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Review
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Mechanisms of Action of Antiseizure Drugs and the Ketogenic Diet

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Review

Mechanisms of Action of Antiseizure Drugs and the Ketogenic Diet

Michael A Rogawski et al. Cold Spring Harb Perspect Med.

Abstract

Antiseizure drugs (ASDs), also termed antiepileptic drugs, are the main form of symptomatic treatment for people with epilepsy, but not all patients become free of seizures. The ketogenic diet is one treatment option for drug-resistant patients. Both types of therapy exert their clinical effects through interactions with one or more of a diverse set of molecular targets in the brain. ASDs act by modulation of voltage-gated ion channels, including sodium, calcium, and potassium channels; by enhancement of γ-aminobutyric acid (GABA)-mediated inhibition through effects on GABAA receptors, the GABA transporter 1 (GAT1) GABA uptake transporter, or GABA transaminase; through interactions with elements of the synaptic release machinery, including synaptic vesicle 2A (SV2A) and α2δ; or by blockade of ionotropic glutamate receptors, including α-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) receptors. The ketogenic diet leads to increases in circulating ketones, which may contribute to the efficacy in treating pharmacoresistant seizures. Production in the brain of inhibitory mediators, such as adenosine, or ion channel modulators, such as polyunsaturated fatty acids, may also play a role. Metabolic effects, including diversion from glycolysis, are a further postulated mechanism. For some ASDs and the ketogenic diet, effects on multiple targets may contribute to activity. Better understanding of the ketogenic diet will inform the development of improved drug therapies to treat refractory seizures.

Figures

Figure 1.
Figure 1.
Diverse molecular targets for antiseizure drugs (ASDs) at excitatory glutamatergic synapses. Seizure protection can be conferred by effects on voltage-gated sodium channels, M-type voltage-gated potassium channels (Kv7), and voltage-gated calcium channels located in presynaptic terminals. Additional presynaptic targets include the synaptic vesicle protein SV2A and the α2δ accessory subunit of voltage-gated calcium channels. These presynaptic targets may act to diminish glutamate release. Postsynaptic targets include ionotropic glutamate receptors of the N-methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) types.
Figure 2.
Figure 2.
Diverse molecular targets for antiseizure drugs (ASDs) at inhibitory γ-aminobutyric acid (GABA)ergic synapses. Seizure protection can be conferred by effects on synaptic or extrasynaptic GABAA receptors or on GABA transaminase (GABA-T) or GABA transporter 1 (GAT1). Furthermore, some ASDs (e.g., valproate) have been shown to increase the activity of the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD), thereby increasing GABA turnover. Astrocytes contain elements, including GABA transporters, which influence the dynamics of GABA, thereby affecting the excitability of the postsynaptic neuron.

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