Amygdala; Animals; Anticonvulsants; Disease Models, Animal; Electric Stimulation; Kindling, Neurologic; Minocycline; Rats; Rats, Wistar; Seizures; Treatment Outcome

Our aim was to examine whether neonatal lipopolysaccharide (LPS) exposure is associated with changes in microglia and whether these alternations could influence later seizure-induced neurobehavioral outcomes. Male pups were first injected intraperitoneally with either LPS or saline on postnatal day 3 (P3) and postnatal day 5 (P5). Immunohistochemical analysis showed that LPS-treated animals exhibited increased microglia activation that persisted into adolescence. At P45, seizures were induced in rats by intraperitoneal injection of kainic acid (KA). Rats treated with LPS neonatally showed significantly greater proinflammatory responses and performed significantly worse in the Y-maze, Morris water maze, and inhibitory avoidance tasks after KA insult. Treatment with minocycline at the time of neonatal LPS exposure to block LPS-induced microglia alternation attenuated the exaggerated neuroinflammatory responses and alleviated memory impairment associated with the KA insult. Our findings suggest that neonatal immune activation can predispose the brain to exacerbated behavioral deficits following seizures in adulthood, possibly by priming microglia.

Topics: Analysis of Variance; Animals; Animals, Newborn; Avoidance Learning; Cytokines; Disease Models, Animal; Female; Hippocampus; Kainic Acid; Lipopolysaccharides; Male; Maze Learning; Memory Disorders; Minocycline; Pregnancy; Rats; Rats, Sprague-Dawley; RNA, Messenger; Seizures; Time Factors; Up-Regulation

Innate immunity mediated by microglia appears to play a crucial role in initiating and propagating seizure-induced inflammatory responses. To address the role of activated microglia in the pathogenesis of childhood epilepsy, we first examined the time course of microglia activation following kainic acid-induced status epilepticus (KA-SE) in Cx3cr1(GFP/+) transgenic mice whose microglia are fluorescently labeled. We then determined whether this seizure-induced microglia activation primes the central immune response to overreact and to increase the susceptibility to a second seizure later in life. We used an inhibitor of microglia activation, minocycline, to block the seizure-induced inflammation to determine whether innate immunity plays a causal role in mediating the long-term epileptogenic effects of early-life seizure. First status epilepticus was induced at postnatal day (P) 25 and a second status at P39. KA-SE at P25 caused nearly a two-fold increase in microglia activation within 24h. Significant seizure-induced activation persisted for 7 days and returned to baseline by 14 days. P39 animals with prior exposure to KA-SE not only responded with greater microglial activation in response to "second hit" of KA, but shorter latency to express seizures. Inhibition of seizure-induced inflammation by 7 day minocycline post-treatment abrogated both the exaggerated microglia activation and the increased susceptibility to the second seizure later in life. The priming effect of early-life seizures is accompanied by modified and rapidly reactivated microglia. Our results suggest that anti-inflammatory therapy after SE may be useful to block the epileptogenic process and mitigate the long-term damaging effects of early-life seizures.

Topics: Animals; Animals, Newborn; Mice; Mice, Transgenic; Microglia; Minocycline; Neural Inhibition; Seizures; Time Factors

Increasing evidence suggests the role of inflammation in enhancing neuronal excitability and contributing to epileptogenesis. Tetracycline-class antibiotics minocycline, doxycycline and tetracycline have been shown to have anti-apoptotic and anti-inflammatory effects.. We investigated the anti-seizure effects of tetracycline-class antibiotics minocycline, doxycycline and tetracycline in vivo by using the maximal electric shock (MES), 6-Hz (minimal clonic seizure) test and subcutaneous Metrazol (scMET) models of epilepsy.. Minocycline, doxycycline and tetracycline showed anticonvulsant effects in abolishing partial seizures in the mouse 6-Hz seizure test. A dose-dependent effect was found, with ED(50) of 170 mg/kg for minocycline, 157 mg/kg for doxycycline, and 255 mg/kg for tetracycline with peak onset at 0.5h. At high doses, minocycline (250 mg/kg) and doxycycline (150 mg/kg) also had toxic effects, from motor impairments to respiratory failure and death. These drugs had no effects on the MES and scMET tests.. In the three tests of anti-seizure activity, minocycline, doxycycline, and tetracycline were found to be protective in one: the 6-Hz seizure model. Our data suggest that minocycline and other tetracycline-class drugs may offer some degree of anticonvulsant effect in the setting of CNS disease trials.

Topics: Animals; Anti-Bacterial Agents; Anticonvulsants; Dose-Response Relationship, Drug; Doxycycline; Epilepsies, Partial; Male; Mice; Minocycline; Neurons; Rats; Rats, Sprague-Dawley; Seizures; Tetracycline

Epileptogenesis is defined as the process of developing epilepsy - a disorder characterized by recurrent seizures - following an initial insult. Neuronal death, aberrant synaptic plasticity and neuroinflammation play essential roles in epileptogenesis. An effective neuroprotective therapeutic agent should counteract one or, ideally, all the above-mentioned mechanisms. However, antiepileptic drugs obtainable nowadays can only suppress seizures, without antiepileptogenic effects. Matrix metalloproteinase-9 (MMP-9) is a member of matrix metalloproteinase (MMP) family that remodels the extracellular matrix. Recently, cumulative evidence indicates that MMP-9, a key participant in neuronal death, aberrant synaptic plasticity and neuroinflammation, is upregulated in experimental epilepsy models. Increased MMP-9 is also implicated in clinical epilepsy studies. Thus, we hypothesize that MMP-9 may be a novel therapeutic target for epilepsy and some agents, such as S24994, atorvastatin and minocycline, may be potential antiepileptogenic drugs.

Topics: Animals; Anti-Bacterial Agents; Atorvastatin; Epilepsy; Gene Expression Regulation, Enzymologic; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Matrix Metalloproteinase 9; Mice; Minocycline; Models, Biological; Neurons; Pyrroles; Rats; Seizures; Treatment Outcome

Cells that can participate in an innate immune response within the central nervous system (CNS) include infiltrating cells (polymorphonuclear leukocytes [PMNs], macrophages, and natural killer [NK] cells) and resident cells (microglia and sometimes astrocytes). The proinflammatory cytokine interleukin-6 (IL-6) is produced by all of these cells and has been implicated in the development of behavioral seizures in the Theiler's murine encephalomyelitis virus (TMEV)-induced seizure model. The assessment, via PCR arrays, of the mRNA expression levels of a large number of chemokines (ligands and receptors) in TMEV-infected and mock-infected C57BL/6 mice both with and without seizures did not clearly demonstrate the involvement of PMNs, monocytes/macrophages, or NK cells in the development of seizures, possibly due to overlapping function of the chemokines. Additionally, C57BL/6 mice unable to recruit or depleted of infiltrating PMNs and NK cells had seizure rates comparable to those of controls following TMEV infection, and therefore PMNs and NK cells do not significantly contribute to seizure development. In contrast, C57BL/6 mice treated with minocycline, which affects monocytes/macrophages, microglial cells, and PMNs, had significantly fewer seizures than controls following TMEV infection, indicating monocytes/macrophages and resident microglial cells are important in seizure development. Irradiated bone marrow chimeric mice that were either IL-6-deficient mice reconstituted with wild-type bone marrow cells or wild-type mice reconstituted with IL-6-deficient bone marrow cells developed significantly fewer behavioral seizures following TMEV infection. Therefore, both resident CNS cells and infiltrating cells are necessary for seizure development.

Topics: Animals; Antibodies, Monoclonal; Central Nervous System; Chemokines; Encephalitis, Viral; Immunohistochemistry; Interleukin-6; Male; Mice; Mice, Inbred C57BL; Minocycline; Neutrophils; Polymerase Chain Reaction; Seizures; Theilovirus

Theiler's murine encephalomyelitis virus infection of C57BL/6 mice results in acute behavioral seizures in 50% of the mice. Treatment of infected mice with minocycline or infection of interleukin (IL)-6-deficient chimeric mice results in a significant decrease in the number of mice developing seizures. However, in those mice that do develop seizures, the pathological changes (neuronal cell loss, inflammation [perivascular cuffing, gliosis, activated microglia/macrophages]), and the numbers of virus infected cells in minocycline-treated or IL-6-deficient chimeric mice are very similar. Therefore, once seizures develop, the pathological changes are consistent regardless of the treatment or genetic background.

Topics: Animals; Astrocytes; Cardiovirus Infections; Disease Models, Animal; Gliosis; Interleukin-6; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Microglia; Minocycline; Seizures; Theilovirus

Cannabinoid-derived drugs are promising agents for the development of novel neuroprotective strategies. Activation of neuronal CB(1) cannabinoid receptors attenuates excitotoxic glutamatergic neurotransmission, triggers prosurvival signalling pathways and palliates motor symptoms in animal models of neurodegenerative disorders. However, in Huntington's disease there is a very early downregulation of CB(1) receptors in striatal neurons that, together with the undesirable psychoactive effects triggered by CB(1) receptor activation, foster the search for alternative pharmacological treatments. Here, we show that CB(2) cannabinoid receptor expression increases in striatal microglia of Huntington's disease transgenic mouse models and patients. Genetic ablation of CB(2) receptors in R6/2 mice, that express human mutant huntingtin exon 1, enhanced microglial activation, aggravated disease symptomatology and reduced mice lifespan. Likewise, induction of striatal excitotoxicity in CB(2) receptor-deficient mice by quinolinic acid administration exacerbated brain oedema, microglial activation, proinflammatory-mediator state and medium-sized spiny neuron degeneration. Moreover, administration of CB(2) receptor-selective agonists to wild-type mice subjected to excitotoxicity reduced neuroinflammation, brain oedema, striatal neuronal loss and motor symptoms. Studies on ganciclovir-induced depletion of astroglial proliferation in transgenic mice expressing thymidine kinase under the control of the glial fibrillary acidic protein promoter excluded the participation of proliferating astroglia in CB(2) receptor-mediated actions. These findings support a pivotal role for CB(2) receptors in attenuating microglial activation and preventing neurodegeneration that may pave the way to new therapeutic strategies for neuroprotection in Huntington's disease as well as in other neurodegenerative disorders with a significant excitotoxic component.

Topics: Animals; Anti-Bacterial Agents; Biomarkers; Corpus Striatum; Humans; Huntingtin Protein; Huntington Disease; Magnetic Resonance Imaging; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microglia; Minocycline; Nerve Degeneration; Nerve Tissue Proteins; Neuroprotective Agents; Nuclear Proteins; Quinolinic Acid; Receptor, Cannabinoid, CB2; Rotarod Performance Test; Seizures

Topics: Abscess; Aged; Anti-Bacterial Agents; Brain Abscess; Focal Infection; Humans; Immunocompetence; Male; Minocycline; Nocardia asteroides; Nocardia Infections; Seizures; Skin Diseases, Bacterial; Trimethoprim, Sulfamethoxazole Drug Combination