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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 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 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

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Table 1. Molecular targets of clinically used ASDs Molecular target ASDs that act on target Voltage-gated ion channels Voltage-gated sodium channels , ,a , ,b ,c , ; possibly , , rufinamide Voltage-gated calcium channels (T-type) Voltage-gated potassium channels (Kv7) Ezogabine GABA inhibition GABAA receptors , , , including , , and ; possibly topiramate, , ezogabine GAT1 GABA transporter GABA transaminase Synaptic release machinery SV2A a2d , ,d Ionotropic glutamate receptors AMPA receptor Mixed/unknown , 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 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

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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 , 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 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 action potential. Although at low frequencies. Because they also show a nearly all sodium channels inactivate on depo- “voltage-dependence” to their blocking action, larization, 1% of the sodium current is non- sodium-channel-blocking ASDs are more po- inactivating, resulting in a small persistent so- tent at inhibiting action potentials superim- dium current (INaP), which is carried by the posed on a depolarized plateau potential as www.perspectivesinmedicine.org same channels as the fast transient current. characteristically occurs with seizures. Thus, INaP facilitates epileptic burst firing by reducing importantly, sodium-channel-blocking ASDs the threshold for action potential generation, preferentially inhibit seizure discharges in rela- sustained repetitive firing, and augmentation tion to normal ongoing neural activity. By vir- of depolarizing synaptic currents (Stafstrom tue of their ability to inhibit the action potential 2007). Some ASDs, most notably phenytoin, in- invasion of nerve terminals, sodium-channel- hibit INaP, an action that is believed to contrib- blocking ASDs inhibit the release of diverse neu- ute to their efficacy (Mantegazza et al. 2010). rotransmitters, including glutamate; whether Voltage-gated sodium channels are multi- this is responsible for the therapeutic activity meric protein complexes, composed of a large of the drugs remains uncertain (Waldmeier a-subunit that forms four subunit-like homol- et al. 1995). ogous domains (designated I–IV) and one or The binding site for sodium on sodium- more smaller b subunits (Meldrum and Rogaw- channel-blocking ASDs is believed to overlap ski 2007). The ion-conducting pore is contained with the binding site of local anesthetics, which within the a-subunit, as are the elements of the is within the pore of the channel and is formed channel that mediate its fundamental physio- by the S6 segments of domains I, II, and IV.

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M.A. Rogawski et al.

Phenytoin, carbamazepine, Presynaptic terminal lamotrigine, lacosamide, of glutamate neuron zonisamide, oxcarbazepine

+ Ezogabine K Na+ Voltage-gated Na+ channel Gabapentin, + pregabalin KV7 K channel SV2A α2δ subunit Levetiracetam of P/Q-type Ca2+ channel

Glutamate Felbamate Perampanel Ezogabine K+

+ Postsynaptic KV7 K NMDA AMPA neuron channel receptor receptor Na+ (Ca2+) Na+ (Ca2+)

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 a2d accessory subunit of voltage-gated calcium channels. These presynaptic targets may act to diminish glutamate release. Postsynaptic targets include iono- tropic glutamate receptors of the N-methyl-D-aspartate (NMDA) and a-amino-3-hydroxy-5-methyl-4-isoxa- zole-propionate (AMPA) types.

Sodium-channel-blocking ASDs bind with proposed that the very slow action of lacos- higher affinity to this site when the channel is amide is caused by an enhancement of a distinct in the inactivated state, and, when such a drug is and poorly understood form of inactivation, bound, the channel is stabilized in the inactivat- referred to as “slow inactivation.” An alterna- ed state (Mantegazza et al. 2010). When neu- tive explanation is that lacosamide binds more rons are depolarized and firing rapidly, sodium slowly to fast-inactivated sodium channels than www.perspectivesinmedicine.org channels spend a greater amount time in the do the other sodium-channel-blocking ASDs. inactivated state and are able to accumulate In any case, the unusually slow development bound drug so that they become trapped in of block produced by lacosamide during high- the inactivated state. This accounts for the use- frequency activity could allow lacosamide to and voltage-dependent blocking action that better discriminate between seizure-like patho- they show. Phenytoin, carbamazepine, and la- logical firing and normal network activity. motrigine are considered “classical” sodium- channel-blocking ASDs. Lacosamide is also be- T-Type Voltage-Gated Calcium Channels lieved to induce its therapeutic effects by inter- acting with sodium channels (Rogawski et al. Low-voltage-activated (T-type) calcium chan- 2015). However, unlike other sodium-channel- nels play a major role in the intrinsic thalamo- blocking ASDs, lacosamide does not inhibit cortical oscillations that underlie the spike-wave high-frequency repetitive spike firing on the discharges of generalized absence seizures (Avoli time scale of hundreds of milliseconds. It does, et al. 2001; Huguenard 2002; Lambert et al. however, inhibit spike firing in long trains of 2014). There are three T-type Ca2þ channel iso- spikes on the time scale of 1–2 sec. It has been forms encoded by separate genes, denoted as

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Antiseizure Drugs and the Ketogenic Diet

Cav3.1 (a1G), Cav3.2 (a1H), and Cav3.3 (a1I). lamocortical circuit, which is associated with All three T-type isoforms are neuronal depolarization and inactivation of expressed in thalamocortical circuits (Talley T-type calcium channels. Effects on other mem- et al. 1999). Cav3.1 is prominently expressed brane currents, including INaP, calcium-activat- in thalamic relay neurons in the dorsal thala- ed potassium current (Broicher et al. 2007), and mus, which plays a key role in absence seizures; inward rectifier potassium current (Huang and Cav3.2—and to a lesser extent Cav3.3—are Kuo 2015), may contribute to the efficacy of prominently expressed in thalamic reticular ethosuximide in absence epilepsy. Remarkably, neurons. All three T-type calcium channel iso- results in animal models indicate that early forms are expressed in the cortex, with Cav3.2 treatment with ethosuximide can have disease- mainly localized to layer V. In non-REM sleep, modifying (i.e., antiepileptogenic) effects, caus- including when d waves, sleep spindles, and ing a persistent reduction in seizures and miti- K-complexes occur, the thalamocortical circuit gation of behavioral comorbidities (Blumenfeld switches from a tonic to oscillatory mode of et al. 2008; Dezsi et al. 2013). These actions may firing, but in absence epilepsy, this switching be caused by epigenetic modifications. A study can occur inappropriately, even during wakeful- showing that children with absence epilepsy ness (Crunelli et al. 2014; Powell et al. 2014). who receive ethosuximide are more likely than T-type calcium channels in the thalamus and those who receive valproate to achieve long- cortex contribute to the abnormal behavior term remission is consistent with the disease- of the circuit. These channels generate low- modifying actions observed in animal studies threshold spikes, leading to burst firing and os- (Berg et al. 2014). cillatory behavior (Suzuki and Rogawski 1989). The efficacy of some other ASDs may also GABAergic neurons of the thalamic reticular depend, at least in part, on actions at T-type nucleus are also critically involved in absence calcium channels. Zonisamide, in addition to seizures as they hyperpolarize thalamic relay effects on voltage-gated sodium channels, may neurons, which de-inactivate T-type calcium also block T-type voltage-gated calcium chan- channels, allowing the channels to generate nels (Powell et al. 2014), thus accounting for burst firing and the propagation of spike-wave its likely efficacy in absence epilepsy (Hughes discharges in the thalamocortical circuit (Da- 2009). Similarly, there is evidence that val- nober et al. 1998). proate, a drug of choice in absence epilepsy, Ethosuximide, which is highly efficacious in may also inhibit T-type calcium channels the treatment of absence seizures—but not oth- (Broicher et al. 2007). er seizure types—is thought to act by inhibition www.perspectivesinmedicine.org of T-type calcium channels in the thalamo- K 7 Voltage-Gated Potassium Channels cortical circuit (Coulter et al. 1989; Broicher v et al. 2007; Go¨ren and Onat 2007). At clinically Voltage-gated potassium channels open in re- relevant concentrations (20–40 mg/ml), some sponse membrane depolarization, permitting but not all investigators have observed a partial efflux of potassium ions, thus driving the mem- (20%–30%) reduction of T-type calcium cur- brane potential toward a hyperpolarized level. rent by ethosuximide. Notwithstanding this This serves to repolarize depolarizing events discrepancy, studies with recombinant T-type (such as action potentials and synaptic poten- calcium channels have confirmed that ethosux- tials) and cause a generalized reduction in ex- imide blocks all three channel types (Gomora citability. In 1998, the first genes for a human et al. 2001). The block increases when the cur- idiopathic epilepsy were identified (Charlier rent is activated from more depolarized poten- et al. 1998). These genes, designated KCNQ2 tials and when T-type calcium channels are and KCNQ3, encoded novel brain potassium inactivated, as occurs especially during high- channel subunits, Kv7.2 and Kv7.3, respectively, frequency activation, so that the drug has which are homologous to a previously identi- selectivity for pathological behavior in the tha- fied cardiac Kv7.1, encoded

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by KCNQ1 (LQT1). These brain potassium itive modulator of the nervous system Kv7 channels mediate the M current, a potassium potassium channels (Kv7.2–Kv7.5), but does current that increases as the membrane poten- not affect the cardiac member of the family tial in neurons approaches action potential (Kv7.1) (Fig. 1). Of particular relevance to the threshold. Kv7 channels, together with hyperpo- antiseizure action of ezogabine is its action on larization-activated cyclic nucleotide-gated po- the M current, which is predominantly carried tassium (HCN) channels and small-conduc- by channels composed of Kv7.2 and Kv7.3, tance calcium-activated potassium (KCa/SK) although Kv7.5 alone or in combination with channels, generate the medium after-hyper- Kv7.3 also contributes (Rogawski 2006; Gun- polarization, which is elicited by a burst of ac- thorpe et al. 2012). Ezogabine causes a hyper- tion potentials and serves to limit further firing polarizing shift in the activation of Kv7 channels (Gu et al. 2005). Kv7 potassium channels also such that more M current is generated near the serve to counteract the spike after-depolariza- resting potential. It also causes a change in the tion generated by recruitment of INaP, which kinetics of single KCNQ channels to favor chan- can lead to bursting (Yue and Yaari 2006). Kv7 nel opening, thus increasing the macroscopic potassium channels, therefore, act as a “brake” M current; ezogabine, nevertheless, does not on epileptic burst firing. The Kv7 family of po- alter the single channel conductance of individ- tassium channels is now known to contain five ual Kv7 channels (Tatulian and Brown 2003). members, including Kv7.1, which is expressed As noted, many Kv7 channels in the brain are predominantly in the heart and Kv7.2–Kv7.5, believed to be Kv7.2/Kv7.3 heteromers, and which are expressed exclusively in the nervous these are highly sensitive to ezogabine (EC50, system (Brown and Passmore 2009). Of these 1.6 mM) (Gunthorpe et al. 2012). Peak plasma Kv7 family members, Kv7.2 and Kv7.3 are high- levels of ezogabine range from 354 to 717 ng/ml ly expressed in neurons relevant to epilepsy, (1.2–2.4 mM) (Hermann et al. 2003), and including principal (pyramidal) cells of the plasma protein binding is 80% so that free plas- hippocampus and neocortex. Kv7.2 and Kv7.3 ma concentrations are estimated to be 0.2– compose heterotetrameric channels in which 0.5 mM; brain concentrations are expected to be four subunits are arranged around a potassium similar. Therefore, therapeutic concentrations selective pore. Kv7.5 channels may also contrib- likely only modestly potentiate the most sen- ute to M current and to neuronal after-hyper- sitive Kv7 channels and do not affect less sensi- polarization, for example, in the CA3 area of the tive channels. The binding site for ezogabine in hippocampus (Tzingounis et al. 2010). Kv7.2/Kv7.3 heteromers is in a pocket formed Studies of the localization of Kv7.2 and by the pore-lining S5 membrane segment of www.perspectivesinmedicine.org Kv7.3 potassium channels by immunohisto- one subunit and the pore-lining S6 membrane chemical techniques have indicated that the segment of the neighboring subunit (Wuttke channels are present at highest density in axons et al. 2005; Lange et al. 2009). Channel opening and their terminals (Vacher et al. 2008). In my- may expose the pocket, permitting binding of elinated fibers, they are present at nodes of Ran- ezogabine, which stabilizes the open channel vier and the channels are also expressed at axon conformation. initial segments. In addition, the channels are Several experimental approaches support expressed at lower levels in the somata of prin- the role of Kv7 potassium channels in the anti- cipal neurons and in some GABAergic neurons. seizure activity of ezogabine. Mice with a ge- Physiological studies in CA1 pyramidal neurons netic defect in these channels show reduced indicate that Kv7 channels are functionally ac- sensitivity to the antiseizure effect of ezogabine tive in the perisomatic region (Hu et al. 2007) (Gunthorpe et al. 2012). Furthermore, the and possibly also on distal dendrites (Yue and KCNQ inhibitor, XE-991, partially blocks the Yaari 2006). antiseizure effect of ezogabine in an electrical Ezogabine (), which is efficacious seizure test (Gunthorpe et al. 2012). However, in the treatment of focal seizures, acts as a pos- the precise way in which activation of Kv7 chan-

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Antiseizure Drugs and the Ketogenic Diet

nels leads to seizure protection remains to be nism and implications of this effect are not elucidated. Consistent with the presynaptic lo- known. In sum, various lines of evidence raise calization of many Kv7 channels, ezogabine has the possibility that effects of ezogabine on been found to inhibit the release of various neu- GABA mechanisms could be of importance in rotransmitters, including GABA and probably its antiseizure activity. also glutamate (Martire et al. 2004). Inhibition of glutamate release is expected to confer seizure GABA INHIBITION protection. The impairment of GABA release or the direct inhibition of inhibitory inter- GABA, the neurotransmitter of local inhibitory neurons (Lawrence et al. 2006; Grigorov et al. interneurons, acts through GABAA and GABAB 2014) would be expected to enhance circuit receptors. GABAA receptors, which are Cys excitability. Indeed, in rodents, retigabine shows loop-type ligand-gated chloride channels, rep- proconvulsant activity at doses (61.9 mg/kg) resent an important target for ASDs and will that are approximately 10-fold greater than be considered here. GABAB receptors, which those associated with seizure protection (U.S. are heterodimeric G-protein-coupled receptors Food and Drug Administration 2010). Para- that activate potassium channels and inhibit doxically, and in contrast to biochemical obser- calcium channels, are distinct in structure and vations, physiological studies have found that function from GABAA receptors and are not a ezogabine “increases” glutamate-mediated syn- target of any ASD. Although only about one in aptic transmission in the hippocampus through five cortical neurons is GABAergic (Sahara et al. a presynaptic action by reducing the inactiva- 2012), these neurons play a critical role in con- tion of voltage-gated sodium channels so that trolling the firing rate and timing of principal sodium-dependent action potentials are elic- (excitatory) neurons. In addition, they syn- ited with greater probability (Vervaeke et al. chronize local neuronal ensembles and restrain 2006). This action could contribute to the pro- the generation of abnormal epileptic behavior. convulsant effects of the drug. If ezogabine does Consequently, enhancement of GABAergic in- confer seizure protection through effects on ex- hibition is a key mechanism of ASD action. citatory neurons, postsynaptic actions to inhibit somatic excitability likely predominate. GABAA Receptors In addition to its effects on Kv7 potassium channels, ezogabine has been reported to inter- GABAA receptors are heteropentameric protein act with the GABA system. At high concen- complexes localized to the postsynaptic mem- trations (.10 mM), ezogabine was shown to brane of inhibitory synapses (Fig. 2) where they www.perspectivesinmedicine.org potentiate GABA-mediated inhibitory trans- mediate fast neuronal inhibition on a millisec- mission by acting as a positive allosteric mod- ond timescale. They are also located extrasynap- ulator of GABAA receptors (Rundfeldt and tically where they respond to ambient GABA in Netzer 2000; Otto et al. 2002). Recent evidence the extracellular milieu and confer tonic (long- that inhibitory effects of the drug on seizure-like term) inhibition. There are 19 known GABAA activity in hippocampal neurons persist in the receptor subunits (a1–6, b1–3, g1–3, d, 1, u, presence of blockade of Kv7 channels has bol- p, and r1–3) (Olsen and Sieghart 2009). How- stered the view that positive modulation of ever, the bulk (60%) of synaptic GABAA re- GABAA receptors could be key to its antiseizure ceptors are believed to have the a1b2g2con- activity (Treven et al. 2015). Thus, at lower figuration, and a considerable fraction of the concentrations than are required for effects on remainder (15%–20%) has a2b3g2. Among synaptic GABAA receptors, ezogabine selective- the receptor subtypes that contribute to tonic ly enhances extrasynaptic GABAA receptors that signaling in brain regions relevant to epilepsy contain the d-subunit (Treven et al. 2015). Ezo- are a4bxd receptors, which are believed to me- gabine has also been reported to increase GABA diate the tonic current in dentate granule cells synthesis (Kapetanovic et al. 1995); the mecha- and thalamocortical neurons, and a5-contain-

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Astrocyte Presynaptic terminal Glutamate of GABA neuron Vigabatrin GAD GABA Synaptic Succinic Succinic GABA-T GABA-T vesicles semi- GABA semi- GABA aldehyde aldehyde

Tiagabine GAT1 GABA Phenobarbital Benzo- diazepines

Postsynaptic Extrasynaptic Synaptic neuron GABAA receptor GABAA receptor CI– CI–

Figure 2. Diverse molecular targets for antiseizure drugs (ASDs) at inhibitory g-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.

ing GABAA receptors in CA1 pyramidal cells the thalamic reticular nucleus (Sohal et al. (Walker and Kullmann 2012). 2003). , presumably because they Benzodiazepines, such a diazepam, loraze- are not specific fora3-containing GABAA recep- pam, and clonazepam, and barbiturates, such as tors, are not active in absence epilepsy and may phenobarbital (Lo¨scher and Rogawski 2012), even aggravate absence seizures. In contrast to are ASDs that act on GABAA receptors as benzodiazepines, barbiturates do not appear positive allosteric modulators (Fig. 2). At higher to increase the frequency of GABA-induced concentrations, barbiturates can directly acti- opening, but instead increase www.perspectivesinmedicine.org vate GABAA receptors in the absence of GABA the channel open time. In addition to effects (Rho et al. 1996), whereas benzodiazepines can- on GABAA receptors, barbiturates modulate not. Benzodiazepines are specific for synaptic other ion channel systems, including calcium GABAA receptors containing the g2 subunit and sodium channels, and these actions may and act to allosterically modulate these recep- contribute to therapeutic activity (ffrench-Mul- tors to increase the channel-opening frequency, len et al. 1993). resulting in enhanced synaptic inhibition. This confers a broad-spectrum antiseizure action. GAT1 GABA Transporter In most epilepsy syndromes, the specific cellu- lar types that are involved in the antiseizure The action of the neurotransmitter GABA is activity of benzodiazepines are not known. terminated by uptake into neurons and glial However, in the case of absence epilepsy, it cells by membrane-bound GABA transporters, is believed that benzodiazepines desynchronize of which there are four types, termed GAT1, the thalamocortical oscillations underlying BGT1, GAT2, and GAT3. GAT1 (encoded by generalized spike-wave discharges by specific the SLC6A1 gene), the predominant form in effects on a3-containing GABAA receptors in the forebrain (including the neocortex and hip-

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Antiseizure Drugs and the Ketogenic Diet

pocampus), is localized to GABAergic termi- vation in extracellular GABA, which is likely nals, as well as to glial processes near GABA responsible for the increase in tonic GABAA re- synapses (Fig. 2). Tiagabine is a highly selective ceptor current. It can be concluded that vigaba- inhibitor of GAT1 in neurons and glia (Schous- trin causes divergent effects on synaptic and boe et al. 2014). Inhibition of GAT1by tiagabine extrasynaptic GABA-mediated inhibition with suppresses the translocation of extracellular seizure protection resulting from a predomi- GABA into the intracellular compartment, thus nance of the extrasynaptic action. Interestingly, raising extracellular GABA levels. Functionally, in the early period after administration of vig- tiagabine prolongs GABA-mediated inhibitory abatrin to animals, there is a reduction in seiz- synaptic responses (Thompson and Ga¨hwiler ure threshold, whereas the antiseizure actions 1992) and the marked elevation in extracellular become evident only later (Lo¨scher et al. 1989; GABA it produces may lead to activation of ex- Stuchlı´k et al. 2001). Thus, vigabatrin has a bi- trasynaptic GABA receptors. phasic action with proconvulsant effects likely related to suppression of synaptic GABAergic neurotransmission and antiseizure effects as a GABA Transaminase result of spillover of GABA into the extracellular 4-Aminobutyrate aminotransferase (GABA space and activation of extrasynaptic GABAA transaminase), an enzyme that catalyzes the receptors. Interestingly, individuals with a rare conversion of GABA and 2-oxoglutarate into genetic deficiency of GABA transaminase expe- succinic semialdehyde and glutamate, is respon- rience refractory seizures, supporting the view sible for the metabolic inactivation of GABA that inhibition of GABA transaminase is, in (Fig. 2). Inhibition of GABA transaminase with fact, the proconvulsant mechanism of vigaba- vigabatrin (g-vinyl GABA), an irreversible sui- trin (Medina-Kauwe et al. 1999). cide inhibitor of the enzyme, leads to marked increases in brain GABA levels (Petroff et al. 1996). Although the antiseizure action of viga- SYNAPTIC RELEASE MACHINERY batrin is believed to reflect inactivation of GABA SV2A transaminase, how this occurs is not straight- forward and does not appear to be caused by Multiple lines of evidence support the conclu- an enhancement of inhibitory synaptic trans- sion that SV2A, a membrane glycoprotein mission. In contrast to the action of tiagabine, found in the secretory vesicles of neurons and vigabatrin does not elicit larger or more pro- endocrine cells and possibly immune cells, is the longed GABAA receptor-mediated synaptic re- molecular target for levetiracetam (Kaminski www.perspectivesinmedicine.org sponses (Overstreet and Westbrook 2001; Wu et al. 2012; Li et al. 2013). There is a strong et al. 2003). Rather, preincubation of brain slices correlation between the affinity of levetiracetam with vigabatrin irreversibly inhibited miniature analogs for binding to SV2A and the potency of and evoked inhibitory postsynaptic currents. the analogs in several animal seizure models. Additional experiments suggested that the par- Moreover, seizure protection conferred by leve- adoxical effect resulted from a reduction in the tiracetam and other SV2A ligands strongly cor- GABA content of synaptic vesicles caused by relates with the degree of SV2A occupancy in GABA transaminase inhibition. In contrast to vivo. Finally, the antiseizure efficacy of levetir- the effect on GABA-mediated synaptic trans- acetam (but not valproate, which does not in- mission, vigabatrin caused an increase in tonic teract with SV2A) is reduced in SV2Aþ/– mice (nonsynaptic) GABAA receptor current. This that have one copy of SV2A disrupted by gene steady current is believed to be mediated by targeting. The precise way in which binding of the action of GABA in the extracellular milieu levetiracetam to SV2A leads to seizure protec- acting on extrasynapic GABAA receptors. High tion is not understood. levels of intracellular GABA cause a reversal of Indeed, the function of SV2A itself is ob- GABA transporters, resulting in a marked ele- scure. Among the various functions proposed

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M.A. Rogawski et al.

are roles in calcium-dependent exocytosis, neu- Pe´rez et al. 2008). This form of synaptic depres- rotransmitter loading/retention in synaptic sion is distinct from that mediated by depletion vesicles, and synaptic vesicle priming, as well of the readily releasable pool of vesicles and is as transport of vesicle constituents. SV2A is not believed to come into play during ordinary one of three homologous SV2 proteins that ongoing activity. It may, however, limit synaptic belong to the major facilitator superfamily of transmission during sustained high-frequency 12-transmembrane domain transporters. De- firing and thus serve as an endogenous mecha- spite substantial effort, no transport function nism to restrain epileptic activity. It is, therefore, of these proteins has yet been identified, al- of interest that levetiracetam has been shown to though studies with protein tomography have cause a small acceleration of supply rate depres- found that SV2A can adopt two alternate con- sion (Garcı´a-Pe´rez et al. 2015). This effect was formations consistent with a transporter role observed in experiments with mouse hippo- (Lynch et al. 2008). Interestingly, however, lev- campal CA1 neurons activated by Schaffer col- binding does not cause a large-scale lateral stimulation in brain slices and also in conformational change in SV2A, or lock a spe- hippocampal neurons in culture, but not in cul- cific conformational state of the protein, as tured neurons from mice lacking SV2A, indicat- would an inhibitor of transport. Apparently, ing that an interaction of levetiracetam with the drug has a more subtle effect on the protein. SV2A is likely to account for the phenomenon. Although the function of SV2A is still poorly Thus, work in various laboratories raises the defined, SV2A2/ – knockout mice show a lethal possibility that levetiracetam confers seizure seizure phenotype demonstrating that SV2A, in protection through an interaction with SV2A some way, serves to restrain seizure activity. by reducing synaptic release in a use-dependent A series of recent studies has examined the fashion that requires high-frequency activation impact of levetiracetam on synaptic transmis- for prolonged periods. sion in brain slice recordings (Meehan et al. With respect to the specificity of levetirace- 2011, 2012). Although the drug had no effect tam’s effect on SV2A, it is important to note that on synaptic physiology with low frequency several other cellular and molecular effects of activation, levetiracetam did reduce the synap- this ASD have been reported at therapeutically tic release of both excitatory (glutamate) and relevant concentrations, including inhibition inhibitory (GABA) neurotransmitters during of high-voltage–gated calcium channels, inhi- high-frequency activation. The frequency de- bition of calcium release from intraneuronal pendence is compatible with the selective sup- stores, effects on the metabolism and turnover pression of epileptic activity. Modulation of of GABA in discrete brain regions, reduction www.perspectivesinmedicine.org synaptic release is a common mechanism of in the firing activity of GABAergic neurons in many ASDs, including sodium-channel block- substantia nigra pars reticulata in vivo, and re- ers, which indirectly inhibit release at both ex- versal of zinc-induced inhibition of GABAA re- citatory and inhibitory synapses by inhibiting ceptors in epileptic tissue (Lo¨scher et al. 1996; action potential firing. It appears that drugs Lyseng-Williamson 2011; Wakita et al. 2014). that suppress inhibition and excitation can ef- The relevance of any of these various pharma- fectively protect against seizures, and they are cological actions to the antiseizure effect of lev- not often proconvulsant. However, it is note- etiracetam remains to be defined. worthy that in some instances ASDs (notably, phenytoin) can have proconvulsant effects, par- a2d-1 ticularly at high doses. With several seconds of heavy use, as likely The gabapentin and pregabalin occurs during epileptic activity, excitatory syn- act by binding to the a2d-1 protein, which is apses undergo a form of short-term plasticity an accessory subunit of voltage-gated calcium that is dependent on the supply of new vesicles channels (Dolphin 2013; Stahl et al. 2013). referred to as “supply-rate depression” (Garcı´a- a2d-1 is located heterogeneously in the brain,

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Antiseizure Drugs and the Ketogenic Diet

particularly, at presynaptic sites on excitatory membrane (Hendrich et al. 2008; Weissmann (glutamatergic) neurons. Dense expression is et al. 2013). Whether this action could account observed in areas relevant to epilepsy, including for the rapid antiseizure effects of gabapenti- in excitatory hippocampal mossy fibers and in noids in animal models is uncertain. the neocortex and amygdala. In contrast, a2d-1 Gabapentin and pregabalin were initially has minimal expression in the thalamus and it is developed as lipophilic, blood–brain barrier noteworthy that gabapentinoids are not active permeable forms of GABA (3-alkylated GABA in absence seizures, which, as discussed above, analogs), but it is generally accepted that effects are dependent on this brain structure. Four a2d on GABA do not contribute to the pharma- subunits have been identified, but gabapenti- cological action of these drugs (Taylor et al. noids only bind to a2d-1 and a2d-2 owing 2007). However, the gabapentinoids do activate to the presence of an RRR motif containing the GABA-synthesizing enzyme glutamic acid a critical arginine that is required for binding. decarboxylase (GAD) (Silverman et al. 1991) In knock-in mutant mice bearing a mutation and elevate GABA turnover at antiseizure doses in this motif (RRR mutated to RRA) in a2d-1, in rats (Lo¨scher et al. 1991) and patients with which eliminates gabapentin and pregabalin epilepsy (Petroff et al. 1996). Interestingly, the binding, the analgesic and anxiolytic-like activ- activating effects of the gabapentinoids on GAD ity of pregabalin is eliminated (Field et al. 2006; and GABA turnover were similar to those re- Lotarski et al. 2011). A corresponding mutation ported for valproate (Lo¨scher 1989; Silverman in a2d-2, which also eliminates binding, has et al. 1991; Taylor et al. 1992). no similar effect on the anxiolytic-like activity of pregabalin demonstrating that a2d-1 and not AMPA RECEPTORS a2d-2 is relevant for its pharmacological ac- tivity; studies to determine whether binding Of the synapses in the brain, 80%–90% are to a2d-1 and not a2d-2 is necessary and suffi- excitatory (Hassel and Dingledine 2012). At cient to account for the antiseizure activity of these synapses, which are often between the pre- gabapentinoids have not been reported. Inter- synaptic terminal of an excitatory neuron and estingly, deletion of a2d-1 or a2d-2 in mice is a dendritic spine of the postsynaptic neuron, associated with absence epilepsy or enhanced neurotransmitter glutamate released from the seizure susceptibility (Ivanov et al. 2004; Davies presynaptic terminal acts on ionotropic (ion et al. 2007). flux conducting) and metabotropic (nonion The precise manner in which binding of flux conducting, G-protein-coupled) glutamate gabapentin and pregabalin to the a2d-1 protein receptors localized to the postsynaptic density. www.perspectivesinmedicine.org results in its pharmacological activity, including Ionotropic glutamate receptors mediate a fast seizure protection, is not well understood (Ro- (millisecond timescale) depolarization of the gawski and Bazil 2008). Although some studies postsynaptic neuron, referred to as the excitato- have found that the drugs inhibit calcium chan- ry postsynaptic potential (EPSP). AMPA recep- nel currents, most have not and it is generally tors, one type of ionotropic glutamate receptor, believed that calcium channel inhibition is not generate the bulk of the EPSP and are there- the mechanism of action of gabapentinoids fore the principal ion channel responsible for (Stefani et al. 1998; van Hooft et al. 2002; Brown fast synaptic excitation. It has been long appre- and Randall 2005). Regardless of whether the ciated that cascading excitation within net- drugs inhibit calcium channel function, they works of synaptically connected neurons is a do seem to block the release of various neuro- key mechanism of epileptic synchronization, transmitters, including glutamate, and this at least in the hippocampal CA3 subfield and, may account for the antiseizure activity (Dooley possibly, in other brain areas (Rogawski 2013). et al. 2007). There is some evidence that Epileptic activity emerges from the network gabapentinoids cause internalization of calci- when GABA-mediated inhibition is deficient um channels by reducing trafficking to the cell and, indeed, chronic alterations in inhibition

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represent a leading hypothesis to explain some irritability, and somnolence, are common, par- forms of epilepsy (Houser 2014). AMPA recep- ticularly at higher doses, emphasizing the im- tors have a special role in epileptic activity as portance of AMPA receptors in brain function. epileptic synchronization cannot occur when Although AMPA receptor antagonists have AMPA receptors are blocked. In contrast, kai- powerful antiseizure effects, they are not anti- nate receptors, which are ionotropic glutamate epileptogenic in animal models (Rogawski et al. receptors that have a similar structure to AMPA 2001; Twele et al. 2015). receptors, do not have a similarly essential role Secondarily generalized tonic–clonic sei- as kainate receptor knockout does not inter- zures and, probably, also primary generalized fere with seizure generation (Fritsch et al. tonic–clonic seizures engage distant regions in 2014). NMDA receptors are thought to contrib- the cerebral cortex, as well as subcortical struc- ute to epileptiform activity, but the blockade tures including thalamus, cerebellum, and basal of NMDA receptors is insufficient to abolish ganglia (Blumenfeld et al. 2009). Glutamatergic epileptiform discharges in many seizure models neurons are responsible for the spread of exci- (Neuman et al. 1988; Lo¨scher 1998). Moreover, tation to these structures and also for thala- NMDA blockers may exacerbate seizures in mocortical projections that synchronize distant humans (Sveinbjornsdottir et al. 1993; Kaste- cortical sites. As is the case at glutamate synap- leijn-Nolst Trenite´ et al. 2015). Pharmacological ses, generally, AMPA receptors generate the bulk blockade of AMPA receptors has broad spec- of the excitatory current during fast synaptic trum antiseizure activity in in vitro and animal transmission in these pathways (Turner and seizure and epilepsy models (Yamaguchi et al. Salt 1998). The involvement of AMPA receptors 1993; Rogawski 2011; Twele et al. 2015). In neo- in long cortical–cortical and cortical–subcor- cortical and hippocampal tissue removed from tical pathways, which mediate the spread of ex- patients with focal epilepsy, there is evidence citation in generalized seizures, is likely the basis that AMPA receptor density is increased (Ma- for the effectiveness of AMPA receptor antago- thern et al. 1998; Zilles et al. 1999; Eid et al. nists in the treatment of secondarily generalized 2002). Thus, it has been proposed that the hy- (Steinhoff et al. 2013) and primary generalized perexcitability in focal epilepsy, in part, relates tonic–clonic seizures, and also in suppressing to strengthened excitatory circuits because of the generalized photoparoxysmal electroen- increased expression of AMPA receptors. AMPA cephalography (EEG) response in patients with receptors may therefore be a pivotal pharmaco- photosensitive epilepsy (Kasteleijn-Nolst Tre- logical target for the control of seizures. nite´ et al. 2015). Perampanel, a potent noncompetitive www.perspectivesinmedicine.org AMPA receptor antagonist, is the first and at MIXED TARGETS present only antiseizure agent available for clin- ical use that selectively targets AMPA receptors Valproate (Fig. 1). Perampanel does not affect NMDA re- Although valproate is one of the most widely ceptor responses and has no known effects on prescribed ASDs, the mechanism by which it other ion channels or molecular targets at ther- protects against seizures is poorly understood. apeutically relevant concentrations (Hanada Valproate has multiple pharmacological actions et al. 2011; Chen et al. 2014). Therapeutic blood (Rogawski and Porter 1990; Lo¨scher et al. 2002). levels are expected to result in brain concentra- Because it has been difficult to relate any one tions that would produce only low levels of in- mechanism to the drug’s broad spectrum of hibition of AMPA receptors (Rogawski and clinical activity, it has been proposed that com- Hanada 2013). However, such low-level block bined actions on several targets could account of AMPA receptors is apparently sufficient to for its therapeutic properties. Although the ac- exert a clinical antiseizure action. Perampanel tions of valproate on GABA systems are not has a relatively low therapeutic window. Adverse straightforward, among the various pharmaco- central nervous system effects, such as dizziness, logical effects that have been described, those

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Antiseizure Drugs and the Ketogenic Diet

related to GABA mechanisms are among the The effects of topiramate on sodium chan- most likely to be relevant to valproate’s antisei- nels occur at relatively low, therapeutically rele- zure activity. For example, valproate increases vant concentrations and could be similar to the the turnover of GABA in a regionally selective effects of other sodium-channel-blocking ASDs manner (Lo¨scher 1989) and this might be asso- (Avoli et al. 1996). In addition to effects on fast ciated with enhanced synaptic or extrasynaptic sodium currents, topiramate, like phenytoin, inhibition. At high concentrations, valproate af- blocks INaP at low concentrations (Sun et al. fects voltage-gated sodium channels, but recent 2007). Effects of topiramate on GABAA recep- studies in brain slice recordings have failed to tors could contribute to the broad spectrum provide support for sodium-channel block as a activity of topiramate. Topiramate is not active relevant mechanism to explain clinical activity in animal models, such as the pentylenetetrazol (Englund et al. 2011). Similarly, despite efficacy (PTZ) test, which are typically sensitive to drugs in absence epilepsy, there is little support for that positively modulate GABAA receptors. effects on T-type calcium channels. It is clear Nevertheless, the drug does have activity in that valproate has pharmacological actions rel- an absence of epilepsy models (Rigoulot et al. evant to its antiseizure activity that remain to be 2003) and can affect pentylenetetrazol thresh- elucidated. old, which is consistent with effects on GABAA receptors. There is evidence that topiramate Felbamate may preferentially modulate a subset of GABAA receptors and that drug sensitivity is dependent Felbamate has been shown to act both as a pos- on the b-subunit type (Simeone et al. 2011). itive modulator of GABA receptors and also to A Several investigators have suggested that ac- inhibit NMDA receptors (Rho et al. 1994). Fel- tions on fast glutamate-mediated excitatory bamate potentiates GABA responses via an neurotransmission could contribute to topira- interaction with a site on the GABA receptor A mate’s antiseizure activity. In cultured neurons, that is distinct from the recog- the drug has been reported to inhibit responses nition site. This action may be of relevance to to kainate, an agonist of AMPA and kainate felbamate’s clinical activity. As discussed above, receptors, leading to the conclusion that topir- NMDA receptors have not been validated as amate could be an antagonist of either AMPA or a target to treat focal or generalized seizures. kainate receptors (Gibbs et al. 2000). Recently, Therefore, it is uncertain whether the NMDA- kainate receptors have been found to be an un- receptor-blocking activity of felbamate is rele- likely target for an antiseizure agent (Fritsch vant to its clinical antiseizure activity. et al. 2014). Whether actions of topiramate on www.perspectivesinmedicine.org glutamate-mediated neurotransmission con- Topiramate tribute to its antiseizure activity remains to be Topiramate shows a variety of pharmacological determined. actions, but the extent to which any of the ac- It has been assumed that the topiramate’s tions are relevant to its broad-spectrum antisei- inhibition of carbonic anhydrase does not con- zure activity is uncertain. Targets potentially tribute to its clinical efficacy because there is relevant to seizure protection include voltage- no cross-tolerance to the antiseizure activity of gated sodium channels, GABAA receptor sub- topiramate when tolerance occurs to the classi- types, AMPA or kainate receptors, and types II cal carbonic anhydrase inhibitor and IV carbonic anhydrase isoenzymes. Unlike in mice. However, a recent review left open the other ASDs, the effects on ion channels are possibility that carbonic anhydrase inhibition not likely to occur through direct modulation could, in part, play a role (Shank and Maryanoff of channel gating. Rather, the pharmacologi- 2008). cal actions of topiramate seem to be mediated Topiramate is well recognized to cause ad- indirectly, possibly through effects on channel verse cognitive effects, including impairment of phosphorylation (Shank et al. 2008). working memory and verbal fluency. A blood-

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concentration-dependent decline in phonemic in the treatment of infantile spasms; whether generative fluency has been shown, but the basis ACTH is truly superior remains to be shown for this effect is not understood (Ahmed et al. conclusively. One possible additional action 2015). of ACTH that could contribute to an enhanced action is through stimulation of neurosteroid Zonisamide synthesis. In addition to its actions with respect to glucocorticoids, ACTH also stimulates de- There are some similarities between topiramate oxycorticosterone (DOC) release from the and zonisamide as they both contain a sulfur zona glomerulosa of the adrenal cortex. DOC atom and both inhibit carbonic anhydrase. In is, in part, converted to the antiseizure neuro- addition, like topiramate, zonisamide may act steroid tetrahydro-DOC, which is a positive al- onvoltage-gated sodium channels (Biton 2007). losteric modulator of GABAA receptors (Reddy Electrophysiological studies, however, do not and Rogawski 2002). It has been hypothesized support an action on GABAA receptors. Unlike that the tetrahydro-DOC could, at least in part, topiramate, there are reports that zonisamide contribute to the ability of ACTH to terminate can inhibit T-type voltage-gated calcium chan- infantile spasms. nels (Matar et al. 2009), which as stated above may account for its activity in absence epilepsy. KETOGENIC DIET Rufinamide The use of dietary manipulations to treat The unique spectrum of clinical activity of epilepsy—in particular, controlling seizures rufinamide in the treatment of Lennox–Gas- through sustained fasting—dates back to the taut syndrome (a highly medically intractable time of Hippocrates (Lennox and Cobb 1928; epileptic encephalopathy) suggests that it has a Wheless 2008). In the early 1920s, investigators distinct mechanism of action (Rogawski 2006). realized that a diet composed principally of fats However, to date, rufinamide has only been could be as effective as fasting and yield long- shown to interact with voltage-gated sodium term suppression of seizures without severe ca- channels and the effects are subtle. Relevant loric deprivation. Thus was born the ketogenic concentrations of the drug may, at least for diet whose hallmark feature is the production some subunit isoforms, cause a depolariza- of ketone bodies (b-hydroxybutyrate, acetoace- tion in the activation voltage and slowing of tate, and acetone) by the liver (Peterman 1924; recovery from inactivation, which would be ex- Freeman and Kossoff 2010). In an era before the pected to reduce neuronal excitability (Gilchrist availability of safe and effective ASDs, the keto- www.perspectivesinmedicine.org et al. 2014). Clearly, the effects on sodium chan- genic diet quickly became popular in large med- nels cannot explain the special clinical profile ical centers. However, with the advent of phe- of rufinamide. nytoin in 1938, the ketogenic diet quickly fell out of favor mainly because the oral was simpler than the strict and exacting dietary Adrenocorticotrophin regimen. Beginning in the mid-1990s, there was The mechanism of adrenocorticotrophin a resurgence of interest in the ketogenic diet as it (ACTH) in the treatment of infantile spasms is was increasingly recognized that the diet has not well understood (Stafstrom et al. 2011). utility in the treatment of drug-resistant epilep- ACTH stimulates glucocorticoid (cortisol) syn- sy (Freeman and Kossoff 2010). Today, the ke- thesis and release from the zona fasciculata togenic diet is an established therapy for diffi- of the adrenal cortex. The cortisol could pro- cult-to-treat epilepsies, particularly in children, duce an anti-inflammatory action or have some and is increasingly being studied for therapeu- other action in the brain to influence infantile tic efficacy in a number of other neurological spasms. Indeed, glucocorticoids are well recog- disorders (Gasior et al. 2006; Neal et al. 2008; nized themselves and have therapeutic activity Stafstrom and Rho 2012).

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Antiseizure Drugs and the Ketogenic Diet

Scientific interest in the mechanisms by molecular targets through which ketone bodies which the ketogenic diet exerts seizure control act to protect against seizures have not yet been has evolved rapidly in parallel with the growth clearly identified, there is strong evidence to in clinical use of the diet over the past 20 years suggest that mitochondria are critically in- (Masino and Rho 2012). Effectiveness of the volved (Masino and Rho 2012). Also, given ketogenic diet has been amply shown in animal that the ketogenic diet is mainly used in younger models of seizures and epilepsy. Still, at present, patients, enhanced efficacy in this population the basic mechanisms of ketogenic diet action could reflect age-dependent changes in the remain incompletely understood. There is sub- expression of monocarboxylate transporters, stantial interest in defining these mechanisms. which import ketone bodies across the blood– Dietary therapy is not feasible for many pa- brain barrier from the systemic circulation tients, but the insights gained from study of (Morris 2005; Pierre and Pellerin 2005). the diet may provide clues to the creation of more effective ASDs to address pharmacoresis- Effects on GABA and Glutamate Metabolism tant epilepsy. Since the 1930s, numerous mech- anistic hypotheses have been advanced to ex- It has been proposed that increased synthesis or plain the antiseizure effects of the ketogenic levels of the inhibitory neurotransmitter GABA diet; the key mechanisms are discussed below or decreased synthesis or levels of the excitatory and summarized in Table 2. neurotransmitter glutamate could explain the antiseizure activity of the ketogenic diet. The implication of such findings is uncertain inas- Direct Effects of Ketone Bodies much as it has not been shown that these ma- The earliest demonstration that ketone bod- nipulations influence neural circuit excitability, ies have antiseizure properties was given in either through synaptic or nonsynaptic actions. the 1930s. Acetoacetate was shown to protect Nevertheless, we summarize the results of some against thujone-induced seizures in rabbits of these studies to illustrate the kinds of obser- (Keith 1933). Further, acetone was shown to vations that have been reported. exert antiseizure activity in several animal mod- The influence of the ketogenic on GABA has els (Likhodii et al. 2003; Gasior et al. 2007). been proposed to originate in changes in gluta- Recently, chronic administration of the major mate metabolism (Yudkoff et al. 2005). Gluta- ketone, b-hydroxybutyrate, was shown to block mate is cleared from the synaptic space by as- spontaneous seizures in epileptic mice (Kim trocytes, which convert glutamate to glutamine et al. 2015). Interestingly, the in vivo evidence through the action of the glial enzyme gluta- www.perspectivesinmedicine.org for the antiseizure effects of ketone bodies has mine synthetase. Glutamine is then exported been discordant with earlier in vitro studies. to neurons where it is hydrolyzed to glutamate Application of acetoacetate or b-hydroxybuty- and can then either be converted to GABA or rate in acute hippocampal brain slices from transaminated to aspartate in a reaction that normal rats failed to reveal effects on GABAA requires oxaloacetate. Because the ketogenic receptors and ionotropic glutamate receptors, diet induces metabolic changes that require and on synaptic transmission (Thio et al. available oxaloacetate to condense with acetyl- 2000). However, more recent data indicate that CoA for incorporation into the tricarboxylic the antiseizure activity of ketone bodies in vitro acid (TCA) cycle, the production of aspartate may require long-term incubation and not sim- from glutamate is reduced. This may result ply acute exposure (Kim et al. 2015). Collective- in enhanced flux through GAD to increase the ly, it appears that ketone bodies afford broad synthesis of GABA. spectrum antiseizure activity in animal models Experimental support for this biochemical and, hence, the possibility that these metabo- hypothesis is mixed. In the study proposing the lites contribute to the therapeutic efficacy of hypothesis, which used a mouse model of keto- the diet cannot be discounted. Although the sis, changes in levels of aspartate were found,

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Table 2. Putative mechanisms of the antiseizure effects of the ketogenic diet Mediator/physiological change Basis Mechanism of antiseizure effects Ketone bodies (acetone, Chronic ketosis as a result of Unknown acetoacetate, and b- elevated FFAs ? Inhibit presynaptic release of hydroxybutyrate have glutamate by competing with antiseizure activity; further, Cl2 for allosteric activation of acetoacetate, and b- vesicular glutamate transporter hydroxybutyrate provide ? Activate KAT P and GABAB resistance to oxidative stress) receptors (reduced ATP also activates KAT P ) ? Inhibit HDAC, leading to increased resistance to oxidative stress ? Inhibit mitochondrial permeability transition Increased GABA synthesis (flux Brain converts ketone bodies to ? Enhanced GABA-mediated through GAD) acetyl-CoA; increased flux inhibition through TCA cycle, consumes oxaloacetate, which is less available to the aspartate aminotransferase reaction; less glutamate is converted to aspartate and relatively more glutamate becomes available to the glutamine synthetase and GAD reactions Adenosine Levels of ATP elevated leading to Activation of adenosine A1 increased conversion to receptors on excitatory neurons adenosine in neurons and astrocytes Increased mitochondrial function Unknown Increase ATP production and and biogenesis enhanced energy reserves Nrf2 Ketogenic diet initially produces Reversal of chronically low GSH in mild oxidative and electrophilic epilepsy stress, activating Nrf2 via redox Induction of genes encoding

www.perspectivesinmedicine.org signaling protective proteins; improvement of the mitochondrial redox state Reduced mitochondrial ROS Enhanced expression of UCPs by Increased UCPs diminish DC fatty acids acting on PPAR and leading to reduced ROS FOX Anaplerosis In ketogenic diet, there is reduction Correct glutamate and GABA in glycolysis and increase in deficiencies in brain oxidation of FA and ketone Enhanced neuronal ATP bodies (glycolytic restriction/ production diversion) Reduce expression of proepileptic BDNF and TrkB through NRSF binding to NRSE; decrease in cytosolic and nuclear levels of NADH Continued

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Antiseizure Drugs and the Ketogenic Diet

Table 2. Continued Mediator/physiological change Basis Mechanism of antiseizure effects PUFAs Ketogenic diet enhances PUFAs directly affect ion channels mobilization of PUFAs from Activation of PPARa and PGC-1a adipose tissue to liver and (coactivator) leads to changes in brains transcription of genes linked to energy, amino acid, and neurotransmitter metabolism Boost activity of UCPs Medium-chain triglycerides Exogenous administration of in Unknown (similar action to the medium-chain triglyceride valproate) ketogenic diet FFA3 Activated by short-chain fatty Inhibit N-type voltage-gated acids and b-hydroxybutyrate calcium channels, leading to reduced glutamate release at synapses FFAs, Free fatty acids; HDAC, histone deacetylase; GABA, g-aminobutyric acid; GAD, glutamic acid decarboxylase; Nrf2, NF E2-related factor 2; TCA, tricarboxylic acid; GSH, glutathione; ROS, reactive oxygen species; UCPs, uncoupling proteins; PPAR, peroxisome proliferator-activated receptor; FOX, forkhead box; FA, ; NRSF, neural restrictive silencing factor; NRSE, neuron restrictive silencing element; PUFAs, polyunsaturated fatty acids; BDNF, brain-derived neurotrophic factor; TrkB, tropomyosin receptor; NADH, nicotinamide adenine dinucleotide (reduced).

along with the expected increases in acetyl-CoA, ity by inhibiting the presynaptic release of glu- but there were no changes in the levels of GABA tamate. The ketone bodies b-hydroxybutyrate or glutamate (Yudkoff et al. 2005). The same and acetoacetate were shown to diminish gluta- study did show increases in glutamine and mate release by directly competing with Cl2 for GABA on infusion of the nitrogen donors ala- allosteric activation of vesicular glutamate nine or leucine. Rats fed the ketogenic diet for transporters (Juge et al. 2010). In the same 3 wk showed a reduction in brain glutamate study, application of the potassium channel levels, but also no change in GABA (Melo blocker 4-aminopyridine to rat brain in vivo et al. 2006). However, in children fed the keto- evoked seizures with concurrent secretion of genic diet, cerebrospinal fluid levels of GABA glutamate, and these effects were blocked by have been shown to increase, but without a acetoacetate. The relevance of this study is fur- www.perspectivesinmedicine.org change in glutamate concentrations (Dahlin ther supported by the recent observation that et al. 2005). Another study in rats fed the keto- b-hydroxybutyrate does indeed induce antisei- genic diet for 3 wk found “increased” levels of zure activity (Kim et al. 2015). glutamate and glutamine in the hippocampus (Bough et al. 2006). Further, using both mild K Channels and GABA Receptors caloric restriction (90% of daily energy require- ATP B ments) and an isocaloric ketogenic diet, inves- It has been proposed that activation of KAT P tigators found significant increases in the mes- channels and GABAB receptors could underlie senger RNA (mRNA) expression of both the action of the ketogenic diet (Ma et al. 2007). isoforms of GAD (GAD65 and GAD67) in sev- In brain slice recordings, acetoacetate and eral brain regions that were independent of ke- b-hydroxybutyrate were found to reduce the togenic effects (Cheng et al. 2004); the function- spontaneous firing rate of GABAergic neurons al implications are unclear given that GABA in the substantia nigra pars reticulata, a putative levels were not increased. subcortical seizure gate, and this action was de- Recently, it has been proposed that the ke- pendent on KAT P channels and GABAB recep- togenic diet could suppress neuronal excitabil- tors. Apart from the fact that KAT P channels and

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GABAB receptors have been previously shown gy reserves, ATP levels, and the expression of not to be germane antiseizure targets except in many enzymes involved in mitochondrial me- special circumstances (Meldrum and Rogawski tabolism, the ketogenic diet has also been 2007), most problematic for the hypothesis is shown to increase mitochondrial biogenesis in the fact that the ketogenic diet and ketone bod- the hippocampus (Bough et al. 2006) and to ies actually increase ATP production, which reduce oxidative stress through multiple cellular would tend to close KAT P channels and enhance mechanisms, including those involving mito- instead of inhibit neuronal excitability (Masino chondria, such as through increases in reduced and Rho 2012). In any case, the same group has glutathione (GSH). The effect on GSH is of shown that the open probability of KAT P chan- particular interest because depletion of GSH is nels in the hippocampus in vitro is enhanced known to occur in epilepsy (Mueller et al. 2001). in the presence of b-hydroxybutyrate (Tanner Increased GSH was shown to correlate with in- et al. 2011). creased activity of glutamate cysteine ligase (GCL), the rate-limiting enzyme in GSH bio- synthesis, and enhanced expression of the GCL Adenosine catalytic subunit, GCLC, and modulatory sub- Recent studies have implicated the potent in- unit, GCLM, in rats fed the ketogenic diet (Jar- hibitory modulator adenosine, which is well rett et al. 2008). recognized to have antiseizure activity (Dun- The increase in GSH and associated changes widdie and Masino 2001), in the action of the were subsequently shown to involve NF E2- ketogenic diet (Masino et al. 2012). Adenosine related factor 2 (Nrf2), a redox-sensitive tran- produces antiseizure effects through activation scription factor that is activated by cellular stress of inhibitory adenosine A1 receptors on excit- and induces a diverse array of genes, including atory neurons. Adenosine is synthesized by the GSH antioxidant pathway (Suzuki et al. hydrolysis of ATP in neurons and astrocytes. 2013). The ketogenic diet resulted in elevated Because levels of ATP are elevated by the keto- levels of Nrf2 for 3 wk, and this was associated genic diet, it is plausible that adenosine syn- with increased activity of NAD(P)H:quinone thesis and release could also be enhanced. Tar- oxidoreductase, a prototypical Nrf2 target þ/ – geted heterozygous (A1R ) or homozygous (Milder et al. 2010). Interestingly, a recent study 2/ – (A1R ) deletion of A1 receptors or increased found that increasing Nrf2 expression in a rat expression of adenosine kinase (Adk-Tg), an model of temporal lobe epilepsy decreased enzyme that enhances clearance of adenosine, spontaneous seizures (Mazzuferi et al. 2013). causes spontaneous electrographic seizures in Acute application of the ketone bodies b- www.perspectivesinmedicine.org mice (Masino et al. 2011). A 3-wk treatment hydroxybutyrate and acetoacetate in hippocam- with the ketogenic led to decreased electro- pal slices enhanced catalase activity in response þ/ – graphic seizures in Adk-Tg and A1R mice, H2O2 (Kim et al. 2010) and decreased oxida- 0 0 but not in animals entirely missing A1R recep- tion of carboxy-2 ,7 -dichlorodihydrofluorescein 2/– tors (A1R ), supporting the concept that diacetate, a dye often used as an indicator of adenosine may be an important mediator of intracellular ROS (Maalouf and Rho 2008). In the ketogenic diet’s antiseizure effects. isolated mitochondria, b-hydroxybutyrate and acetoacetate have been shown to decrease ROS levels in response to glutamate by enhancing Bioenergetic and Mitochondrial Changes oxidation of NADH (Maalouf et al. 2007). Ad- Pathological changes in mitochondrial energy ditionally, b-hydroxybutyrate and acetoacetate metabolism and reactive oxygen species (ROS) reduced mitochondrial ROS both basally and in production are known to occur with epilepto- response to the ATPsynthase inhibitor oligomy- genesis, and the ketogenic diet has been found cin (Kim et al. 2007). to profoundly affect these processes (Rowley A possible mechanism mediating the de- and Patel 2013). In addition to enhancing ener- crease in mitochondrial ROS production with

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Antiseizure Drugs and the Ketogenic Diet

the ketogenic diet is enhanced expression of un- Seizure susceptibility is further augmented by coupling proteins (UCPs). Increased activity of the reduction in these neurotransmitters and UCPs can diminish the mitochondrial mem- reduced energy (ATP) production as a result brane potential (DC), resulting in a decrease of diminished acetyl-CoA. A key feature of the in ROS production, and this has been associated ketogenic diet is a relative reduction in glycoly- with increased resistance to kainate-induced sis and an increase in nonglucose sources of fuel seizures (Sullivan et al. 2003). Additionally, fat- through the oxidation of fatty acids and ketone ty acids can induce increases in UCP expression bodies, which ultimately feed the TCA cycle possibly through enhanced activity of transcrip- through a process known as anaplerosis (i.e., tion factors, such as the peroxisome prolifera- the replenishing of depleted metabolic cycle in- tor-activated receptor (PPAR) and the forkhead termediates). Anaplerosis is believed to correct box (FOX) family of transcription factors (Azzu the neurotransmitter (glutamate and GABA) and Brand 2010). In mice fed the ketogenic diet, deficiencies and enhance neuronal ATPproduc- UCP activity was enhanced and this was asso- tion, which ultimately leads to a reduction in ciated with increased levels of UCP2, UCP4, seizure susceptibility. Glycolytic restriction is and UCP5 in the hippocampus (Sullivan et al. thought to be an important mechanism medi- 2004). Additionally, ROS production—assessed ating the antiseizure properties of the ketogenic in the presence of oligomycin to maximize diet (Masino and Rho 2012). Indeed, caloric DC—was reduced in mice fed the ketogenic restriction has antiseizure, and possibly antiepi- diet (Sullivan et al. 2004). leptogenic, effects (Mantis et al. 2004). The ear- Recently, b-hydroxybutyrate was shown to liest clinical observation supporting this notion be an inhibitor of class I histone deacetylases is the rapid reversal of seizure control on inges- (HDACs) in vitro and in vivo, and this activity tion of carbohydrates or glucose in patients on was associated with increased resistance to oxi- the ketogenic diet (Huttenlocher 1976). Addi- dative stress (Shimazu et al. 2013). Specifically, tionally, studies in animals using labeled meta- b-hydroxybutyrate increased acetylation of his- bolic precursors have shown that the ketogenic tone H3 lysine 9 (H3K9) and histone H3 lysine diet reduces glycolysis (Yudkoff et al. 2005; 14 and enhanced transcription of genes regulat- Melo et al. 2006). ed by FOXO3A, including the antioxidant en- Recently, attempts have been made to mim- zymes manganese superoxide dismutase and ic the antiseizure activity of the ketogenic diet catalase. Further, b-hydroxybutyrate (adminis- using glycolytic inhibitors. In vitro application tered in vivo for 24 h via an osmotic pump) of 2-deoxy-D-glucose (2-DG), an inhibitor of decreased protein carbonylation and 4-hydrox- phosphoglucose isomerase, reduced epilepti- www.perspectivesinmedicine.org ynonenal and lipid peroxides in the kidney. Al- form bursts induced in hippocampal slices by though the investigators did not report such bicuculline, 4-aminopyridine, and increased effects in neuronal tissue or cells, it is possible extracellular Kþ (Stafstrom et al. 2009). Addi- that direct inhibition of HDACs and the ensuing tionally, in vivo administration of 2-DG pro- transcriptional changes may mediate some of vides protection against audiogenic and 6-Hz the antioxidant effects known to occur in the stimulation-induced seizures in mice and also brain with the ketogenic diet. produced an antiseizure and antiepileptogenic effect in a rat kindling model (Garriga-Canut et al. 2006; Stafstrom et al. 2009; Gasior et al. Glycolytic Restriction/Diversion 2010). The antiseizure effects of 2-DG may be It has been proposed that increased neuro- partially mediated by changes in the expression transmission caused by the hyperexcitability in of genes encoding brain-derived neurotrophic neural networks in chronic epilepsy leads to de- factor and its receptor TrkB, both of which pletion of TCA cycle intermediates, including are regulated by the activity of the transcription a-ketoglutarate, which is a precursor for gluta- factor neural restrictive silencing factor (NRSF), mate and GABA (Borges and Sonnewald 2012). which represses transcription by binding to the

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neuron restrictive silencing element (NRSE) in of PUFAs from adipose tissue to liver and brain promoter regions (Garriga-Canut et al. 2006). (Taha et al. 2005). Large quantities of PUFAs are NRSF transcriptional repression was enhanced not a typical component of the ketogenic diet, by 2-DG and this was associated with a reduc- thus increases in PUFAs must be the result of tion in acetylation and an increase in methyla- endogenous production and export into the tion of H3K9 at the NRSE promoter, epigenetic circulation (Fraser et al. 2003). PUFAs affect modifications associated with suppression of diverse ion channels, including voltage-gated gene transcription. NRSF-mediated repression sodium and potassium channels (Vreugdenhil required an interaction with the transcriptional et al. 1996), and it has been speculated that corepressor carboxyl-terminal binding protein actions of PUFAs on such ion channels could that was disrupted with increasing concentra- mediate the antiseizure effects of the ketogenic tions of NADH, a cofactor that is elevated on diet (Michael-Titus and Priestley 2013). An ad- increased glycolytic flux. This suggests that the ditional mechanism whereby PUFAs could af- antiseizure actions of 2-DG may be mediated fect seizure susceptibility is through activation by a decrease in cytosolic and nuclear levels of of peroxisome proliferator-activated receptor-a NADH and subsequent influences on histone (PPARa), a nuclear receptor that regulates the modifications. transcription of numerous genes linked to en- Fructose-1,6-bisphosphate (FBP) also in- ergy, amino acid, and neurotransmitter metab- hibits glycolysis by diverting the metabolism of olism. Recently, it was shown that fenofibrate, glucose to the pentose phosphate pathway and aPPARa ligand, exerts anticonvulsant activity affords antiseizure effects invivo. FBP was found comparable to the ketogenic diet in adult rats to protect against pilocarpine, kainate, and (Porta et al. 2009). The specific genes relevant to PTZ-induced seizures in rats (Lian et al. 2007) this effect remain to be determined. and also affected kindling acquisition (Ding In pediatric patients with epilepsy, 3–4 wk et al. 2010). FBP had broader activity than val- of ketogenic diet treatment led to elevations in proate and 2-DG, whereas the ketogenic diet was circulating levels of b-hydroxybutyrate, corti- not active in the models. These results reinforce sol, and free fatty acids (FFAs) (Fraser et al. the view that diversion of metabolism away from 2003). Most PUFAs were also increased in the glycolysis is a promising antiseizure strategy. serum, including the triglyceride and phospho- Triheptanoin, the triglyceride of the C7 fatty lipid forms of linoleic acid (LA), heptanoate, is an anaplerotic substrate that acid (AA) and (DHA), restores levels of TCA intermediates (Hadera triglyceride levels of stearic acid, and palmitic et al. 2014). Oral administration of triheptanoin acid in phospholipids. Additionally, these alter- www.perspectivesinmedicine.org has been shown to have antiseizure effects in ations in fatty acids were associated with seizure some animal models, providing support for reduction in 78% of the children. Interestingly, the anaplerosis hypothesis (Willis et al. 2010; seizure control was correlated with circulating Kim et al. 2013). A recent report suggests that AA levels, but not EEG changes. triheptanoin may also have anti-ictal activity in Whether PUFA ingestion can render anti- humans (Pascual et al. 2014). seizure effects remains controversial. Oral sup- plementation with 5 g of omega-3 PUFA for 6 mo appeared to reduce the frequency and se- Fatty Acid Oxidation and Polyunsaturated verity of seizures in a small observational study Fatty Acids (Schlanger et al. 2002). However, in a 12-wk Intake of a high-fat diet, such as the ketogenic randomized, placebo-controlled parallel group diet, increases the rate of fatty acid oxidation. study in adults with epilepsy, administration of This leads to changes in the levels and types of (EPA) and DHA (1 g polyunsaturated fatty acids (PUFAs) in the cir- EPA, 0.7 g DHA daily) reduced seizure frequen- culation, liver, and brain. In particular, it has cy for the first 6 wk of treatment, but this effect been show that there is enhanced mobilization did not persist in spite of sustained increases in

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Antiseizure Drugs and the Ketogenic Diet

DHA and EPA and decreases in AA and LA in Whether administration of a specific medium- the plasma (Yuen et al. 2005). In an additional chain triglyceride in the presence of a normal randomized, blinded trial of PUFA supplemen- diet could represent an epilepsy treatment ap- tation (EPA plus DHA, 2.2 mg/d in a 3:2 ratio proach remains to be determined. over 12 wk) in adults with uncontrolled epilep- sy, there was a lack of clear efficacy when com- Free Fatty Acid Receptor 3 pared with placebo (Bromfield et al. 2008). In rats fed the ketogenic diet, there were Free fatty acid receptor 3 (FFA3) is a G-protein marked reductions of PUFA levels in plasma coupled receptor whose endogenous ligands and adipose tissue, but enhanced mobilization may include short-chain fatty acids, such as ac- of the PUFA AA and DHA to the liver and brain etate and propionate. A study in dissociated (Taha et al. 2005). This was accompanied by sympathetic neurons recently showed that b- an initial increase in plasma levels of b-hy- hydroxybutyrate is also an agonist of FFA3, droxybutyrate, followed by a reduction by day causing inhibition of N-type voltage-gated cal- 10 of the diet. Following a calorie-restricted cium channels (Won et al. 2013). A prior study ketogenic diet, mRNA expression of the rate- also found the ketone body to interact with limiting enzyme for ketone body production, FFA3, but in this case it was an antagonist (Ki- HMG-CoAS2, was found to increase in both mura et al. 2011); the basis for the discrepancy is the liver and brain, in contrast to feeding with not apparent. As of yet, the relevance of these an isocaloric standard chow, which resulted in actions to brain function remains to be deter- enhanced expression only in the liver (Culling- mined. ford et al. 2002). Collectively, these and other animal studies suggest that diet-induced chang- CONCLUSION es in brain content and metabolism of PUFAs may be important contributors to antiseizure In recent years, there have been dramatic ad- effects of the ketogenic diet (Taha et al. 2010). vances in our understanding of how ASDs pre- vent seizures. ASDs interact with a wide variety of molecular targets. There are unique aspects Medium-Chain Triglycerides to the mechanism of each ASD so that it is rarely The medium-chain triglyceride ketogenic diet the case that two ASDs have what could be con- is as efficacious as the classic ketogenic diet in sidered the same mechanisms of action (gaba- which the primary fat source is long-chain tri- pentin and pregabalin are perhaps exceptions). glycerides (Huttenlocher et al. 1971; Neal et al. Although some ASDs have a single cognate tar- www.perspectivesinmedicine.org 2009; Liu and Wang 2013). This diet increases get, for many of the drugs, clinical activity the plasma levels of medium straight-chain fatty is likely the result of actions on several targets. acids. Recently, medium-chain triglycerides of This makes the definition of “mechanism of various structural classes have been shown to action” challenging, but it is perhaps not sur- reduce the frequency of epileptiform discharges prising that control of epilepsy, which is a in in vitro slice models and to inhibit behavioral functional disorder of neural networks, would and EEG seizures in a rat status epilepticus benefit from therapeutic interventions at vari- model; modest activity was also reported in ous points in the network. various in vivo models used to screen for anti- Although ASDs provide control of seizures seizure activity (Chang et al. 2012, 2013, 2015). for many people with epilepsy, a disappoint- Valproate is a short-branched-chain fatty acid. ingly large number do not achieve seizure free- Certain structurally novel medium-chain fatty dom with . The ketogenic diet is an acids have been identified that have greater ac- alternative approach that may provide seizure tivity than valproate in seizure models and that control in cases of drug-resistant epilepsy. There lack the HDAC activity of valproate, which has are still many open questions regarding the been proposed as a basis for its teratogenicity. mechanisms of the ketogenic diet. However, as

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reviewed here, effects of the diet on intermedi- man secondarily generalized tonic-clonic seizures. Brain ary metabolism are likely to be central to its 132: 999–1012. therapeutic activity. These mechanisms are Borges K, Sonnewald U. 2012. Triheptanoin—A medium chain triglyceride with odd chain fatty acids: A new ana- fundamentally different from those believed to plerotic anticonvulsant treatment? Epilepsy Res 100: be relevant to ASDs. Consequently, study of 239–244. the ketogenic diet may open avenues to the cre- Bough KJ, Wetherington J, Hassel B, Pare JF, Gawryluk JW, ation of entirely novel treatment strategies for Greene JG, Shaw R, Smith Y, Geiger JD, Dingledine RJ. 2006. Mitochondrial biogenesis in the anticonvulsant pharmacoresistant epilepsies. Such treatment mechanism of the ketogenic diet. Ann Neurol 60: 223– approaches may improve on the efficacy of 235. the diet and be more convenient and palatable. Broicher T, Seidenbecher T, Meuth P,Munsch T, Meuth SG, There is, therefore, strong justification for con- Kanyshkova T,Pape HC, Budde T.2007. T-current related effects of antiepileptic drugs and a Ca2þ channel antag- tinued investigation of ketogenic diet mecha- onist on thalamic relay and local circuit interneurons in nisms. a rat model of absence epilepsy. Neuropharmacology 53: 431–446. Bromfield E, Dworetzky B, Hurwitz S, Eluri Z, Lane L, Re- plansky S, Mostofsky D. 2008. A randomized trial of ACKNOWLEDGMENTS polyunsaturated fatty acids for refractory epilepsy. Epilep- sy Behav 12: 187–190. M.A.R.’s research is supported by the National Brown DA, Passmore GM. 2009. Neural KCNQ (Kv7) chan- Institute of Neurological Disorders and Stroke nels. Br J Pharmacol 156: 1185–1195. (NS079202). J.M.R.’s research is supported by Chang P,Orabi B, Deranieh RM, Dham M, Hoeller O, Shim- the Canadian Institutes of Health Research. shoni JA, Yagen B, Bialer M, Greenberg ML, Walker MC, et al. 2012. 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Antiseizure Drugs and the Ketogenic Diet

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Mechanisms of Action of Antiseizure Drugs and the Ketogenic Diet

Michael A. Rogawski, Wolfgang Löscher and Jong M. Rho

Cold Spring Harb Perspect Med 2016; doi: 10.1101/cshperspect.a022780 originally published online January 22, 2016

Subject Collection Epilepsy: The Biology of a Spectrum Disorder

The Epilepsy Spectrum: Targeting Future Common Mechanisms Underlying Research Challenges Epileptogenesis and the Comorbidities of Gregory L. Holmes and Jeffrey L. Noebels Epilepsy Andrey Mazarati and Raman Sankar Role of Sodium Channels in Epilepsy The Diathesis−Epilepsy Model: How Past Events David I. Kaplan, Lori L. Isom and Steven Petrou Impact the Development of Epilepsy and Comorbidities Christophe Bernard Mechanisms of Action of Antiseizure Drugs and Potassium Channels in Epilepsy the Ketogenic Diet Rüdiger Köhling and Jakob Wolfart Michael A. Rogawski, Wolfgang Löscher and Jong M. Rho Epilepsy and Autism GABAergic Synchronization in Epilepsy Ashura W. Buckley and Gregory L. Holmes Roustem Khazipov Immunity and Inflammation in Epilepsy Status Epilepticus Annamaria Vezzani, Bethan Lang and Eleonora Syndi Seinfeld, Howard P. Goodkin and Shlomo Aronica Shinnar Hyperpolarization-Activated Cyclic Neonatal and Infantile Epilepsy: Acquired and Nucleotide-Gated (HCN) Channels in Epilepsy Genetic Models Gary P. Brennan, Tallie Z. Baram and Nicholas P. Aristea S. Galanopoulou and Solomon L. Moshé Poolos The Role of Calcium Channels in Epilepsy Epigenetics and Epilepsy Sanjeev Rajakulendran and Michael G. Hanna David C. Henshall and Katja Kobow Interneuron Transplantation as a Treatment for Microcircuits in Epilepsy: Heterogeneity and Hub Epilepsy Cells in Network Synchronization Robert F. Hunt and Scott C. Baraban Anh Bui, Hannah K. Kim, Mattia Maroso, et al.

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