1-s2.0-S0165614707000491-main

Antiepileptic drugs in migraine: fromclinical aspects to cellular mechanismsPaolo Calabresi1,2, Francesca Galletti1,2, Cristiana Rossi1,2, Paola Sarchielli1

and Letizia M. Cupini3

1 Clinica Neurologica, Universita degli Studi di Perugia, Ospedale S. Maria della Misericordia, Perugia 06156, Italy2 Istituto di Ricerca e Cura a Carattere Scientifico, Fondazione Santa Lucia, Via del Fosso di Fiorano, Rome 00143, Italy3 Reparto di Neurologia, Ospedale S. Eugenio, Piazzale dell’Umanesimo, Rome 00144, Italy

Review TRENDS in Pharmacological Sciences Vol.28 No.4

Migraine and epilepsy share several clinical features, andepilepsy is a comorbid condition of migraine. Clinicalstudies have shown that some antiepileptic drugs areeffective at preventing migraine attacks. A rationale fortheir use in migraine prophylaxis is the hypothesis thatmigraine and epilepsy share several common pathoge-netic mechanisms. An imbalance between excitatoryglutamate-mediated transmission and GABA-mediatedinhibition in specific brain areas has been postulated inthese two pathological conditions. Moreover, abnormalactivation of voltage-operated ionic channels has beenimplicated in both migraine and epilepsy. Corticalspreading depression has been found to be involvedin the pathophysiology of epilepsy, in addition to thegeneration of migraine aura.

IntroductionMigraine is characterized by episodes of head pain that isoften throbbing and frequently unilateral, and can besevere. In migraine without aura, attacks are usuallyassociated with nausea, vomiting or sensitivity to light,sound or movement. In some patients, migraine attacksare usually preceded or accompanied by transient focalneurological symptoms, which are usually visual; suchpatients are described as having migraine with aura.

By contrast, the term ‘epilepsy’ encompasses severaldifferent syndromes whose cardinal feature is a predispo-sition to recurrent unprovoked seizures. Although specificseizures can be classified according to their clinical fea-tures (e.g. complex partial seizures and generalized tonic–clonic seizures), epilepsy syndromes can also be classifiedaccording to the type of seizure, the presence or absence ofneurological or developmental abnormalities, and electro-encephalographic (EEG) findings.

Both migraine and epilepsy are usually included in thespectrum of neurological chronic disorders with episodicmanifestations that are known to be characterized byrecurrent attacks of nervous system dysfunction with areturn to baseline between attacks.

The hypothesis of a possible clinical continuum betweenmigraine and epileptic syndromes as entities resultingfrom altered neuronal excitability with a similar geneticbasis has been postulated [1]. Epilepsy is a comorbid

Corresponding author: Calabresi, P. ([email protected]).Available online 6 March 2007.

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condition of migraine; it occurs more commonly in patientswith migraine than in the general population, and theprevalence of migraine in epileptic patients is higher thanin controls [1].

Some antiepileptic drugs (AEDs) are effective in theprevention of migraine [2,3]. A rationale for this use is thehypothesis that migraine and epilepsy share severalpathogenetic mechanisms [1]. Here, we describe studiesshowing the efficacy of some AEDs in migraine prophy-laxis, and we try to correlate these clinical results withexisting knowledge concerning the cellular and molecularmechanisms of action of these drugs. In particular, wefocus our attention on AEDs whose efficacy has beensupported by clinical evidence [3].

Prophylactic therapy with AEDs in migraineMost AEDs target the glutamate-mediated and/or theGABA-mediated systems in conjunction with a modulationof voltage-gated sodium (Na+) and calcium (Ca2+) channels[4,5]. However, an imbalance between excitatory gluta-mate-mediated transmission and GABA-mediated inhi-bition has been postulated, not only in migraine andepilepsy (Figures 1,2), but also in several neurodegenera-tive diseases that do not seem to share clinical features andpathogenetic mechanisms with migraine. Similarly, anabnormal activation of voltage-gated ion channels has beenimplicated not only in migraine and epilepsy, but alsoin other distinct neurological diseases. Thus, it can beargued that the imbalance between excitatory and inhibi-tory transmission is selectively expressed in brain regionscrucially involved in the pathophysiology of migraine, suchas specific brainstem structures and cortical areas.

Moreover, kindling, a pathological plastic changelowering the threshold for subsequent attacks, whichoccurs in experimental epilepsy, has some similarities withthe process of sensitization postulated in pain, in additionto migraine [6,7]. These plastic changes require the long-termmodulation of gene expression both in epilepsy and inmigraine. Finally, cortical spreading depression (SD), aspreading neuroglial depolarization wave, is thought to beimplicated in the neurological symptoms in migraine withaura, in addition to the pathophysiology of epilepsy [8,9](Box 1).

Although it is well known that AEDs exert theiranticonvulsant action by targeting most of these pathoge-netic steps [2,5,10,11] (Figures 1–3), the reasonswhy only a

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Figure 1. Pre- and postsynaptic sites of action of AEDs on excitatory glutamate-mediated transmission. The figure shows that AEDs target multiple voltage-gated channels

at both pre- and postsynaptic levels. Note that TPM also modulates postsynaptic AMPA receptors.

Review TRENDS in Pharmacological Sciences Vol.28 No.4 189

few compounds among the various AEDs are effective inthe prophylactic treatment of migraine are still unknown.

Interestingly, it is also worth noting that drugs otherthan AEDs, such as the b-blocker propranolol, the Ca2+

channel blocker flunarizine and the tricyclic antidepress-ant amitriptyline, are also effective in migraine prevention[3]. Although these drugs do not exert a direct antiepilepticaction, it has been shown for some of them, and for theAEDs effective in migraine prevention, that chronic treat-ment suppresses cortical SD in an experimental model[12]. This study raises the fascinating hypothesis thatthe AEDs effective in migraine prevention and also theother classes of drugs acting in migraine prophylaxis exerta therapeutic action in humans by inhibiting SD. Func-tional imaging and electrophysiological approaches couldbe used to test this hypothesis clinically in migraineurs.

Among the primary headaches, migrainemakes amajorcontribution to the high prevalence in the general popu-lation [3]. Several circumstancesmightwarrant preventivetreatment in migraine [3]. Timely use of prophylactictreatment might modify or prevent the transformationto chronic migraine and the extreme disability that charac-terizes a significant subset of the migraine population [7].Recently, research into the mechanisms of migraine andthe progressive recognition that cortical hyperexcitabilitycontributes to this condition have led to the identificationof potential new therapies for the prevention of migraineattacks among the AED class of agents (Table 1).

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The effectiveness of valproic acid (VPA) in migraineprevention was first reported in an open-label study[13]. The efficacy of VPA was also shown in a double-blind,randomized, crossover study [14]. The treatment wasgenerally well tolerated, and most of the patients had areduction in migraine frequency, severity and duration. Atriple-blind, placebo- and dose-controlled crossover studyshowed the efficacy of a slow-release form of this drug [15].The most common side effects were nausea and dyspepsia,tiredness, increased appetite and weight gain, and wereusually mild or moderate. In a multicenter, double-blind,randomized, placebo-controlled study, VPA was shown tobe effective in the prophylaxis of episodic migraine [16].The efficacy and safety of VPA as prophylactic monother-apy was established in a large, multicenter, double-blind,randomized, placebo-controlled study [17]. A more recentdouble-blind, randomized, placebo-controlled, parallel-group study confirmed the efficacy of the extended-releaseversion of VPA [18].

Results from an open-label study demonstrated areduced severity and frequency of headaches in patientswith migraine (with and without aura) after treatmentwith gabapentin (GPT) [19]. A double-blind, randomized,placebo-controlled trial showed that GPT caused areduction in the frequency and intensity of migraineattacks. Adverse events were mild and no patients with-drew because of side effects [20]. A subsequent double-blind, randomized, placebo-controlled, multicenter study

Figure 2. The effects of AEDs on inhibitory GABA-mediated transmission. GPT, TPM and VPA influence GABA synthesis and turnover by acting at multiple and distinct

biochemical steps. Moreover, TPM also directly targets the GABAA receptor channel complex. Abbreviations: GABAT, GABA transaminase; SSA, succinic semialdehyde.

190 Review TRENDS in Pharmacological Sciences Vol.28 No.4

confirmed the efficacy and safety of GPT [21]. Similarresults were reported in a prospective, open, multicenter,randomized clinical study usingGPT over a 16-week period[22].

The efficacy of topiramate (TPM) inmigraine preventionwas first investigated in a double-blind, placebo-controlledstudy [23]. TPM-treated patients experienced a signifi-cantly lower migraine frequency, and TPM was well tol-erated. The adverse effects that occurred more frequentlyin TPM-treated patients were paresthesia, weight loss,altered taste, anorexia and memory impairment. In aprospective trial, TPM was found to be effective as anadjunctive treatment in patients whose prior response to

Box 1. Possible pathophysiological mechanisms shared by

migraine and epilepsy

Molecular and synaptic level

� Abnormalities in the function of voltage-gated Na+ channels

� Abnormalities in the function of voltage-gated Ca2+ channels

� Reduced GABA-mediated inhibition at the presynaptic and/or the

postsynaptic level

� Increased glutamate-mediated excitation at the presynaptic and/

or the postsynaptic level

Network level

� Lower threshold for the induction of SD

� Lower threshold for the induction of long-term changes in

neuronal excitability (sensitization and kindling)


prophylactic management had been less than satisfactory[24]. A large, multicenter, randomized, double-blind, con-trolled trial assigned patients to placebo and 50, 100 and200 mg TPM. The mean migraine monthly frequencydecreased significantly for patients treated with 100 mgand 200 mg TPM compared with placebo [25]. Similarresults were obtained by another randomized, double-blind, placebo-controlled study [26]. In a recent study,100 and 200 mg doses of TPM were compared with pro-pranolol, and both drugs were found to have therapeuticefficacy [27].

To date, there has been no single placebo-controlledstudy that supports the use of lamotrigine (LTG) inmigraine. The safety and efficacy of LTG versus placeboin migraine prophylaxis was evaluated in a double-blind,randomized, parallel-group trial. This study failed to showa significant therapeutic effect of LTG and revealedadverse effects at a higher dose (200 mg/day) of LTG[28]. A possible interpretation of this negative result isthat this drug selectively influences a subpopulation ofmigraine patients, such as those showing aura. In accord-ance with this hypothesis, two small, open clinicalstudies found that LTG is effective in preventing migraineaura symptoms and in influencing migraine headachefrequency [29,30]. Recently, patients suffering frommigraine with aura received LTG in a three-year, con-trolled, prospective, open study. LTG significantly reducedboth the frequency and duration of migraine aura [31].

Figure 3. AEDs target multiple cortical and subcortical neuronal structures. At the cortical level, AEDs reduce SD. AEDs control sensory information in the thalamus, and

pain sensitization in the striatum. In the brainstem, AEDs target multiple sites, such as the PAG, locus coeruleus, dorsal raphe nucleus, trigeminal nucleus caudalis and

mesencephalic dopamine-containing areas [ventral tegmental area (VTA) and substantia nigra pars compacta (SNpc)]. AEDs also modulate peripheral neurogenic

inflammation mediated by trigeminal neurons. Abbreviations: DA, dopamine; Glu, glutamate; NA, noradrenaline.


Targets of AEDs in epilepsy and migraineThe efficacy of AEDs in migraine seems to be mediated byan interaction with multiple sites of action. These AEDstarget several molecular sites in the brain, altering vol-tage-gated ion channels and chemical transmissionthrough an interaction with ion channels, and neurotrans-mitter receptors and metabolism [2,5]. Interaction withthese multiple sites decreases abnormal brain excitabilityand protects vulnerable neurons in conditions with a highenergy demand, such as neuronal hyperactivity and meta-bolic impairment [10,11].

Voltage-dependent Na+ channels

AEDs function by modifying the excitability of nervesthrough effects on voltage-gated Na+ channels (Figure 1).The crucial role of Na+ channels in the pathogenesis ofmigraine has been recently supported by genetic studieson familial hemiplegic migraine (FHM). A heterozygousmissensemutation in the neuronal voltage-gatedNa+ chan-nel gene SCN1A has been found in families with FHM andalso in some forms of epilepsy. Interestingly, although thismutationgives rise to the rarest subtypeofFHM, it is crucialfor the inactivation of the channel and causes a gain offunction [32]. Because this region of the channel is alsotargeted by several AEDs [2,5], it could be argued thatthe use of this class of drugs can limit the neuronal hyper-excitability also implicated in sporadic migraine.


Sensitization of sensory neurons following the release ofinflammatory mediators is associated with an increase inNa+ conductance [33], and increases in the expression ofNa+ channels occur in models of persistent inflammation[34].

Findings from experimental models have shown thatsterile neurogenic inflammation occurs as a consequence ofactivation of the trigeminovascular system [35]. Thismechanism might have a role in the pathophysiology ofmigraine.

Modulation of the gating of brain Na+ channelsaccounts, at least in part, for the efficacy of most of theAEDs in epilepsy [5]. These drugs block the repetitivefiring generated during the depolarized state but theyare less effective in modulating single action potentialsinduced at a more hyperpolarized membrane potential.This ‘use-dependent’ effect explains why these drugs selec-tively affect abnormal discharges induced by either epi-lepsy or pain [2]. A crucial question arises from the clinicalexperience of AED use in the various pathological con-ditions causing pain: why have drugs such as phenytoin,carbamazepine and oxcarbazepine, which have beenshown to block some forms of neuropathic pain (i.e. tri-geminal neuralgia and post-herpetic neuralgia) [2], notbeen reported to be effective in migraine?

One possible answer could be that the ‘selective’ and‘potent’ modulation of Na+ channels exerted by these AEDs

Table 1. Clinical studies of antiepileptic drugs for the prophylactic treatment of migrainea

Study design and period

of treatment

Number of

patients

Headache type Daily drug dosage Results Refs

VPA

D-B, P-C (eight weeks) 32 MwoA and MwA 400 mg Reduction in migraine frequency, intensity and

duration in 80% of the treated patients

[14]

Multicenter, randomized,

D-B, P-C (eight weeks)

107 Migraine, not

specified

Adjusted to a serum

level of 70–120 mg/l

50% or greater reduction in migraine headache

frequency. No effect on headache intensity and

duration

[16]


D-B, P-C (eight weeks)

171 MwoA and MwA 500 mg; 1000 mg;

1500 mg

Reduction in frequency of migraine attacks

greater in patients receiving 1000 mg compared

with those receiving placebo

[17]

Randomized, D-B, P-C

(17 weeks)

237 MwoA and MwA 500–1000 mg

extended release

Significant reduction in four-week migraine rate

(1.2 in divalproex group compared with 0.6 in

the placebo group: P < 0.006); this reduction

was maintained throughout the treatment period

[18]

GPT


(three months)

63 MwoA and MwA 1200 mg Significant reduction in the frequency and intensity

of headache in 47.6% of GPT-treated patients

[20]


(eight weeks)

143 MwoA and MwA 1800 mg; 2400 mg Significant reduction in four-week migraine rate

(2.7 for GPT-treated patients maintained on a

stable dose of 2400 mg/day and 3.5 for placebo-

treated patients)

[21]

TPM

Single-center, randomized,

D-B, P-C (8 weeks)

35 MwoA and MwA 100–200 mg Significant reduction in mean 28-day migraine

frequency (36% of patients compared with 14%

of placebo group)

[23]


D-B, P-C (18 weeks)


200 mg

Significant reduction in mean monthly migraine

frequency with TPM at doses of 100 and 200 mg

[25]


D-B, P-C, parallel group

(18 weeks)


200 mg

Significant reduction in mean monthly migraine

frequency with TPM at doses of 100 and 200 mg

(reduction of 50% or more in monthly migraine

frequency in TPM group)

[26]

Multicenter, randomized

versus propranolol or

placebo, D-B (18 weeks)


versus propranolol

160 mg

Significant reduction in monthly migraine frequency,

overall 50% responder rate and monthly migraine

days in TPM group. TPM 100 mg and propranolol

exhibited similar efficacy profiles

[27]

aAbbreviations: C-O, cross over; D-B, double-blind; P-C, placebo controlled; MwA, migraine with aura; MwoA, migraine without aura.


is sufficient to block forms of neuropathic pain generatedby a ‘simple’ ectopic electrical mechanism but is unable tocounteract the complex mechanisms underlying migrainethat also involves vascular and inflammatory responses.Conversely, VPA, TPM, GPT and LTG, by targetingmultiple channels and neurotransmitter functions, inaddition to various intracellular metabolic and transcrip-tional cascades, could be more suitable to treat a ‘complex’pain condition such as migraine.

A second explanation could relate to the modulation of apersistent Na+ current [5]. This current has a key role inregulating neuronal excitability near the firing threshold.Interestingly, VPA and TPM inhibit the persistent Na+

current at concentrations lower than those blocking thefast Na+ current [11]. Thus, the efficacy of certain AEDs inmigraine could be related to their ability to counteract apersistent Na+ conductance.

Voltage-dependent Ca2+ channels

Abnormal neuronal activity of Ca2+ channels can representan additional target of AEDs inmigraine (Figure 1). Accord-ingly, recent genetic studies on FHM suggest that not onlyabnormalities in Na+, but also in Ca2+ channels have acrucial role in migraine pathogenesis. A missense mutationof the gene encoding the a1A subunit of the P/Q-type Ca2+

channel has been discovered in patients suffering fromFHM [36]. This finding raises the possibility that sporadic


forms ofmigraine could also be considered channelopathies.However, at present, there is no evidence supporting theinvolvement of this channel in the commonest forms ofmigraine.

Ca2+ channelsmodulate neurogenic dural vasodilatationand calcitonin gene-related peptide-induced dilatation [37].P/Q-, N- and L-type Ca2+ channels are presynapticallyexpressed on trigeminovascular neurons, and blockade ofthese channels prevents calcitonin gene-related peptiderelease and dural blood vessel dilatation.

Ca2+ channels also have a key role in the physiology ofperiaqueductal gray (PAG), a structure that contributes tomigrainepathophysiology [4,35,38]. P/Q-typeCa2+ channelsin the PAG modulate trigeminal nociception, and dysfunc-tional activity of these channels influences migraine [39].

GPT is theAED forwhich interactionwithCa2+ channelshas been analyzed in the most detail. The main moleculartarget of GPT is an accessory subunit of Ca2+ channels,called a2d [2,5]. Regulation of the a2d subunit has a uniquerole in neuroplasticity after peripheral nerve injury causingallodynia. Allodynia represents a condition in which innoc-uous tactile stimulation elicits pain behavior [40]. Increaseda2d subunit expression precedes the onset of allodynia anddiminishes in animals recovering from tactile allodynia.Spinal administration of GPT suppresses experimentalallodynia [40], a crucial mechanism in pain sensitization[41].


Thea2d subunit seems tobe common toallCa2+ channels.Thus, it is conceivable that GPT modulates the activity ofmore than one type of neuronal Ca2+ channel. This regu-latory function can be exerted at both presynaptic andpostsynaptic sites of action. Both P/Q- and N-type highvoltage-activated channels are located at presynaptic levelsand control neurotransmitter release [42]. At presynapticlevels,GPTreducesglutamate releaseby interactingwithP/Q-type, rather than N-type, Ca2+ channels [42].

The inhibition of L-type Ca2+ channels is a possiblemechanism to explain the therapeutic action of TPM inmigraine [2,5,43]. The reduction of intracellular Ca2+

levels by LTG during paroxysmal depolarizing events[44] and, possibly, during SD spreading, could accountfor the selective therapeutic effect of this AED in migrainewith aura.

Glutamate-mediated transmission

AEDs target not only voltage-operatedbut also ligand-gatedchannels (Figure 1). Glutamate receptors are present at thetrigeminal nucleus caudalis, where interneurons and des-cending inhibitory systems integrate afferent nociceptivesignals involved in migraine [45]. Moreover, the injection ofglutamate antagonists within the trigeminocervical com-plex causes an inhibition of neuronal firing triggered bystimulation of the superior sagittal sinus [46], suggestingthat the modulation of glutamate receptors can be con-sidered as one of the major mechanisms of action of AEDsin migraine prophylaxis. An enhancement of glutamate-mediated neurotransmission might contribute to centralsensitization, a phenomenon at the basis of chronic headpain.

Nociceptive stimuli increase glutamate levels in thePAG, which, through ionotropic and metabotropic gluta-mate receptors, participates in modulating the hyperalge-sia induced by peripheral noxious stimulation [47].

Cerebrospinal fluid and plasma glutamate levels areincreased in migraine [48]. An abnormal level of excitatoryamino acids in specific migraine-related brain areas can becaused by an impaired activity of glutamate transporters.Accordingly, mutations in the gene encoding the excitatoryamino acid transporter 1 contribute to glutamate-mediatedhyperexcitability, inducing migraine attacks [49].

TPM inhibits excitatory synaptic currents mediated byAMPA receptors [2,5]. Similarly, VPA decreases the ampli-tude of AMPA-mediated postsynaptic currents recordedfrom pyramidal neurons [50]. However, VPA fails to modu-late excitatory synaptic transmission in other neuronalsubtypes [11].

A presynaptic mechanism of action seems to be involvedin the glutamate-mediated modulation by GPT and LTG[10]. Glutamate release is inhibited by GPT in the caudaltrigeminal nucleus following induction of tactile allodyniabut not under normal conditions [51].

A new mechanism, involving astrocytes in epilepticactivity, has also been implicated in migraine and mightrepresent a target for AEDs that are effective in head-ache. Paroxysmal depolarizations can be initiated by therelease of glutamate from extrasynaptic sources. VPA andGPT reduce the ability of astrocytes to transmit gluta-mate-mediated signaling [52]. Similarly, TPM reduces


AMPA-induced Ca2+ transients and inhibits glutamatereceptor GluR1 subunit phosphorylation in cortical astro-cytes [53].

GABA-mediated transmission

GABA-mediated inhibition is involved in thepathophysiological events that underlie migraine, andcan represent a target for AEDs in migraine treatment(Figure 2). Clinical and genetic studies have providedevidence in favor of a possible relationship betweenGABAA receptor dysfunction and migraine [54]. GABA-mediated transmission can also be altered in FHM. Accord-ingly, inhibitory GABA-containing synapses expressingFHM1mutant P/Q-type Ca2+ channels are altered, leadingto an impaired release of this inhibitory transmitter inspecific brain areas implicated in migraine attacks [55].

In addition, GABA-mediated inhibition controlstrigeminovascular nociception. Neurons recorded in thetrigeminocervical complex and activated by stimulation ofthe superior sagittal sinus are inhibited by GABA receptoragonists [56]. TPM can reduce neuronal firing in the trige-minocervical complex through multiple GABA-mediatedmechanisms [2,5,10,43].

GABA-mediated transmission is a main target for theantiepileptic and antimigraine actions of VPA. VPA is aGABA transaminase inhibitor and an activator of glutamicacid decarboxylase [2,5]. VPA, by enhancing GABA-mediated inhibition, reduces the neurogenic inflammationimplicated in migraine [57]. VPA decreases dural plasmaextravasation induced either by trigeminal stimulation orby intravenous substance P administration [57]. The sameeffect is caused by muscimol, a GABAA receptor agonist[57].

VPA reduces c-fos expression caused by intracisternalinjection of capsaicin within the trigeminal nucleus cau-dalis through GABA-mediated mechanisms [58]. Also,GPT acts onGABA-mediated neurotransmission, althoughit has no effect on GABA receptors [2,5,10].

The modulation of GABA-mediated transmission byVPA, TPM and GPT is unlikely to represent the onlymechanism of action of these AEDs inmigraine prevention.Accordingly, no beneficial action has been reported inmigraine prophylaxis following treatment with drugswhose mechanism of action is limited to an interactionwith the GABA transmission. Thus, it could be argued thatthese AEDs achieve their therapeutic effect in migraineprevention through modulation of the GABA system, inaddition to an action at other crucial sites.

SD

Cortical SD has been associated with the induction ofmigraine, and in particular with migraine aura [4,9,12].At present, there are no clear data about the pathophy-siological similarity between migraine aura and epilepticaura. In fact, although these two clinical conditions mightshare some mechanisms, they also show differences induration and in features of clinical presentation.

SD is characterized by rapid and nearly completedepolarization of a massive population of brain cells, withan extensive redistribution of ions between intracellularand extracellular compartments [8]. This ionic alteration


generates an ‘all-or-none’ process that propagates slowly asa wave in brain tissue. AEDsmight selectively increase thethreshold for induction and reduce the progression of SD tocounteract the frequency and intensity ofmigraine attacks.

Agents blocking N-methyl-d-aspartate (NMDA) or Na+

channels reduce SD. In particular, it has been postulatedthat the cooperative action of the persistent Na+ currentplus NMDA receptor-induced current is the major triggerof SD [8]. Similarly, the blockade of some Ca2+ channelscan prevent SD [8]. Accordingly, an elevated threshold forcortical SD in mice with mutations in the a1A subunit of P/Q-type calcium channels was found [59]. More recently, agenetic mousemodel of FHM1was also found to express anincreased susceptibility to SD associated with functionalabnormalities of these Ca2+ channels [60]. The Ca2+ chan-nel subtypes that represent the best target in SD andmigraine are still unclear. GPT and LTG function moreselectively on P/Q- and N-type, rather than on L-type, Ca2+

channels. Conversely, TPM mainly inhibits L-type Ca2+

channels. Interestingly, TPM has an inhibitory effect onthe initiation and propagation of cortical SD [61].

The observation that SD requires the activation of apersistent Na+ conductance [8] can also account for thespecific therapeutic effect of VPA and TPM in migraine. Asreported earlier, both of these AEDs inhibit a persistentNa+ conductance at concentrations that do not affect fastNa+ currents [2,5,10,11]. Because most AEDs effective inthe treatment ofmigraine augment brainGABA levels, it isreasonable to assume that the modulation of GABA func-tion represents an additional mechanism to limit theinduction of SD.

Glial cells have a crucial role in the initiation andpropagation of SD [8]. Neurons are surrounded byrestricted interstitial space and by a glia-buffering systemregulating extracellular potassium and glutamate levels.Thus, when glial uptake is reduced, potassium and gluta-mate released from neurons accumulate in the extracellu-lar space and induce SD. The recent finding that AEDs (inparticular, VPA) target glial cells to block epileptic seizures[52] suggests that normalization of the functional activityof glial cells might contribute to the therapeutic effects ofAEDs, limiting SD and migraine attacks. Accordingly, ithas recently been shown that astrocytes might also beinvolved in the maintenance of central pain sensitization[62].

Chronic but not acute treatment with TPM and VPAblocks SD induced in vivo [12]. Interestingly, a similareffect is also achieved by chronic treatment with propra-nolol and amitriptyline, suggesting that the inhibition ofSD is a common target for AEDs and for other classes ofdrugs currently used in migraine prophylaxis (Figure 3).

Concluding remarksAt present, controlled clinical studies indicate that VPA,TPM and GPT might be useful in migraine prevention.Conversely, for other AEDs, there is insufficient evidenceof efficacy in treating migraine. The choice of a specificAED should take into account the characteristics of theindividual patient; the spectrum of efficacy, tolerabilityand safety; the adverse events profile; comorbid conditions;concomitant drug interactions and cost.


Ageneral feature of the AEDs effective in the preventionofmigraine attacks is the ability to targetmultiple pre- andpostsynaptic mechanisms (Figures 1,2). In particular, thenegative modulation of voltage-gated Na+ and Ca2+ chan-nels is a common feature of these drugs. Moreover, theseAEDs share the ability to inhibit, although through differ-ent mechanisms, glutamate-mediated transmission inspecific brain areas selectively involved in migraine patho-genesis, such as the trigeminal nuclei and PAG. Finally, anincrease in endogenous GABA tone and a modulation ofGABA receptors represent an additional shared effectof the AEDs used in migraine prophylaxis. Modulationof these multiple molecular targets can interfere with generegulation and increase the threshold for the activation ofSD and pain sensitization, the two crucial pathophysiolo-gical mechanisms involved in migraine generation.

Future clinical studies dealing with the efficacy andtolerability of AEDs in migraine prevention, in additionto pathogenetic studies, will lead to the identification ofmore-selective therapeutic targets.

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