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Home , Felbamate, GABA analogue, GABA receptor

E/~l/tp\lo,34(Suppl. 5):Sl-SR. 1993 Raven Press, Ltd.. New York International League Against

Antiepileptic Mechanisms of Action

*?Robert L. Macdonald and *Kevin M. Kelly

Deparlmenls qf*Neurology and tPhysio1og.v. University of Michigan Medical Cmter, Ann Arbor, Michigan. U.S.A

Summary: Clinically used antiepileptic (AEDs) de- trigine may decrease sustained high-frequency repetitive crease membrane excitability by interacting with ion channels firing. The mechanisms of action of felbamate are unknown. or receptors. Currently available AEDs ap- (GBP) appears to bind to a specific binding site pear to act on sodium channels, GABAAreceptors, or calcium in the with a restricted regional channels. , , and possibly distribution, but the identity of the binding site and the (VPA) decrease high-frequency repetitive firing of action po- of GBP remain uncertain. Key Words: tentials by enhancing inactivation. Benzo- - Neuropharmacology -Neurotransmitten- diazepines and enhance GABAA - GABA -Phen ytoi n -Carbamazepi ne- Ethosuxi mide-Tri- mediated inhibition. and possibly VPA reduce methadione--Barbiturates-Valproate- a low-threshold calcium current. The mechanisms of action Felbamate-Gabapentin--Neural inhibi- of AEDs currently under development are less clear. Lamo- tion-Sodium-Calcium.

A limited number of antiepileptic drugs (AEDs) are PHENYTOIN AND CARBAMAZEPINE available for use in the treatment of patients with epi- lepsy. In the United States, AEDs are limited primarily PHT and CBZ have been shown to interact with to phenytoin (PHT), carbamazepine (CBZ), barbitu- sodium channels at concentrations found free in the rates and (PRM), benzodiazepines (BZDs), plasma of patients being treated for epilepsy (Macdon- valproate (VPA), and ethosuximide (ESM). Three ad- ald, 1989). These AEDs were shown to reduce the fre- ditional AEDs may be available in the United States quency of sustained repetitive firing of action potentials in the near future: felbamate (FBM), gabapentin (GBP), in neurons in cell culture (McLean and Macdonald, and lamotrigine (LTG). It is likely that the currently 1983, 1986b). The characteristic property of these used AEDs as well as the new AEDs have as their pri- AEDs was that they did not reduce the amplitude or mary targets of action neurotransmitter receptors or duration of single action potentials but reduced the ion channels. Three primary neurotransmitter receptor ability of neurons to fire trains of action potentials at or ion channels are targeted by the currently prescribed high frequency. The limitation of high frequency re- AEDs and at least one of the newly developed petitive firing was voltage-dependent, limitation of fir- ones: voltage-dependent sodium channels, voltage- ing being increased after depolarization and reduced dependent calcium channels, and GABAA receptor after hyperpolarization. Once developed, the limitation channels. Basic actions at these ion channels or neu- of firing was prolonged, lasting several hundred milli- rotransmitter receptor channels may be responsible for seconds. The action of the AEDs appeared to be due the clinical actions bf those AEDs. The interaction of to a shift of sodium channels to an inactive state that clinically available AEDs and the three new AEDs was similar to the normally occumng inactive state FBM, GBP, and LTG with those specific neurotrans- but from which recovery was delayed. mitter receptors or ion channels will be the subject of The actions of PHT and CBZ on mammalian my- this review. elinated nerve fibers have been studied (Schwarz and Grigat, 1989). Both AEDs produced a voltage- dependent block of sodium channels that could be re- Address correspondence and reprint requests to Dr. R. L. Mac- donald at Neuroscience Laboratory Building, I103 East Huron, Ann moved by hyperpolarization. PHT produced a shift of Arbor, MI 48104-1607, U.S.A. the steady-state sodium channel inactivation curve to

Sl s2 R. L. MACDONALD AND K. M.KELLY

more negative voltages. Both PHT and CBZ reduced myelinated nerve, and rat hippocampal pyramidal the rate of recovery of sodium channels from inacti- neurons. vation. In control solutions, sodium channels recovered Thus, evidence from voltage-clamp experiments has from complete inactivation within a few milliseconds confirmed the basic mechanism of action of PHT and after 500-ms depolarization to 25 mV. In the presence CBZ. Both AEDs appear to stabilize the inactive form of 100 pM PHT, recovery was prolonged to 90 ms. of the sodium channel in a voltage-dependent fashion, With 100 pM CBZ, recovery was prolonged to 40 ms. the effect being lessened at large negative membrane At 50 pM, PHT and CBZ each produced a frequency- potentials and increased at less-negative membrane dependent block. At 50 pM, PHT produced an initial potentials. Both AEDs slow the rate of recovery from block of 50%. With repetitive stimulation at 10 Hz, sodium channel inactivation and shift the steady-state the block increased to approximately 80% over 2.5 s. sodium inactivation curve to more negative voltages. Recovery from that block required approximately That stabilization of the inactive form of the receptor 2.5 s. At 100 pM. CBZ also produced a frequency- results in frequency-dependent block of sodium chan- dependent block that was somewhat less pronounced nels and blockade of sustained high-frequency repeti- than that produced by PHT. Thus, PHT and CBZ pro- tive firing of action potentials evoked from reduced duced voltage- and frequency-dependent block of so- membrane potentials. Of interest is the finding that dium channels. Because the concentration-response PHT has a stronger slowing effect than CBZ, which curves could be fitted assuming a first-order reaction, would result in slightly different actions of those AEDs it was suggested that one drug molecule binds to one under different conditions of repetitive firing. receptor near or at the sodium channel. The data also are consistent with PHT and CBZ binding with higher affinity to inactivated sodium channels rather than to ETHOSUXIMIDE AND open or resting sodium channels. Of interest was the A number of AEDs have been demonstrated to finding that PHT had a longer time dependence for modify the properties of voltage-dependent calcium frequency-dependent block and for recovery from channels (Macdonald, 1989). PHT, barbiturates, and block than did CBZ. This difference would result in a BZDs reduce calcium influx into synaptic terminals more pronounced frequency-dependent block for PHT and block presynaptic release of neurotransmitter. than for CBZ. Thus, although PHT and CBZ have However, those actions have been demonstrated only quulitutivcly similar actions on sodium channels, the at high drug concentrations that are above therapeutic actions are quuntitutivcly somewhat different. That fact free serum concentrations. Thus, it has been concluded may explain, at least in part, differences in the efficacy that AEDs do not have their primary actions on cal- of the two AEDs among patients. cium channels. However, it has been shown that cal- Similar voltage-clamp experiments were performed cium channels are heterogeneous. In primary afferent on isolated mammalian brain neurons (Wakamori et neurons, at least four different types of channels have al., 1989). Hippocampal pyramidal neurons from the been described (Nowycky et al., 1985; Mintz et al., CA 1 region were obtained from 1- and 2-week-old rats. 1992). These channels have been called L channels, T PHT at 200 pM produced a 20-mV negative shift in channels, N channels, and P channels. These channel the steady-state inactivation curve for sodium channels types have different voltage ranges for activation and and produced frequency-dependent block of sodium inactivation and different rates of activation and in- channels. Frequency-dependent block was shown at activation. It also is likely that these are not the only frequencies as low as 1 Hz, and the block increased to types of calcium channels present on neurons. The 50% at 10 Hz. Thus, the ability of PHT to enhance finding that neurons express multiple calcium channels inactivation in neurons in cell culture and in mam- suggests that AEDs may act on specific subtypes of malian myelinated nerve fibers also was present in iso- channels. This fact has been demonstrated for the lated mammalian neurons. AEDs ESM, trimethadione (TMO), and VPA, which The effect of PHT on human sodium channels also are effective in the treatment of generalized absence has been examined (Tomaselli et al., 1989). Total . mRNA was extracted from human brain and injected Generalized absence epilepsy is characterized clini- into Xenopus oocytes. The human brain sodium chan- cally by brief periods of loss of consciousness and elec- nels expressed in oocytes also were blocked by PHT in trically by generalized 3-Hz spike and wave EEG dis- a voltage-, frequency-, and time-dependent fashion. charges. It has been suggested that thalamic relay The effects of PHT on human sodium channels were neurons play a critical role in the generation of the very similar to those on cultured mouse neurons, rat abnormal thalamocortical rhythmicity that underlies

Epilepsiu. Vol. 34. Siippl. 5. I993 AED MECHANISMS OF ACTION s3 the 3-Hz spike and wave discharge. Whole-cell voltage- GABA binds to GABAA receptors to regulate gating clamp recordings from acutely dissociated relay neu- (opening and closing) of the chloride . The rons from the rat thalamus have demonstrated the single-channel-gating properties of the main conduc- presence of low-threshold (T-type) and high-threshold tance state of the native GABAA receptor in murine calcium currents (Coulter et al., 1989~).The low- spinal cord neurons in culture have been characterized threshold T currents had properties such that T channel (Macdonald et al., 1989~;Weiss and Magleby, 1989; activation was necessary and sufficient to cause the Twyman et al., 1990). Binding of GABA increases the generation of low-threshold calcium spikes in thalamic probability of channel opening, and the open channel relay neurons. It was shown that both ESM and di- can close and rapidly reopen to create bursts of open- methadione (DMO), the active metabolite of TMO, ings. To explain this complex gating behavior, inves- reduced the T-type calcium current of thalamic neu- tigators have modeled the single-channel activity of the rons isolated from guinea pigs or rats (Coulter et al., main conductance state using a reaction scheme in- 19896,~).The reduction of the T-type current was pro- corporating 2 sequential GABA binding sites, 3 open duced at concentrations of ESM and DMO that have states, and 10 closed states (Macdonald et al., 1989~; clinical relevance. PHT and CBZ, which are ineffective Twyman et al., 1990). in the control of generalizeki absence seizures, had and BZD drugs can modulate the minimal effects on the T-type calcium current. The GABAA receptor current by regulating the single- ESM-induced reduction of the T-type current was channel properties of the receptor. To enhance the voltage dependent. The reduction was most prominent current, a drug may increase the channel conductance, at negative membrane potentials and less prominent increase the channel open-and-burst frequencies, and/ at more positive membrane potentials. ESM did not or increase the channel open-and-burst durations. The alter the voltage dependency of steady-state inactivation kinetic model of the GABAA receptor has been used or the time course of recovery from inactivation. DMO to study the mechanisms of action of AEDs that act reduced the T-type calcium current by a mechanism through the GABAA receptor. similar to that of ESM. Another suc- Barbiturates enhance the GABAA receptor current cinimide, a-methyl-a-phenylsuccinimide, also reduced by binding to an allosteric regulatory site on the re- T-type calcium currents, whereas a convulsant succin- ceptor (Olsen, 1987). Results from fluctuation analysis imide, tetramethylsuccinimide, reduced the T-type suggest that (PB) and in- calcium current only at very high concentrations creased the mean channel open duration of GABAA (Coulter et al., 1990). These results suggest that anti- receptor currents without altering channel conductance convulsant and DMO, compounds that (Study and Barker, 198 I). Single-channel recordings are effective in the treatment of generalized absence of barbiturate-enhanced single GABAA receptor cur- epilepsy, may exert their primary action by reducing rents directly demonstrate that barbiturates increase the low-threshold or T-type calcium current in thalamic mean channel open duration but do not alter receptor relay neurons. conductance or opening frequency (Macdonald et al., 1989b; Twyman et al., 1989). BENZODIAZEPINES AND BARBITURATES For alpIreceptors expressed in Xenopus oocytes or The y-aminobutyric acid, (GABAA) receptor is a Chinese hamster ovary (CHO) cells, currents were in- macromolecular protein containing binding sites for creased by pentobarbital (Moss et al., 1990; Verdoorn at least GABA, , , barbiturates et al., 1990). Furthermore, the concentration depen- and BZDs, and a chloride ion-selective channel dence for the effect was the same for receptors with (DeLorey and Olsen, 1992). The receptor appears to different a and p subunits coexpressed with y2 and be composed of combinations of different isoforms of with p2y2alone in Xenopus oocytes (Verdoorn et al., a, p, y, 6, and p polypeptide subunits (Schofield et al., 1990). These results directly demonstrate that the a 1987; Pritchett et al., 1989~;Shivers et al., 1989; Cut- and p subunits contain the allosteric regulatory site for ting et al., I99 1). GABAA receptors composed of only barbiturates. a and fl subunits form chloride channels that are an- GABAA receptors have a high-affinity binding site tagonized by picrotoxin and have an increased response for BZDs, and BZD- and GABAA receptor-binding in the presence of pentobarbital but lack sensitivity to sites have been demonstrated to be coupled allosteri- BZDs; the presence of a y subunit in addition to other cally (Olsen, 1987). BZDs increase GABAA receptor subunits is necessary for full GABAA receptor phar- current. Results from fluctuation analysis suggest that macology (Pritchett et al., 1989b). The subunit com- the BZD increases GABAA receptor current binations that are expressed in vivo are uncertain. by increasing opening frequency without altering

Epilepsiu. Vol. 34, Suppl. 5. I993 s4 R. L. MACDONALD AND K. M. KELLY

channel conductance or open duration (Study and 100-1,000 pM. However, the magnitude of the effect Barker, 198 I). Single-channel recordings have con- was modest, with a 16% reduction seen at 1,000 pM firmed that BZDs increase receptor opening frequency VPA. Whether this modest reduction in T-type calcium without altering mean open time or conductance (Vi- current is sufficient to explain the effect of VPA on cini et al., 1987; Rogers et al., 1989). generalized absence seizures is unclear. Furthermore, GABAA receptors expressed in Xenopzis oocytes and the basis for the discrepancy between the results ob- CHO cells formed from alpIsubunits are insensitive to tained in rat thalamic neurons and those obtained in BZDs (Pritchett et al., 19896; Moss et al., 1990). The rat primary afferent neurons remains uncertain. It may basis for this insensitivity wasdetermined when two forms be that different cell types have different sensitivities of a third GABAAreceptor subunit, the yI and y2 sub- to those drugs or that the small effect is difficult to units, were isolated from a human fetal brain cDNA characterize. Whether this is a relevant mechanism of library (Pritchett et al., 39896). When the y2 subunit action for VPA remains to be determined. was coexpressed transiently with aI and PI subunits in human embryonic kidney cells, fully functional FELBAMATE GABAA receptors were formed that were sensitive to BZDs, (3-carbolines, barbiturates, and picrotoxin. FBM, 2-phenyl- I ,3-propanediol dicarbamate, is a receptors are heterogeneous, with dicarbamate that has a structure similar to meprobam- BZDI and BZDII receptors having been characterized ate, an antianxiety agent. In experimental animals, (Klepner et al., 1978). The identification of the three FBM was effective in blocking seizures induced by specific subunits forming GABAA receptors led to clar- maximal electroshock, , and picro- ification of the basis for this heterogeneity. Expression toxin (Swinyard et al., 1986). FBM inhibited bicucul- of alP,y2GABAA receptors in human kidney cells line-induced seizures at high concentrations but was produces receptors similar to BZDI receptors, whereas ineffective against strychnine-induced seizures (Sofia expression of a2PIy2and a3Ply2GABAA receptors et al., 1991). These results suggest that FBM can both produces receptors similar to BZDII receptors (Pritchett increase threshold and prevent the electrical et al., 1989~).Thus, despite the finding that the y sub- spread of seizure activity (Swinyard et al., 1986). In unit confers benzodiazepine sensitivity to GABAA re- clinical studies, FBM has been effective against complex ceptors, the CY subunit appears to determine the type partial seizures in adults and the Lennox-Gastaut syn- of BZD receptor expressed. BZDII receptors are also drome in children. heterogeneous, being formed from a2Ply2 or a3P1y2 FBM has been tested for interaction with the GABAA subunit combinations. The physiological and phar- receptor complex, a possible mechanism of its anti- macological significance of the differential expression convulsant activity. In rat brain cortical membranes, of CY subunits remains to be determined. FBM did not affect binding to the GABA-, BZD-, or picrotoxin-binding sites of the GABAA re- ceptor complex. In addition, in radiolabeled CI- influx VALPROATE studies in cultured mouse spinal cord neurons, FBM The effect of VPA on sodium channels has been did not affect GABA-induced 36C1-influx (Ticku et al., studied less extensively. It remains uncertain whether 199 I). These results suggest that FBM may not have VPA has the same mechanism of action as PHT and a direct effect on the GABAA receptor complex. How- CBZ. Although VPA blocked sustained high-frequency ever, FBM in subprotective doses enhanced the pro- repetitive firing of neurons in culture (McLean and tective effects of DZP against seizures induced by max- Macdonald, I986a), detailed voltage-clamp experi- imal electroshock, pentylenetetrazol, and isoniazid but ments on VPA actions on sodium currents have not not by , suggesting that FBM may have in- been performed. It cannot be determined whether VPA direct effects on the GABAA receptor complex or may has a mechanism of action similar to that of PHT and be involved in other mechanisms of action (Gordon CBZ until these studies have been performed. et al., 1991). FBM also has been tested for a possible VPA is one of the most effective drugs against gen- effect on excitatory amino acid receptors. FBM inhib- eralized absence seizures. Interestingly, initial studies ited N-methyl-D-aspartate (NMDA)- and quisqualate- of VPA did not demonstrate any effect on the low- induced seizures in mice but did not significantly threshold calcium current. A later study, however, inhibit MK-801 binding (Sofia et al., 1991). The sig- demonstrated that VPA reduced T-type calcium cur- nificance of these results remains to be determined. rents in primary afferent neurons (Kelly et al., 1990). Despite these early studies, the anticonvulsant mech- The effect was produced over a concentration range of anism of action of felbamate remains unknown.

Epilepsia. Vol. 34, Suppl 5. 1993 AED MECHANISMS OF ACTION s5

GABAPENTIN shown to decrease inhibition evoked by paired-pulse orthodromic stimulation of pyramidal neurons in the GBP, 1 -(aminomethyl)-cyclohexaneacetic acid, is a rat hippocampal slice preparation (Dooley et al., 1985; cyclic GABA analogue originally designed to mimic Taylor et al., 1988); however, the specific effect of GBP the stenc conformation of GABA (Schmidt, 1989), to is not known. have high lipid solubility to penetrate the blood-brain GBP protected mice from convulsions caused by barrier, and to be a centrally active GABA with strychnine, a , but was un- potential therapeutic value (Rogawski and Porter, able to displace ['Hlstrychnine in binding studies at 1990). GBP has been shown to have anticonvulsant the highest concentrations tested (Bartoszyk et al., activity in a variety of animal seizure models (Bartoszyk 1986). Electrophysiological studies showed no effect of et al., 1986) and is effective in the treatment of human GBP on the response of spinal cord neurons to ion- partial and generalized tonic-clonic seizures. tophoretically applied glycine (Rock et al., unpublished Despite demonstrated efficacy of GBP against a va- data). riety of seizures, the anticonvulsant mechanism of ac- GBP has been tested in animal seizure models in tion is not known. Early research suggested that GBP which seizures are induced by administration of excit- may act on GABAergic neurotransmitter systems be- atory amino acids. GBP prolonged the onset latency cause it protected mice from tonic extension in chem- of clonic convulsions and tonic extension and death ical convulsion models using inhibitors of GABA syn- in mice after the mice were given intraperitoneal in- thesis (e.g., 3-mercaptopropionic acid, isonicotinic acid, jections of NMDA but not or quinolinic semicarbazide) or antagonists acting on the GABAA acid. GBP did not have a clear effect on convulsions receptor complex (e.g., bicuculline, picrotoxin) (Bar- when those compounds or glutamate was injected into toszyk et al., 1983; Bartoszyk and Reimann, 1985). the lateral ventricle of rats (Bartoszyk, 1983). Intra- However, subsequent research has not clearly dem- peritoneal injections in mice of GBP or the NMDA onstrated a specific effect of GBP on GABAergic neu- receptor competitive antagonist 3-((*)-2-carboxypi- rotransmitter systems. Inhibition of monoamine release perazin-4-yl)-propyl- 1 -phosphonic acid (CPP) antag- by GBP in electrically stimulated rabbit caudate nu- onized tonic seizures. The effect of GBP, but not CPP, cleus (Reimann, 1983) and rat cortex (Schlicker et al., was dose dependently antagonized by the administra- 1985) was not modified by GABA, , or bicu- tion of , an agonist at the on the culline, suggesting that GBP did not act on GABAAor NMDA receptor complex, suggesting an involvement GABAB receptors. Binding experiments in rat brain of the strychnine-insensitive glycine site of the NMDA and spinal cord have shown that GBP has no significant receptor in the antiepileptic activity of GBP (Oles et affinity for the GABAA- or GABAB-binding sites mea- al., 1990). sured by [3H] and [3H]baclofendisplacement, In unpublished studies, GBP reportedly antagonized respectively. GBP did not significantly inhibit the NMDA-induced, but not kainate-induced, depolariza- binding of [3H]DZP, had only a weak inhibitory effect tions in rat thalamic and hippocampal slice prepara- on the GABA-degrading GABA-aminotrans- tions and antagonized NMDA-induced currents in the ferase, did not elevate GABA content in nerve termi- presence of glycine in cultured striatal neurons, an ef- nals, and did not affect the GABA uptake system (Bar- fect that was reversed by the addition of serine or in- toszyk et al., 1986). However, GBP has been shown to creased glycine (Chadwick, 1992). Other studies did increase GABA turnover in several regions of rat brain not show a significant effect of GBP on neuronal re- (Loscher et al., 1991), and recent research has shown sponses to iontophoretic application of glutamate or that GBP binds to a novel high-affinity site in partially on membrane depolarizations and single-channel cur- purified synaptic plasma membranes from rat neocor- rents evoked by NMDA with or without coapplication tex and is potently displaced by the anticonvulsant drug of glycine (Kelly et al., 199 1 ). Those results, in part, 3-isobutyl GABA (Taylor et al., 1993). are similar to the findings of others in which GBP had In electrophysiological studies, gabapentin did not no effect on spinal cord neuron depolarizations elicited affect depolarizations elicited by iontophoretic appli- by iontophoretically applied glutamate (Taylor et al., cation of GABA on cultured mouse spinal cord neu- 1988) or pressure-ejected NMDA (Wamil et al., 1991~). rons (Taylor et al., 1988; Rock et al., unpublished data). In addition, in extracellular recordings from rat hip- In addition, GBP appeared to act by GABA receptor- pocampal slice preparations, GBP had no effect on independent mechanisms in studies with rat hippo- long-term potentiation, making it unlike NMDA re- campal slices (Haas'and Wieser, 1986) and the feline ceptor antagonists (Taylor et al., 1988). trigeminal nucleus (Kondo et al., 199 1). GBP has been GBP had no effect on sustained repetitive firing of

Epilepsiu. Vol. 34, Suppl. 5. I993 S6 R. L. MACDONALD AND K. M. KELLY action potentials in mouse spinal cord neurons (Taylor ever, that relationship has not been demonstrated in et al., 1988; Rock et al., unpublished data). In other structure-activity studies (Rogawski and Porter, 1990). experiments using the same neuronal preparation, high LTG has anticonvulsant activity in several animal sei- concentrations of GBP ( 100 pM) reduced sustained zure models, including hindlimb extension in maximal repetitive firing of action potentials. After overnight electroshock and maximal pentylenetetrazol seizures exposure of the cultures to GBP, sustained repetitive in rodents (Miller et al., 1986). LTG has been shown firing of action potentials was reduced by GBP (1 pM) to be effective as add-on therapy in the treatment of (Wamil et al., 1991b). The different results of these human partial and generalized tonic-clonic seizures. studies done on mouse spinal cord neurons suggest The action of LTG on the release of endogenous that the antiepileptic activity of GBP is not due to in- amino acids from rat slices in vitro has hibition of sustained repetitive firing of sodium action been studied. LTG potently inhibited the release of potentials. glutamate and aspartate evoked by the sodium-channel Although GBP is most effective in the treatment of activator veratrine and was much less effective in the human partial and generalized tonic-clonic seizures, inhibition of release of acetylcholine or GABA. At high the effect of GBP on absence seizures has been studied concentrations, LTG had no effect on spontaneous or both in animal models of absence seizures and as add- potassium-evoked amino acid release. These studies on therapy in patients whose epilepsy is drug resistant. suggested that LTG acted at voltage-dependent sodium In animal studies using pentylenetetrazol-induced channels, resulting in decreased presynaptic release of clonic seizures, GBP protected mice from clonic con- glutamate (Leach et al., 1986). In radioligand studies, vulsions in both the subcutaneous pentylenetetrazol the binding of [3H]batrachotoxinin A 20-a-benzoate, test and the intravenous threshold test (Bartoszyk et a that binds to receptor site 2 on voltage- al., 1986). However, in a rat genetic model of absence dependent sodium channels, was inhibited by LTG in epilepsy, GBP increased EEG spike and wave bursts rat brain synaptosomes. In electrophysiological studies, in a dose-dependent manner (Foot and Wallace, 199 1). LTG blocked sustained repetitive firing in cultured In one human study, GBP reduced >50% of absence mouse spinal cord neurons in a dose-dependent man- seizures in half of the patients (Bauer et al., 1989), and ner at concentrations therapeutic in the treatment of in another human study, GBP reduced absence seizures human seizures (Cheung et al., 1992). These results and generalized spike and wave complexes in patients suggest that the antiepileptic effect of LTG is due to a undergoing 24-h EEG monitoring (Rowan et al., 1989). specific interaction at the voltage-dependent sodium In studies of mouse spinal cord neurons, GBP channel that may result in a preferential decrease in blocked responses to Bay K 8644, an agonist at the presynaptic glutamate release. dihydropyridine-binding site of the L-type (Wamil et al., 1991~).In other electrophysi- CONCLUSION ological studies, however, GBP did not significantly Currently available AEDs appear to have only three affect any calcium channel current subtype tested (i.e., major mechanisms of action. AEDs that are effective T, N, or L), suggesting that the basic mechanism of against generalized tonic-clonic and partial seizures action was not on voltage-dependent calcium channels appear to reduce sustained high-frequency repetitive (Kelly et al., 1991). firing of action potentials by delaying recovery of so- The results of several studies have not shown GBP dium channels from inactivation. AEDs that are effec- to have a major effect on ligand- or voltage-gated chan- tive against generalized absence seizures appear to re- nels. Further study of the high-affinity binding site of duce low-threshold (T-type) calcium channel current. GBP and the AED 3-isobutyl GABA may contribute Finally, AEDs that are effective against myoclonic sei- significantly to our understanding of the mechanism zures generally enhance GABAA receptor inhibition. of action of GBP. Although currently available AEDs have been shown to be effective, there clearly are a number of patients, LAMOTRIGINE especially those with complex partial seizures, whose LTG, 3,5,-diamino-6-(2,3-dichlorophenyl)-1,2,4- epilepsy is refractory to available AEDs. FBM, LTG, triazine, a phenyltriazine with weak antifolate activity, and GBP have shown promise in clinical trials and was developed after the observation that PB, PRM, and may be of some help in managing some patients with PHT resulted in reduced folate concentrations and that refractory epilepsy. Although the mechanisms of action folates could induce seizures in experimental animals of those AEDs is unclear, at least GBP and FBM may (Reynolds et al., 1966). It was proposed that antifolate have novel mechanisms of action. Furthermore, it is activity may be related to anticonvulsant activity; how- likely that additional new AEDs that are under devel-

Epilepsia. Vol. 34. Suppl. S, 1993 AED MECHANISMS OF ACTION s7

opment will have actions on different neurotransmitter acid (GABA) p, cDNA: a GABA receptor subunit highly expressed receptors or channels. For example, considerable effort in the . Proc Nut1 Acad Sci USA 1991;88:2673-7. DeLorey TM, Olsen RW. y-Aminobutyric acid,, receptor structure has been directed toward developing compounds that and function. J Biol Chem I992;267: 16747-50. are antagonists of excitatory amino acid transmission. Dooley DJ, Bartoszyk GD, Rock DM, Satzinger G. Preclinical char- It is to be hoped that new AEDs that act on different acterization of the anticonvulsant gabapentin. Book ofabstractx XVIth Epi1ep.s)- Internutionul Congress. Hamburg, Germany. neurotransmitter receptors or channels will permit pa- 1985. tients whose seizures are currently untreatable to be Foot M, Wallace J. Gabapentin. Epili,psj, Res 1991(suppl 3): 109- treated pharmacologically. 14. Gordon R, Gels M. Diamantis W, Sofia RD. 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