New GABA-Targeting Therapies for the Treatment of Seizures and Epilepsy: I. Role of GABA as a Modulator of Seizure Activity and Recently Approved Medications Acting on the GABA System

CNS Drugs · 3 authors, 6 centres

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TL;DR

This narrative review summarizes the role of GABA in seizure modulation and evaluates the pharmacology, efficacy, and tolerability of the recently approved GABAergic antiseizure medications cenobamate and ganaxolone.

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It focuses on two recently approved GABAergic antiseizure medications: cenobamate and ganaxolone. The review notes that cenobamate has a more robust clinical efficacy profile than ganaxolone for focal seizures. The implications are that understanding GABAergic mechanisms guides the development of future therapies.

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narrative_review

SPECIALTY

neurology

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ORIGINAL PAPER

PMC10501955

New GABA-Targeting Therapies for the Treatment of Seizures and Epilepsy: I. Role of GABA as a Modulator of Seizure Activity and Recently Approved Medications Acting on the GABA System

CNS Drugs

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ABSTRACT

γ-Aminobutyric acid (GABA) is the most prevalent inhibitory neurotransmitter in the mammalian brain and has been found to play an important role in the pathogenesis or the expression of many neurological diseases, including epilepsy. Although GABA can act on different receptor subtypes, the component of the GABA system that is most critical to modulation of seizure activity is the GABA A -receptor-chloride (Cl − ) channel complex, which controls the movement of Cl − ions across the neuronal membrane. In the mature brain, binding of GABA to GABA A receptors evokes a hyperpolarising (anticonvulsant) response, which is mediated by influx of Cl − into the cell driven by its concentration gradient between extracellular and intracellular fluid. However, in the immature brain and under certain pathological conditions, GABA can exert a paradoxical depolarising (proconvulsant) effect as a result of an efflux of chloride from high intracellular to lower extracellular Cl − levels. Extensive preclinical and clinical evidence indicates that alterations in GABAergic inhibition caused by drugs, toxins, gene defects or other disease states (including seizures themselves) play a causative or contributing role in facilitating or maintaning seizure activity. Conversely, enhancement of GABAergic transmission through pharmacological modulation of the GABA system is a major mechanism by which different antiseizure medications exert their therapeutic effect. In this article, we review the pharmacology and function of the GABA system and its perturbation in seizure disorders, and highlight how improved understanding of this system offers opportunities to develop more efficacious and better tolerated antiseizure medications. We also review the available data for the two most recently approved antiseizure medications that act, at least in part, through GABAergic mechanisms, namely cenobamate and ganaxolone. Differences in the mode of drug discovery, pharmacological profile, pharmacokinetic properties, drug–drug interaction potential, and clinical efficacy and tolerability of these agents are discussed.

CITATION EXPORT

Emilio Perucca, Meir Bialer, H. Steve White. New GABA-Targeting Therapies for the Treatment of Seizures and Epilepsy: I. Role of GABA as a Modulator of Seizure Activity and Recently Approved Medications Acting on the GABA System. CNS Drugs. (2023). https://doi.org/10.1007/s40263-023-01027-2

AUTHORS

3 · 6 CENTRES

Emilio Perucca, Meir Bialer, H. Steve White

1grid.1008.90000 0001 2179 088XDepartment of Medicine (Austin Health), The University of Melbourne, Melbourne, VIC Australia
2grid.1002.30000 0004 1936 7857Department of Neuroscience, Central Clinical School, Monash University, Melbourne, VIC Australia
3grid.9619.70000 0004 1937 0538Institute of Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
4grid.9619.70000 0004 1937 0538David R. Bloom Center for Pharmacy, The Hebrew University of Jerusalem, Jerusalem, Israel
5grid.34477.330000000122986657Department of Pharmacy, School of Pharmacy, University of Washington, Seattle, WA USA
6Melbourne Brain Centre, 245 Burgundy Street, Heidelberg, VIC 3084 Australia