Treatment of cholinergic‐induced status epilepticus with polytherapy targeting <scp>GABA</scp> and glutamate receptors

Niquet, Jérôme; Nguyen, Donna; Furtado, Marcio de Araujo; Lumley, Lucille A.

doi:10.1002/epi4.12713

Cited by 6 publications

(2 citation statements)

References 124 publications

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“…However, symptom reduction is noted for different types of treatment, according to the observed pathology, with monotherapy methods using only one type of medication, and polytherapy techniques targeting different therapeutic targets, altering pharmacological doses, or alternating active ingredients derived from the same class of action [49][50][51]. Due to the complexity of the disease and its multiple variants, it is necessary to search for new therapeutic targets in order to develop innovative pharmacological strategies, as the same drug may have different effects, depending on the patient [52][53][54].…”

Section: New Therapeutic Targets and Pharmacological Strategiesmentioning

confidence: 99%

Pathophysiology to Risk Factor and Therapeutics to Treatment Strategies on Epilepsy

Boleti,

Cardoso,

Frihling

et al. 2024

Brain Sciences

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Epilepsy represents a condition in which abnormal neuronal discharges or the hyperexcitability of neurons occur with synchronicity, presenting a significant public health challenge. Prognostic factors, such as etiology, electroencephalogram (EEG) abnormalities, the type and number of seizures before treatment, as well as the initial unsatisfactory effects of medications, are important considerations. Although there are several third-generation antiepileptic drugs currently available, their multiple side effects can negatively affect patient quality of life. The inheritance and etiology of epilepsy are complex, involving multiple underlying genetic and epigenetic mechanisms. Different neurotransmitters play crucial roles in maintaining the normal physiology of different neurons. Dysregulations in neurotransmission, due to abnormal transmitter levels or changes in their receptors, can result in seizures. In this review, we address the roles played by various neurotransmitters and their receptors in the pathophysiology of epilepsy. Furthermore, we extensively explore the neurological mechanisms involved in the development and progression of epilepsy, along with its risk factors. Furthermore, we highlight the new therapeutic targets, along with pharmacological and non-pharmacological strategies currently employed in the treatment of epileptic syndromes, including drug interventions employed in clinical trials related to epilepsy.

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Section: New Therapeutic Targets and Pharmacological Strategiesmentioning

confidence: 99%

Pathophysiology to Risk Factor and Therapeutics to Treatment Strategies on Epilepsy

Boleti,

Cardoso,

Frihling

et al. 2024

Brain Sciences

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“…Numerous studies have focused on neurophysiological changes during SE, particularly changes in GABA-AR trafficking ( Niquet et al, 2016 ). Time-dependent internalization of postsynaptic GABA-ARs is a significant observation in the early stages of refractory SE ( Niquet et al, 2023 ). Within 10–20 minutes of OPNA-induced seizure onset, over half of postsynaptic receptors that contain the benzodiazepine site disappear in neurons ( Naylor et al, 2005 ).…”

Section: Benzodiazepine Limitations and Mechanisms Of Antiseizure Res...mentioning

confidence: 99%

Neurosteroids as Novel Anticonvulsants for Refractory Status Epilepticus and Medical Countermeasures for Nerve Agents: A 15-Year Journey to Bring Ganaxolone from Bench to Clinic

Reddy

2023

J Pharmacol Exp Ther

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This article describes recent advances in the use of neurosteroids as novel anticonvulsants for refractory status epilepticus (RSE) and as medical countermeasures (MCs) for organophosphates and chemical nerve agents (OPNAs). We highlight a comprehensive 15-year journey to bring the synthetic neurosteroid ganaxolone (GX) from bench to clinic. RSE, including when caused by nerve agents, is associated with devastating morbidity and permanent long-term neurologic dysfunction. Although recent approval of benzodiazepines such as intranasal midazolam and intranasal midazolam offers improved control of acute seizures, novel anticonvulsants are needed to suppress RSE and improve neurologic function outcomes. Currently, few anticonvulsant MCs exist for victims of OPNA exposure and RSE. Standard-of-care MCs for postexposure treatment include benzodiazepines, which do not effectively prevent or mitigate seizures resulting from nerve agent intoxication, leaving an urgent unmet medical need for new anticonvulsants for RSE. Recently, we pioneered neurosteroids as next-generation anticonvulsants that are superior to benzodiazepines for treatment of OPNA intoxication and RSE. Because GX and related neurosteroids that activate extrasynaptic GABA-A receptors rapidly control seizures and offer robust neuroprotection by reducing neuronal damage and neuroinflammation, they effectively improve neurologic outcomes after acute OPNA exposure and RSE. GX has been selected for advanced, Biomedical Advanced Research and Development Authority–supported phase 3 trials of RSE and nerve agent seizures. In addition, in mechanistic studies of neurosteroids at extrasynaptic receptors, we identified novel synthetic analogs with features that are superior to GX for current medical needs. Development of new MCs for RSE is complex, tedious, and uncertain due to scientific and regulatory challenges. Thus, further research will be critical to fill key gaps in evaluating RSE and anticonvulsants in vulnerable (pediatric and geriatric) populations and military persons. SIGNIFICANCE STATEMENT Following organophosphate and nerve agent intoxication, refractory status epilepticus (RSE) occurs despite benzodiazepine treatment. RSE occurs in 40% of status epilepticus patients, with a 35% mortality rate and significant neurological morbidity in survivors. To treat RSE, neurosteroids are better anticonvulsants than benzodiazepines. Our pioneering use of neurosteroids for RSE and nerve agents led us to develop ganaxolone as a novel anticonvulsant and neuroprotectant with significantly improved neurological outcomes. This article describes the bench-to-bedside journey of bringing neurosteroid therapy to patients, with ganaxolone leading the way.

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Treatment of cholinergic‐induced status epilepticus with polytherapy targeting GABA and glutamate receptors

Niquet

Nguyen

Furtado³

et al. 2023

Epilepsia Open

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Despite new antiseizure medications, the development of cholinergic‐induced refractory status epilepticus (RSE) continues to be a therapeutic challenge as pharmacoresistance to benzodiazepines and other antiseizure medications quickly develops. Studies conducted by Epilepsia . 2005;46:142 demonstrated that the initiation and maintenance of cholinergic‐induced RSE are associated with trafficking and inactivation of gamma‐aminobutyric acid A receptors (GABA A R) thought to contribute to the development of benzodiazepine pharmacoresistance. In addition, Dr. Wasterlain's laboratory reported that increased N‐methyl‐ d ‐aspartate receptors (NMDAR) and alpha‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptors (AMPAR) contribute to enhanced glutamatergic excitation ( Neurobiol Dis . 2013;54:225; Epilepsia . 2013;54:78). Thus, Dr. Wasterlain postulated that targeting both maladaptive responses of reduced inhibition and increased excitation that is associated with cholinergic‐induced RSE should improve therapeutic outcome. We currently review studies in several animal models of cholinergic‐induced RSE that demonstrate that benzodiazepine monotherapy has reduced efficacy when treatment is delayed and that polytherapy with drugs that include a benzodiazepine (eg midazolam and diazepam) to counter loss of inhibition, concurrent with an NMDA antagonist (eg ketamine) to reduce excitation provide improved efficacy. Improved efficacy with polytherapy against cholinergic‐induced seizure is demonstrated by reduction in (1) seizure severity, (2) epileptogenesis, and (3) neurodegeneration compared with monotherapy. Animal models reviewed include pilocarpine‐induced seizure in rats, organophosphorus nerve agent (OPNA)‐induced seizure in rats, and OPNA‐induced seizure in two mouse models: (1) carboxylesterase knockout (Es1 −/− ) mice which, similarly to humans, lack plasma carboxylesterase and (2) human acetylcholinesterase knock‐in carboxylesterase knockout (KIKO) mice. We also review studies showing that supplementing midazolam and ketamine with a third antiseizure medication (valproate or phenobarbital) that targets a nonbenzodiazepine site rapidly terminates RSE and provides further protection against cholinergic‐induced SE. Finally, we review studies on the benefits of simultaneous compared with sequential drug treatments and the clinical implications that lead us to predict improved efficacy of early combination drug therapies. The data generated from seminal rodent studies of efficacious treatment of cholinergic‐induced RSE conducted under Dr. Wasterlain's guidance suggest that future clinical trials should treat the inadequate inhibition and temper the excess excitation that characterize RSE and that early combination therapies may provide improved outcome over benzodiazepine monotherapy.

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Treatment of cholinergic‐induced status epilepticus with polytherapy targeting GABA and glutamate receptors

Cited by 6 publications

References 124 publications

Pathophysiology to Risk Factor and Therapeutics to Treatment Strategies on Epilepsy

Pathophysiology to Risk Factor and Therapeutics to Treatment Strategies on Epilepsy

Neurosteroids as Novel Anticonvulsants for Refractory Status Epilepticus and Medical Countermeasures for Nerve Agents: A 15-Year Journey to Bring Ganaxolone from Bench to Clinic

Treatment of cholinergic‐induced status epilepticus with polytherapy targeting GABA and glutamate receptors

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