Animal Models Of Seizures Research Articles

What new modeling approaches will help us identify promising drug treatments?

Despite the development of numerous novel antiepileptic drugs (AEDs) in recent years, several unmet clinical needs remain, including resistance to AEDs in about 30 % of patients with epilepsy, adverse effects of AEDs that can reduce quality of life, and the lack of treatments that can prevent development of epilepsy in patients at risk. Animal models of seizures and epilepsy have been instrumental in the discovery and preclinical development of novel AEDs, but obviously the previously used models have failed to identify drugs that address unmet medical needs. Thus, we urgently need fresh ideas for improving preclinical AED development. In this review, a number of promising models will be described, including the use of simple vertebrates such as zebrafish (Danio rerio), large animal models such as the dog and newly characterized rodent models of pharmacoresistant epilepsy. While these strategies, like any animal model approach also have their limitations, they offer hope that new more effective AEDs will be identified in the coming years.

Nicotine decreases the activity of glutamate transporter type 3

Nicotine, the main ingredient of tobacco, elicits seizures in animal models and cigarette smoking is regarded as a behavioral risk factor associated with epilepsy or seizures. In the hippocampus, the origin of nicotine-induced seizures, most glutamate uptake could be performed primarily by excitatory amino acid transporter type 3 (EAAT3). An association between temporal lobe epilepsy and EAAT3 downregulation has been reported. Therefore, we hypothesized that nicotine may elicit seizures through the attenuation of EAAT3 activity. We investigated chronic nicotine exposure (72h) cause reduction of the activity of EAAT3 in a Xenopus oocyte expression system using a two-electrode voltage clamp. The roles of protein kinase C (PKC) and phosphatidylinositol 3-kinase (PI3K) were also determined. Nicotine (0.001–1μM) resulted in a time- and dose-dependent decrease in EAAT3 activity with maximal inhibition at nicotine concentrations of 0.03μM or higher and at an exposure time of 72h. Vmax on the glutamate response was significantly reduced in the nicotine group (0.03μM for 72h), but the Km value of EAAT3 for glutamate was not altered. When nicotine-exposed oocytes (0.03μM for 72h) were pretreated with phorbol-12-myristate-13-acetate (PMA, a PKC activator), the nicotine-induced reduction in EAAT3 activity was abolished. PKC inhibitors (staurosporine, chelerythrine, and calphostin C) significantly reduced basal EAAT3 activity, but there were no significant differences among the PKC inhibitors, nicotine, and PKC inhibitors+nicotine groups. Similar response patterns were observed among PI3K inhibitors (wortmannin and LY294002), nicotine, and PI3K inhibitors+nicotine. In conclusion, this study suggests that nicotine decreases EAAT3 activity, and that this inhibition seems to be dependent on PKC and PI3K. Our results may provide an additional mechanism for nicotine-induced seizure.

Effect of plant polyphenols on seizures – animal studies

SUMMARY Introduction. Flavonoids are a large group of natural compounds that have been considered to be beneficial in ameliorating some age-dependent disorders. However, a potential use of these compounds in epilepsy treatment has not been systematically reviewed. Aim. This review describes the pharmacological activity of some polyphenols (flavonoids) in different animal models of seizures e.g. pentylenetetrazole-induced seizures, kainate-induced seizures and pentylenetetrazole kindling in rats. Method and Discussion. A literature review was conducted using PubMed from 1963 to October 2013 relating effects of flavonoids on experimentally-induced seizures in rodents. Articles chosen for references were queried with the following prompts: “flavonoids and epilepsy”, “flavonoids and seizures”, “plant polyphenols and epilepsy”, and “plant polyphenols and seizures”. Out of 84 reports 32 pharmacological studies with chemically well-defined flavonoids and using widely accepted animal models of seizures have been taken into account in this review. No clinical data on the antiepileptic effect of flavonoids have been reported so far. Conclusion. The reviewed data suggest the possible benefits of some chemically well-defined polyphenolic compounds of plant origin in antiepileptic treatment. Among flavonoids, resveratrol, baicalein, quercetin and rutin showed significant antiseizure activity. The ability of flavonoids to prevent brain excitability and to protect the brain against oxidative stress-induced damage suggests a potential use of some flavonoids at least as adjunctive therapy for the treatment of epilepsy.

Cannabidivarin (CBDV) suppresses pentylenetetrazole (PTZ)-induced increases in epilepsy-related gene expression

To date, anticonvulsant effects of the plant cannabinoid, cannabidivarin (CBDV), have been reported in several animal models of seizure. However, these behaviourally observed anticonvulsant effects have not been confirmed at the molecular level. To examine changes to epilepsy-related gene expression following chemical convulsant treatment and their subsequent control by phytocannabinoid administration, we behaviourally evaluated effects of CBDV (400 mg/kg, p.o.) on acute, pentylenetetrazole (PTZ: 95 mg/kg, i.p.)-induced seizures, quantified expression levels of several epilepsy-related genes (Fos, Casp 3, Ccl3, Ccl4, Npy, Arc, Penk, Camk2a, Bdnf and Egr1) by qPCR using hippocampal, neocortical and prefrontal cortical tissue samples before examining correlations between expression changes and seizure severity. PTZ treatment alone produced generalised seizures (median: 5.00) and significantly increased expression of Fos, Egr1, Arc, Ccl4 and Bdnf. Consistent with previous findings, CBDV significantly decreased PTZ-induced seizure severity (median: 3.25) and increased latency to the first sign of seizure. Furthermore, there were correlations between reductions of seizure severity and mRNA expression of Fos, Egr1, Arc, Ccl4 and Bdnf in the majority of brain regions in the CBDV+PTZ treated group. When CBDV treated animals were grouped into CBDV responders (criterion: seizure severity ≤3.25) and non-responders (criterion: seizure severity >3.25), PTZ-induced increases of Fos, Egr1, Arc, Ccl4 and Bdnf expression were suppressed in CBDV responders. These results provide the first molecular confirmation of behaviourally observed effects of the non-psychoactive, anticonvulsant cannabinoid, CBDV, upon chemically-induced seizures and serve to underscore its suitability for clinical development.

Benzyloxybenzylammonium chlorides: Simple amine salts that display anticonvulsant activity

Several antiepileptic drugs exert their activities by inhibiting Na+ currents. Recent studies demonstrated that compounds containing a biaryl-linked motif (Ar-X-Ar′) modulate Na+ currents. We, and others, have reported that compounds with an embedded benzyloxyphenyl unit (ArOCH2Ar′, OCH2=X) exhibit potent anticonvulsant activities. Here, we show that benzyloxybenzylammonium chlorides (+H3NCH2C6H4OCH2Ar′ Cl−) displayed notable activities in animal seizure models. Electrophysiological studies of 4-(2′-trifluoromethoxybenzyloxy)benzylammonium chloride (9) using embryonic cortical neurons demonstrated that 9 promoted both fast and slow inactivation of Na+ channels. These findings suggest that the potent anticonvulsant activities of the earlier compounds were due, in part, to the benzyloxyphenyl motif and provide support for the use of the biaryl-linked pharmacophore in future drug design efforts.

Nitric oxide synthase inhibition reverts muscarinic receptor down-regulation induced by pilocarpine- and kainic acid-evoked seizures in rat fronto-parietal cortex

We investigated how nitric oxide (NO) synthase inhibitor modulates muscarinic receptor expression in epileptic rats. We found that subchronic treatment (4 days) with Nω-nitro-l-arginine reduced the down-regulation of muscarinic receptors induced by pilocarpine and kainic acid in rat fronto-parietal cortex, notwithstanding the dramatic potentiation of seizures induced by both convulsants. Furthermore, functional experiments in fronto-parietal cortex slices, showed that Nω-nitro-l-arginine reduces the down-regulating effect of pilocarpine on carbachol-induced phosphoinositol hydrolysis. Finally, Nω-nitro-l-arginine greatly potentiated the induction of basic fibroblast growth factor (FGF2) by pilocarpine. These data suggest a potential role of NO in a regulatory feedback loop to control muscarinic receptor signal during seizures. The dramatic potentiation of convulsions by NO synthase inhibitors in some animal models of seizures could derive from preventing this feedback loop.

Fructose-1,6-diphosphate protects against epileptogenesis by modifying cation-chloride co-transporters in a model of amygdaloid-kindling temporal epilepticus

Fructose-1,6-diphosphate (FDP) shifts the metabolism of glucose from glycolysis to the pentose phosphate pathway and has anticonvulsant activity in several acute seizure animal models. In the present study, we investigated the anti-epileptogenic effects of FDP in an amygdaloid-kindling seizure model, which is an animal model of the most common form of human temporal lobe epilepsy. We found that 1.0g/kg FDP slowed seizure progression and shortened the corresponding after-discharge duration (ADD). FDP increased the number of stimulations needed to reach seizure stages 2–5 and prolonged the cumulative ADD prior to reaching stages 3–5. It also shortened staying days and cumulative ADD in stages 4–5. However, it demonstrated no significant protective effect when administered after the animals were fully kindled. In hippocampal neurons, cation-chloride co-transporters (CCCs) are suggested to play interesting roles in epilepsy by modulating γ-aminobutyric acid (GABA)ergic activity through controlling GABAA receptor-mediated reversal potential. We examined the potential link between FDP and the hippocampal expression of two main members of the CCCs: the neuron-specific K+–Cl−co-transporter 2 (KCC2) and Na+–K+–Cl−co-transporter 1 (NKCC1). FDP inhibited the kindling-induced downregulation of KCC2 expression and decreased NKCC1 expression during the kindling session. Taken together, our data reveal that FDP may have protective activity against epileptogenesis, from partial to generalized tonic–clonic seizures. Furthermore, our findings suggest that the FDP-induced imbalance between KCC2 and NKCC1 expression may be involved in the neuroprotective effect.

Cannabidivarin‐rich cannabis extracts are anticonvulsant in mouse and rat via a CB1 receptor‐independent mechanism

Epilepsy is the most prevalent neurological disease and is characterized by recurrent seizures. Here, we investigate (i) the anticonvulsant profiles of cannabis-derived botanical drug substances (BDSs) rich in cannabidivarin (CBDV) and containing cannabidiol (CBD) in acute in vivo seizure models and (ii) the binding of CBDV BDSs and their components at cannabinoid CB1 receptors. The anticonvulsant profiles of two CBDV BDSs (50-422 mg·kg(-1) ) were evaluated in three animal models of acute seizure. Purified CBDV and CBD were also evaluated in an isobolographic study to evaluate potential pharmacological interactions. CBDV BDS effects on motor function were also investigated using static beam and grip strength assays. Binding of CBDV BDSs to cannabinoid CB1 receptors was evaluated using displacement binding assays. CBDV BDSs exerted significant anticonvulsant effects in the pentylenetetrazole (≥100 mg·kg(-1) ) and audiogenic seizure models (≥87 mg·kg(-1) ), and suppressed pilocarpine-induced convulsions (≥100 mg·kg(-1) ). The isobolographic study revealed that the anticonvulsant effects of purified CBDV and CBD were linearly additive when co-administered. Some motor effects of CBDV BDSs were observed on static beam performance; no effects on grip strength were found. The Δ(9) -tetrahydrocannabinol and Δ(9) -tetrahydrocannabivarin content of CBDV BDS accounted for its greater affinity for CB1 cannabinoid receptors than purified CBDV. CBDV BDSs exerted significant anticonvulsant effects in three models of seizure that were not mediated by the CB1 cannabinoid receptor and were of comparable efficacy with purified CBDV. These findings strongly support the further clinical development of CBDV BDSs for the treatment of epilepsy.

Neuroactive steroids for the treatment of status epilepticus

Benzodiazepines are the current first-line standard-of-care treatment for status epilepticus but fail to terminate seizures in about one third of cases. Synaptic GABAA receptors, which mediate phasic inhibition in central circuits, are the molecular target of benzodiazepines. As status epilepticus progresses, these receptors are internalized and become functionally inactivated, conferring benzodiazepine resistance, which is believed to be a major cause of treatment failure. GABAA receptor positive allosteric modulator neuroactive steroids, such as allopregnanolone, also potentiate synaptic GABAA receptors, but in addition they enhance extrasynaptic GABAA receptors that mediate tonic inhibition. Extrasynaptic GABAA receptors are not internalized, and desensitization of these receptors does not occur during continuous seizures in status epilepticus models. Here we review the broad-spectrum antiseizure activity of allopregnanolone in animal seizure models and the evidence for its activity in models of status epilepticus. We also demonstrate that allopregnanolone inhibits ongoing behavioral and electrographic seizures in a model of status epilepticus, even when there is benzodiazepine resistance. Parenteral allopregnanolone may provide an improved treatment for refractory status epilepticus.

SGE‐102: A novel therapy for refractory status epilepticus

Refractory status epilepticus (SE) has a mortality rate of up to 35%. Current treatment protocols for the treatment of SE begin with benzodiazepines and then proceed to conventional anticonvulsants. If seizures continue, SE is considered refractory (RSE) and treatment with anesthetic agents in undertaken. Twenty-four h to 48h after initiation of anesthesia with midazolam, pentobarbital or thiopental, or propofol, an attempt is made to wean the anesthetic. If this fails and seizures recur, SE is considered highly refractory (HRSE) and repeated attempts are undertaken. No randomized trial data are available to guide the choice of anesthetic agent in either RSE or HRSE status. Medication resistance in established SE is thought to result, in part, from internalization of synaptic γ-aminobutyric acid (GABA) receptors, making them unavailable for modulation. Neurosteroids act on both synaptic and extrasynaptic GABAA receptors, which are not internalized, and are therefore hypothesized to have a role in the treatment of RSE. SGE-102 is a neurosteroid metabolite of progesterone with demonstrated anticonvulsant properties in animal seizure models. A randomized double-blind placebo-controlled adjunctive trial of SGE will include subjects randomized at the time that initial treatment with anesthesia is initiated. Subjects will receive midazolam and either SGE-102 or placebo. Midazolam will be tapered and discontinued between hours 24 and 48. SGE-102 or placebo will be continued through hour 120. The primary end point will be the difference in proportion of subjects from each arm who remain seizure free through hour 120. Secondary end points will include the proportion of subjects who are seizure free at hour 168, 2days after discontinuation of the experimental agent. The study will be powered to have a 90% chance of detecting a clinically meaningful reduction in seizure recurrence at 120h. Comprehensive safety and pharmacokinetic data will also be obtained during the course of the trial.

Epilepsy therapy development: Technical and methodologic issues in studies with animal models

The search for new treatments for seizures, epilepsies, and their comorbidities faces considerable challenges. This is due in part to gaps in our understanding of the etiology and pathophysiology of most forms of epilepsy. An additional challenge is the difficulty in predicting the efficacy, tolerability, and impact of potential new treatments on epilepsies and comorbidities in humans, using the available resources. Herein we provide a summary of the discussions and proposals of the Working Group 2 as presented in the Joint American Epilepsy Society and International League Against Epilepsy Translational Workshop in London (September 2012). We propose methodologic and reporting practices that will enhance the uniformity, reliability, and reporting of early stage preclinical studies with animal seizure and epilepsy models that aim to develop and evaluate new therapies for seizures or epilepsies, using multidisciplinary approaches. The topics considered include the following: (1) implementation of better study design and reporting practices; (2) incorporation in the study design and analysis of covariants that may influence outcomes (including species, age, sex); (3) utilization of approaches to document target relevance, exposure, and engagement by the tested treatment; (4) utilization of clinically relevant treatment protocols; (5) optimization of the use of video-electroencephalography (EEG) recordings to best meet the study goals; and (6) inclusion of outcome measures that address the tolerability of the treatment or study end points apart from seizures. We further discuss the different expectations for studies aiming to meet regulatory requirements to obtain approval for clinical testing in humans. Implementation of the rigorous practices discussed in this report will require considerable investment in time, funds, and other research resources, which may create challenges for academic researchers seeking to contribute to epilepsy therapy discovery and development. We propose several infrastructure initiatives to overcome these barriers.

Up-down Regulation of HO-1 and iNOS Gene Expressions by Ethyl Pyruvate via Recruiting p300 to Nrf2 and Depriving It from p65

Ethyl pyruvate (EP), a simple ester of pyruvic acid, has been shown to exert robust neuroprotection in various neuropathological conditions, such as, cerebral ischemia and KA-induced seizure animal models. The neuroprotective effect of EP is attributable to the anti-inflammatory, anti-oxidative, and anti-apoptotic effects. In the present study, we investigated convergence of anti-inflammatory and anti-oxidative functions of EP and present a novel molecular mechanism underlying anti-inflammatory effects of EP, which is conveyed by p300, a transcriptional co-activator for both Nuclear factor E2-related factor 2 (Nrf2) and p65. In BV2 cells, a microglia cell line, EP induced translocation of Nrf2 from the cytosol to the nucleus and enhanced the expression of hemeoxygenase 1 (HO-1) in a dose-dependent manner and 1h incubation with 10mM EP increased HO-1 to 4.9-fold. Nrf2 was found to translocate from the cytosol to the nucleus beginning 30min after EP-treatment and binds to the antioxidant response element (ARE) located on HO-1 promoter. Interestingly, LPS-induced inducible NO synthase (iNOS) induction was substantially suppressed in EP-pre-treated BV2 cells and it was reverted by Nrf2 knockdown. We found that EP-induced Nrf2 accumulation in the nucleus recruits p300, a transcriptional co-activator of both Nrf2 and p65, inhibiting p65-p300 interaction. Competition between Nrf2 and p65 for p300 binding was confirmed by glutathione S-transferase (GST) pull down assay and reporter gene analysis. These results demonstrate that EP induced nuclear translocation of Nrf2 which binds to ARE along with p300 and hampers iNOS expression via depleting p300 from p65. This is a novel anti-inflammatory mechanism conveyed by EP, which enhances protective effect by converging anti-inflammatory and anti-oxidative effects and might be applicable to various Nrf2-activating agents, such as phytochemicals.

Spontaneous Ca++ oscillations in astrocytes initiate high-frequency oscillations in model hippocampal network

Tonic-Clonic (TC) seizures typically follow episodes of high frequency oscillations (HFOs). The dynamics of these HFOs have been studied in various types of animal and computational seizure models. Hippocampal slice experiments have shown high frequency activity can be decoupled through the use of gap-junction blockers[1]. This has generally been attributed to gap-junctions between neurons, however we hypothesize that this may be caused by blocking gap-junctions been astrocytes. To test this hypothesis we constructed a model network consisting of three distinct cell populations (Figure ​(Figure1).1). Spontaneous calcium oscillations through astrocytes cause a release of glutamate driving the neuronal population to fire with high frequency (100-140 Hz) oscillations. By decreasing gap-junction conductance within the pyramidal and basket cell populations no noticeable difference in high frequency power was seen in the time-frequency analysis, suggesting that HFOs may not require electrical coupling between neurons. Next, to test the role of calcium waves in generation of high frequency activity we decreased gap-junction conductance between all astrocytes. This resulted in a decrease in HFO power between 100-140 Hz. These results of the simulations suggest that spontaneous calcium waves through astrocytic gap junctions may induce high-frequency activity in reduced hippocampal pyramidal populations. Pathology studies of patients with mesial Temporal Lobe Epilepsy have shown an increase in astrocytic connexin43 expression, the main component in astrocyte gap-junctions[2]. The results of this experiment open a new opportunity in targeted drug therapies for epileptics, one that specifically targets astrocyte gap-junctions. Figure 1 A reduced three cell hippocampal circuit. The curved arrows correspond to gap-junction coupling within the population. Gliotransmitter effects are modeled as inward current into the neuronal population following elevation in calcium within astrocytes. ...

Pathological Changes of Astrocytes under Seizure

Multiple lines of studies support the view that defective functions of astrocytes contribute to neuronal hyper-excitability in the epileptic brain. Autopsy and surgical resection specimens find that post-traumatic seizures and chronic temporal lobe epilepsy may originate from glial scars. Astrogliosis, a component of glial scar, which involves structural and metabolic changes in astrocytes, is often a prominent feature of temporal epilepsy and most animal models of recurrent seizures. Although glial scar formation has been recognized for over 120 years, fundamental aspects of the cellular mechanisms are poorly understood. We here provide an overview of the experimental findings about astrogliosis in seizures, which involves the changes in astrocytic structure and loss of domain. These structure changes are paralleled by functional changes, including expression levels of glutamate transporter and glutamine synthetase. Reactive astrocytes have also been shown to down- regulate the activities of K + channels, leading to impairment of clearance of K+. The functional remodeling may contribute to

Derivatives of valproic acid are active against pentetrazol-induced seizures in immature rats

Propylisopropyl acetamide (PID) and valnoctamide (VCD) are two CNS-active constitutional isomers of valproic acid (VPA) corresponding amide (and prodrug) valpromide. VPA is a major antiepileptic drug (AED) used also in children. Consequently, the purpose of the current study was to see if PID, VCD and two of VCD stereoisomers are active also in juvenile anticonvulsant animal seizure models. Rat pups 7, 12, 18 and 25 days old were pretreated with PID, VCD or the VCD stereoisomers (2S,3S)-VCD, and (2R,3S)-VCD and 30 min later pentetrazol (100mg/kg s.c.) was administered. The incidence of seizures, their expression pattern and their latencies were registered and the severity was expressed by means of a five-point scale. All four tested compounds exhibited anticonvulsant activity against generalized tonic-clonic seizures. Lower doses suppressed specifically the tonic phase in 7-, 12- and 18-day-old rats, while higher doses abolished both phases of generalized seizures. This effect was most pronounced in 12-day-old rats. Twenty-five-day-old rats exhibited suppression of the entire pattern of generalized seizures. There were no significant differences among the drugs used. The CNS-active amide derivatives of VPA, VCD (racemate or individual stereoisomers) and PID exhibit potent anticonvulsant activity against generalized convulsive seizures in developing rats. The majority of these developmental effects are quantitative; while a specific selective action on the tonic phase of generalized seizures is the main qualitative change found in our study.

Hippocampal NMDA receptor in an animal model of absence seizure

Introduction: The glutamergic receptors affect the synchronization of spike and wave discharges in different animal models of absence seizure. We studied the distribution of a NMDA subtype receptor in CA1 area of the hippocampus. Materials and Methods: Expression of NMDA subreceptor R2, the predominant excitatory neurotransmitter receptor in the brain, was investigated in rats suffering from absence-like seizures. Results: Rats with absence-like seizures exhibited decreased number of these NMDA subreceptors in the hippocampal formation. Conclusion: Changes of expression of these receptors in the hippocampus may be involved in cognition deficits in absence epilepsy.

1. The anticonvulsant effects of docosahexaenoic acid in rodents

Docosahexaenoic acid (DHA) in an omega 3 polyunsaturated acid with reported anticonvulsant properties. Like phenytoin and carbamazepine it is thought to temporarily stabilize voltage-dependent sodium channels in their inactivated state. Past reports from other groups have reported dramatic suppression of seizures in animal seizure models by DHA. We have not been able to replicate those dramatic anticonvulsant effects in our own studies. We have, however, been able to demonstrate moderate elevations of seizure threshold in chronic, subchronic and acute experiments. Of interest is the fact that the threshold rises occur almost immediately in acute studies, but take 3+ months to appear in studies where DHA is used as a dietary supplement. We believe that the delayed effects of DHA in dietary studies may relate to the complex pharmacokinetics of DHA following oral administration. The fact that dietary DHA is slow to act may explain the failure of experimenters to find antiseizure effects in some of the shorter clinical and animal trials.

Hippocampal gene expression dysregulation of Klotho, nuclear factor kappa B and tumor necrosis factor in temporal lobe epilepsy patients

BackgroundPrevious research in animal seizure models indicates that the pleiotropic cytokine TNF is an important effector/mediator of neuroinflammation and cell death. Recently, it has been demonstrated that TNF downregulates Klotho (KL) through the nuclear factor kappa B (NFkB) system in animal models of chronic kidney disease and colitis. KL function in the brain is unclear, although Klotho knockout (Kl−/−) mice exhibit neural degeneration and a reduction of hippocampal synapses. Our aim was to verify if the triad KL-NFKB1-TNF is also dysregulated in temporal lobe epilepsy associated with hippocampal sclerosis (TLE(HS)) patients.FindingsWe evaluated TNF, NFKB1 and KL relative mRNA expression levels by reverse transcription quantitative PCR (RT-qPCR) in resected hippocampal tissue samples from 14 TLE(HS) patients and compared them to five post mortem controls. Four reference genes were used: GAPDH, HPRT1, ENO2 and TBP. We found that TNF expression was dramatically upregulated in TLE(HS) patients (P <0.005). NFKB1 expression was also increased (P <0.03) while KL was significantly downregulated (P <0.03) in TLE(HS) patients. Hippocampal KL expression had an inverse correlation with NFKB1 and TNF.ConclusionsOur data suggest that, similar to other inflammatory diseases, TNF downregulates KL through NFkB in TLE(HS) patients. The remarkable TNF upregulation in patients is a strong indication of hippocampal chronic inflammation. Our finding of hippocampal KL downregulation has wide implications not only for TLE(HS) but also for other neuronal disorders related to neurodegeneration associated with inflammation.

Cannabinoid 1 receptor as therapeutic target in preventing chronic epilepsy

ObjectiveTemporal lobe epilepsy (TLE) is the most common form of refractory epilepsy. Cannabinoid type 1 (CB1) receptor regulates neuronal excitability and has been shown to mediate the anticonvulsant effects of cannabinoids in acute animal models of seizure. However, the potential of cannabinoids for preventing chronic epileptic damage as consequence of an inciting event (acute seizure) remains under explored.MethodsWe investigated the neuroprotective role of the CB1 receptor against the hippocampal damage occurring in a chronic pilocarpine (PILO) model of TLE in rats. We simulated a therapeutic approach by administering the CB1 agonist WIN55.212–2 to rats for 15 days, beginning 24 hours after the induction of acute epileptic syndrome with PILO.ResultsAfter 6 months, the animals treated with WIN55.212–2 for 15 days following PILO administration, showed (relative to vehicle control): decreased epileptic behavior, reduced abnormal fiber sprouting in the dentate gyrus, preservation of GABA‐ergic neurons, less oxidative injury through NADPH oxidase activation, and normalization of CB1 receptor distribution and expression. Taken together, these data suggest that novel compounds targeting CB1 receptor or downstream signaling pathways may be efficacious in the prevention of chronic TLE.InterpretationGiven the prevalence and severity of TLE, there is great potential of such compounds.

AMPA receptors as a molecular target in epilepsy therapy

Epileptic seizures occur as a result of episodic abnormal synchronous discharges in cerebral neuronal networks. Although a variety of non-conventional mechanisms may play a role in epileptic synchronization, cascading excitation within networks of synaptically connected excitatory glutamatergic neurons is a classical mechanism. As is the case throughout the central nervous system, fast synaptic excitation within and between brain regions relevant to epilepsy is mediated predominantly by AMPA receptors. By inhibiting glutamate-mediated excitation, AMPA receptor antagonists markedly reduce or abolish epileptiform activity in in vitro preparations and confer seizure protection in a broad range of animal seizure models. NMDA receptors may also contribute to epileptiform activity, but NMDA receptor blockade is not sufficient to eliminate epileptiform discharges. AMPA receptors move into and out of the synapse in a dynamic fashion in forms of synaptic plasticity, underlying learning and memory. Often, the trigger for these dynamic movements is the activation of NMDA receptors. While NMDA receptor antagonists inhibit these forms of synaptic plasticity, AMPA receptor antagonists do not impair synaptic plasticity and do not inhibit memory formation or retrieval. The demonstrated clinical efficacy of perampanel, a high-potency, orally active non-competitive AMPA receptor antagonist, supports the concept that AMPA receptors are critical to epileptic synchronization and the generation and spread of epileptic discharges in human epilepsy.