Perampanel but Not Amantadine Prevents Behavioral Alterations and Epileptogenesis in Pilocarpine Rat Model of Status Epilepticus

Mohammad, Hanan; Sathiya, S.; Wei, Zhao; Moien‐Afshari, Farzad; Taghibiglou, Changiz

doi:10.1007/s12035-018-1230-6

Cited by 31 publications

(27 citation statements)

References 77 publications

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“…Animal models of status epilepticus show self-sustained synchronized activity. Several studies have reported that AMPA receptor antagonists can terminate status epilepticus in animal models [157][158][159][160][161][162][163][164]. A recent study demonstrated that perampanel terminated status epilepticus in a pilocarpine model of status epilepticus, but amantadine, an NMDA receptor antagonist, did not [163].…”

Section: Synchronized Activitymentioning

confidence: 99%

“…Several studies have reported that AMPA receptor antagonists can terminate status epilepticus in animal models [157][158][159][160][161][162][163][164]. A recent study demonstrated that perampanel terminated status epilepticus in a pilocarpine model of status epilepticus, but amantadine, an NMDA receptor antagonist, did not [163]. Similarly, the NMDA antagonist ketamine did not demonstrate a stable effect in animal models of status epilepticus when administered as monotherapy, but showed synergistic efficacy when administered in combination therapy with other drugs [165][166][167][168].…”

Section: Synchronized Activitymentioning

confidence: 99%

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Ionotropic Glutamate Receptors in Epilepsy: A Review Focusing on AMPA and NMDA Receptors

2020

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It is widely accepted that glutamate-mediated neuronal hyperexcitation plays a causative role in eliciting seizures. Among glutamate receptors, the roles of N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors in physiological and pathological conditions represent major clinical research targets. It is well known that agonists of NMDA or AMPA receptors can elicit seizures in animal or human subjects, while antagonists have been shown to inhibit seizures in animal models, suggesting a potential role for NMDA and AMPA receptor antagonists in anti-seizure drug development. Several such drugs have been evaluated in clinical studies; however, the majority, mainly NMDA-receptor antagonists, failed to demonstrate adequate efficacy and safety for therapeutic use, and only an AMPA-receptor antagonist, perampanel, has been approved for the treatment of some forms of epilepsy. These results suggest that a misunderstanding of the role of each glutamate receptor in the ictogenic process may underlie the failure of these drugs to demonstrate clinical efficacy and safety. Accumulating knowledge of both NMDA and AMPA receptors, including pathological gene mutations, roles in autoimmune epilepsy, and evidence from drug-discovery research and pharmacological studies, may provide valuable information enabling the roles of both receptors in ictogenesis to be reconsidered. This review aimed to integrate information from several studies in order to further elucidate the specific roles of NMDA and AMPA receptors in epilepsy.

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Section: Synchronized Activitymentioning

confidence: 99%

Section: Synchronized Activitymentioning

confidence: 99%

Ionotropic Glutamate Receptors in Epilepsy: A Review Focusing on AMPA and NMDA Receptors

2020

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“…Recently, the first AMPA antagonist, perampanel, was approved for treatment of epilepsy . Perampanel was shown to exert antiepileptogenic effects in different epilepsy models, including kindling and pilocarpine . In view of the finding that both glutamate receptor subtypes are critically involved in epileptogenesis, combinations of clinically available NMDA and AMPA antagonists are interesting candidates for antiepileptogenesis.…”

Section: Combination Treatmentmentioning

confidence: 99%

“…Let us hope that the next few years will yield results that will lead to human epilepsy prevention studies—before the authors retire. It is interesting to note that some pharmaceutical companies currently plan epilepsy prevention trials based on promising preclinical data on clinically approved drugs, for instance with eslicarbazepine acetate for post‐stroke epilepsy . Furthermore, several startup companies (eg, OB Pharmaceuticals, Expesicor, LVM Biosciences) are currently developing novel innovative antiepileptogenic therapeutics.…”

Section: Summary/conclusionmentioning

confidence: 99%

“…It is interesting to note that some pharmaceutical companies currently plan epilepsy prevention trials based on promising preclinical data on clinically approved drugs, for instance with eslicarbazepine acetate for poststroke epilepsy. 45,280 Furthermore, several startup companies (eg, OB Pharmaceuticals, Expesicor, LVM Biosciences) are currently developing novel innovative antiepileptogenic therapeutics. This renewed interest of both academia and industry in antiepileptogenesis suggests that the long hoped-for breakthrough may perhaps be on the horizon.…”

Section: Summary/conclusionmentioning

confidence: 99%

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Repurposed molecules for antiepileptogenesis: Missing an opportunity to prevent epilepsy?

et al. 2020

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Prevention of epilepsy is a great unmet need. Acute central nervous system (CNS) insults such as traumatic brain injury (TBI), cerebrovascular accidents (CVA), and CNS infections account for 15%‐20% of all epilepsy. Following TBI and CVA, there is a latency of days to years before epilepsy develops. This allows treatment to prevent or modify postinjury epilepsy. No such treatment exists. In animal models of acquired epilepsy, a number of medications in clinical use for diverse indications have been shown to have antiepileptogenic or disease‐modifying effects, including medications with excellent side effect profiles. These include atorvastatin, ceftriaxone, losartan, isoflurane, N‐acetylcysteine, and the antiseizure medications levetiracetam, brivaracetam, topiramate, gabapentin, pregabalin, vigabatrin, and eslicarbazepine acetate. In addition, there are preclinical antiepileptogenic data for anakinra, rapamycin, fingolimod, and erythropoietin, although these medications have potential for more serious side effects. However, except for vigabatrin, there have been almost no translation studies to prevent or modify epilepsy using these potentially “repurposable” medications. We may be missing an opportunity to develop preventive treatment for epilepsy by not evaluating these medications clinically. One reason for the lack of translation studies is that the preclinical data for most of these medications are disparate in terms of types of injury, models within different injury type, dosing, injury–treatment initiation latencies, treatment duration, and epilepsy outcome evaluation mode and duration. This makes it difficult to compare the relative strength of antiepileptogenic evidence across the molecules, and difficult to determine which drug(s) would be the best to evaluate clinically. Furthermore, most preclinical antiepileptogenic studies lack information needed for translation, such as dose–blood level relationship, brain target engagement, and dose‐response, and many use treatment parameters that cannot be applied clinically, for example, treatment initiation before or at the time of injury and dosing higher than tolerated human equivalent dosing. Here, we review animal and human antiepileptogenic evidence for these medications. We highlight the gaps in our knowledge for each molecule that need to be filled in order to consider clinical translation, and we suggest a platform of preclinical antiepileptogenesis evaluation of potentially repurposable molecules or their combinations going forward.

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α‐Amino‐3‐Hydroxy‐5‐Methyl‐4‐Isoxazolepropionic Acid Receptor Plasticity Sustains Severe, Fatal Status Epilepticus

Adotevi

Lewczuk

Sun

et al. 2019

Annals of Neurology

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Objective Generalized convulsive status epilepticus is associated with high mortality. We tested whether α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptor plasticity plays a role in sustaining seizures, seizure generalization, and mortality observed during focal onset status epilepticus. We also determined whether modified AMPA receptors generated during status epilepticus could be targeted with a drug. Methods Electrically induced status epilepticus was characterized by electroencephalogram and behavior in GluA1 knockout mice and in transgenic mice with selective knockdown of the GluA1 subunit in hippocampal principal neurons. Excitatory and inhibitory synaptic transmission in CA1 neurons was studied using patch clamp electrophysiology. The dose response of N,N,H,‐trimethyl‐5‐([tricyclo(3.3.1.13,7)dec‐1‐ylmethyl]amino)‐1‐pentanaminiumbromide hydrobromide (IEM‐1460), a calcium‐permeable AMPA receptor antagonist, was determined. Results Global removal of the GluA1 subunit did not affect seizure susceptibility; however, it reduced susceptibility to status epilepticus. GluA1 subunit knockout also reduced mortality, severity, and duration of status epilepticus. Absence of the GluA1 subunit prevented enhancement of glutamatergic synaptic transmission associated with status epilepticus; however, γ‐aminobutyric acidergic synaptic inhibition was compromised. Selective removal of the GluA1 subunit from hippocampal principal neurons also reduced mortality, severity, and duration of status epilepticus. IEM‐1460 rapidly terminated status epilepticus in a dose‐dependent manner. Interpretation AMPA receptor plasticity mediated by the GluA1 subunit plays a critical role in sustaining and amplifying seizure activity and contributes to mortality. Calcium‐permeable AMPA receptors modified during status epilepticus can be inhibited to terminate status epilepticus. ANN NEUROL 2020;87:84–96

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Perampanel but Not Amantadine Prevents Behavioral Alterations and Epileptogenesis in Pilocarpine Rat Model of Status Epilepticus

Cited by 31 publications

References 77 publications

Ionotropic Glutamate Receptors in Epilepsy: A Review Focusing on AMPA and NMDA Receptors

Ionotropic Glutamate Receptors in Epilepsy: A Review Focusing on AMPA and NMDA Receptors

Repurposed molecules for antiepileptogenesis: Missing an opportunity to prevent epilepsy?

α‐Amino‐3‐Hydroxy‐5‐Methyl‐4‐Isoxazolepropionic Acid Receptor Plasticity Sustains Severe, Fatal Status Epilepticus

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