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Mechanisms of Action of Antiseizure Drugs and the Ketogenic Diet

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Mechanisms of Action of Antiseizure Drugs and the Ketogenic Diet Downloaded from http://perspectivesinmedicine.cshlp.org/ on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press Mechanisms of Action of Antiseizure Drugs and the Ketogenic Diet Michael A. Rogawski1, Wolfgang Lo¨scher2, and Jong M. Rho3,4,5 1Department of Neurology, University of California, Davis, Sacramento, California 95817 2Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine, Hannover, Germany 3Department of Pediatrics, University of Calgary, Calgary, Alberta, Canada 4Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada 5Department of Physiology and Pharmacology, University of Calgary, Alberta, Canada Correspondence: [email protected]; [email protected]; [email protected] 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 g-aminobutyric acid (GABA)-medi- ated inhibition through effects on GABAA receptors, the GABA transporter 1 (GAT1) GABA uptake transporter, or GABA transaminase; through interactions with elements of the syn- aptic release machinery, including synaptic vesicle 2A (SV2A) and a2d; or by blockade of ionotropic glutamate receptors, including a-amino-3-hydroxy-5-methyl-4-isoxazole-propi- onate (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 polyunsat- urated fattyacids, mayalso playa 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. www.perspectivesinmedicine.org ntiseizure drugs (ASDs), often referred to as there is insufficient evidence to conclude that Aantiepileptic drugs or anticonvulsant drugs, any ASD can produce clinically useful disease are administered chronically with the intent of modification. The symptomatic relief from sei- preventing the occurrence of epileptic seizures zures that ASDs provide occurs through inter- in a person at risk. Although limited results actions with a variety of cellular targets. The from animal studies or uncontrolled clinical actions on these targets can be categorized studies suggest that some ASDs might have anti- into four broad groups: (1) modulation of volt- epileptogenic actions (Kaminski et al. 2014), age-gated ion channels, including sodium, cal- Editors: Gregory L. Holmes and Jeffrey L. Noebels Additional Perspectives on Epilepsy: The Biology of a Spectrum Disorder available at www.perspectivesinmedicine.org Copyright # 2016 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a022780 Cite this article as Cold Spring Harb Perspect Med 2016;6:a022780 1 Downloaded from http://perspectivesinmedicine.cshlp.org/ on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press M.A. Rogawski et al. Table 1. Molecular targets of clinically used ASDs Molecular target ASDs that act on target Voltage-gated ion channels Voltage-gated sodium channels Phenytoin, fosphenytoin,a carbamazepine, oxcarbazepine,b eslicarbazepine acetate,c lamotrigine, lacosamide; possibly topiramate, zonisamide, rufinamide Voltage-gated calcium channels (T-type) Ethosuximide Voltage-gated potassium channels (Kv7) Ezogabine GABA inhibition GABAA receptors Phenobarbital, primidone, benzodiazepines, including diazepam, lorazepam, and clonazepam; possibly topiramate, felbamate, ezogabine GAT1 GABA transporter Tiagabine GABA transaminase Vigabatrin Synaptic release machinery SV2A Levetiracetam a2d Gabapentin, gabapentin enacarbil,d pregabalin Ionotropic glutamate receptors AMPA receptor Perampanel Mixed/unknown Valproate, felbamate, topiramate, zonisamide, rufinamide, adrenocorticotrophin From Rogawski and Cavazos 2015; adapted, with permission. GABA, g-Aminobutyric acid; GAT1, g-aminobutyric acid transporter 1; SV2A, synaptic vesicle protein 2A; AMPA, a-amino-3-hydroxy-5-methyl-4-isoxazole-propionate. aFosphenytoin is a prodrug for phenytoin. bOxcarbazepine serves largely as a prodrug for licarbazepine, mainly S-licarbazepine. cEslicarbarbazepine acetate is a prodrug for S-licarbazepine. dGabapentin enacarbil is a prodrug for gabapentin. cium, and potassium channels; (2) enhance- ensembles. In addition, ASDs inhibit the spread ment of g-aminobutyric acid (GABA) inhibi- of abnormal firing to adjacent and distant brain tion through effects on GABAA receptors, the sites. This occurs through strengthening of the GAT1 GABA transporter or GABA transami- inhibitory surround, a function predominantly nase; (3) direct modulation of synaptic release of GABA released from interneurons acting on www.perspectivesinmedicine.org through effects on components of the release GABAA receptors, and by inhibition of gluta- machinery, including synaptic vesicle protein mate-mediated excitatory neurotransmission 2A (SV2A) and the a2d subunit of voltage- within the network of principal (relay) neurons. gated calcium channels; and (4) inhibition of Some seizures, including typical generalized ab- synaptic excitation mediated by ionotropic glu- sence seizures, result from elevated thalamo- tamate receptors, including a-amino-3-hydroxy- cortical synchronization. ASDs effective against 5-methyl-4-isoxazole-propionate (AMPA) re- these seizure types interfere with the rhythm- ceptors (Table 1). The result of the interactions generating mechanisms that underlie synchro- at these diverse targets is to modify the intrinsic nized activity in the thalamocortical circuitry. excitability properties of neurons or to alter fast In this review, we consider each of the principal inhibitory or excitatory neurotransmission. targets of ASDs and discuss how, to the extent These actions reduce the probability of seizure known, these agents affect the activity of these occurrence by modifying the bursting proper- targets. The goal of epilepsy therapy is the com- ties of neurons (reducing the capacity of neu- plete elimination of seizures. This objective is rons to fire action potentials at high rate) and not achievable for many patients. When ASDs reducing synchronization in localized neuronal are not able to control seizures, some patients 2 Cite this article as Cold Spring Harb Perspect Med 2016;6:a022780 Downloaded from http://perspectivesinmedicine.cshlp.org/ on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press Antiseizure Drugs and the Ketogenic Diet may benefit from dietary therapies. The keto- logical properties, including rapid inactivation. genic diet is the most widely used and best val- The a subunits alone are able to form a func- idated such treatment approach. Here, we re- tional sodium channel, but b subunits (b1–b4 view a variety of theories to explain the action are known) can modulate the kinetics and traf- of the ketogenic diet in the treatment of epilepsy ficking of the channel (Patino and Isom 2010). ranging from the view that the antiseizure ac- Of the 10 known a subunits, using the channel tivity relates to ketone bodies or the production and receptor nomenclature of Alexander et al. of inhibitory mediators, such as adenosine, to (2013), Nav1.1, Nav1.2, Nav1.3, and NaV1.6 the hypothesis that it is a result of shifts in in- are the four most abundantly expressed sub- termediary metabolism. units in the brain (Yu and Catterall 2003; Vacher et al. 2008). Mutations in voltage-gated sodium channels have been associated with various ge- VOLTAGE-GATED ION CHANNELS netic forms of epilepsy (Oliva et al. 2012). ASDs that protect against seizures through Voltage-Gated Sodium Channels an interaction with voltage-gated sodium chan- Voltage-gated sodium channels play an essential nels are commonly referred to as “sodium chan- role in the initiation and propagation of action nel blockers” (Fig. 1). They are among the most potentials in neurons (Mantegazza et al. 2010). frequently used drugs in the treatment of both Neuronal depolarizations by only a few mil- focal and primary generalized tonic–clonic sei- livolts, which ordinarily result from activa- zures. Such drugs include phenytoin, carba- tion of synaptic glutamate receptors (mainly mazepine, lamotrigine, oxcarbazepine (as well AMPA receptors, but also N-methyl-D-aspartate as its active metabolite licarbazepine), rufina- [NMDA] receptors), cause sodium channels to mide, and lacosamide. ASDs that interact with open and enable influx of sodium along its elec- voltage-gated sodium channels also show a trochemical gradient. These channels then inac- characteristic “use-dependent” blocking action tivate within milliseconds. The influx of sodium so that they inhibit high-frequency trains of ac- ions during the brief time that sodium channels tion potentials much more potently than they are open generates the depolarizing component attenuate individual action potentials or firing (upstroke) of the
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