Mechanisms of Action of Antiseizure Drugs and the Ketogenic Diet

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.

Intermittent metabolic switching, neuroplasticity and brain health

“…This pathway is highly conserved because fasting enhances long-term memory formation in multiple tasks in Drosophila melanogaster by a mechanism requiring CREB activation in mushroom body neurons 40 . Ketones, particularly BHB, upregulate GABAergic tone, which can protect against seizures 41,42 , and may mediate adaptive responses of neuronal circuits to IMS. The monoamine neurotransmitters serotonin, noradrenaline and dopamine may also play important roles in the effects of IMS on neuronal network activity 43,44 .…”

Synaptic Vesicle Glycoprotein 2A Ligands in the Treatment of Epilepsy and Beyond

“…Indeed, a vast number of studies, conducted at therapeutically relevant concentrations, did not show any direct interaction of levetiracetam with mechanisms through which other ASDs act, including inhibition of sodium and low-voltage activated calcium (T-type) channels [17]. However, some cellular and molecular effects of levetiracetam have been reported at therapeutically relevant concentrations, including inhibition of high-voltage-gated (N-type) calcium and AMPA currents, inhibition of calcium release from intracellular stores, effects on the metabolism and turnover of GABA in discrete brain regions, reduction in the firing activity of GABAergic neurons in substantia nigra pars reticulata in vivo, and reversal of zinc-induced inhibition of GABA A receptors [5]. Although these effects may contribute to the unique pharmacological profile of levetiracetam, their modest magnitude suggested that they do not represent the primary mechanism of action.…”

“…Among the various functions proposed are roles in calcium-dependent exocytosis, neurotransmitter loading/retention in synaptic vesicles, and synaptic vesicle priming, as well as transport of vesicle constituents [5]. The latter is supported by homology with the major facilitator superfamily (MFS) of membrane transport proteins [32] and by the suggestion that SV2A is a galactose transporter [33].…”

“…1), they all act to reduce hyperexcitability by either decreasing excitatory or enhancing inhibitory neurotransmission. This involves modulation of voltage-gated ion channels, enhancement of γ-aminobutyric acid (GABA)-mediated inhibition, interactions with elements of the synaptic release machinery, or blockade of ionotropic glutamate receptors [4, 5]. However, approximately 30 % of patients with epilepsy are not controlled by current medications [3] and, despite a high prevalence of acquired epilepsy, no preventive treatment exists for patients at risk of developing epilepsy [3].…”

Metabolic Therapy for Temporal Lobe Epilepsy in a Dish: Investigating Mechanisms of Ketogenic Diet using Electrophysiological Recordings in Hippocampal Slices

“…Thus, a natural question is how the ketogenic diet produces its beneficial effects in temporal lobe epilepsy. Broad reviews on the diet’s mechanisms are available (Lutas and Yellen, 2013; Rogawski et al, 2016); here, we focus on work from multiple laboratories studying ketogenic diet’s antiseizure mechanisms using acute hippocampal slice preparations.…”