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Antiepileptic drugs in migraine: from clinical aspects to cellular mechanisms

Paolo Calabresi1,2, Francesca Galletti1,2, Cristiana Rossi1,2, Paola Sarchielli1 and Letizia M. Cupini3
1 2

Clinica Neurologica, Universita ` degli Studi di Perugia, Ospedale S. Maria della Misericordia, Perugia 06156, Italy Istituto di Ricerca e Cura a Carattere Scientico, Fondazione Santa Lucia, Via del Fosso di Fiorano, Rome 00143, Italy 3 Reparto di Neurologia, Ospedale S. Eugenio, Piazzale dellUmanesimo, Rome 00144, Italy

Migraine and epilepsy share several clinical features, and epilepsy is a comorbid condition of migraine. Clinical studies have shown that some antiepileptic drugs are effective at preventing migraine attacks. A rationale for their use in migraine prophylaxis is the hypothesis that migraine and epilepsy share several common pathogenetic mechanisms. An imbalance between excitatory glutamate-mediated transmission and GABA-mediated inhibition in specic brain areas has been postulated in these two pathological conditions. Moreover, abnormal activation of voltage-operated ionic channels has been implicated in both migraine and epilepsy. Cortical spreading depression has been found to be involved in the pathophysiology of epilepsy, in addition to the generation of migraine aura. Introduction Migraine is characterized by episodes of head pain that is often throbbing and frequently unilateral, and can be severe. In migraine without aura, attacks are usually associated with nausea, vomiting or sensitivity to light, sound or movement. In some patients, migraine attacks are usually preceded or accompanied by transient focal neurological symptoms, which are usually visual; such patients are described as having migraine with aura. By contrast, the term epilepsy encompasses several different syndromes whose cardinal feature is a predisposition to recurrent unprovoked seizures. Although specic seizures can be classied according to their clinical features (e.g. complex partial seizures and generalized tonic clonic seizures), epilepsy syndromes can also be classied according to the type of seizure, the presence or absence of neurological or developmental abnormalities, and electroencephalographic (EEG) ndings. Both migraine and epilepsy are usually included in the spectrum of neurological chronic disorders with episodic manifestations that are known to be characterized by recurrent attacks of nervous system dysfunction with a return to baseline between attacks. The hypothesis of a possible clinical continuum between migraine and epileptic syndromes as entities resulting from altered neuronal excitability with a similar genetic basis has been postulated [1]. Epilepsy is a comorbid
Corresponding author: Calabresi, P. (calabre@unipg.it). Available online 6 March 2007.
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condition of migraine; it occurs more commonly in patients with migraine than in the general population, and the prevalence of migraine in epileptic patients is higher than in controls [1]. Some antiepileptic drugs (AEDs) are effective in the prevention of migraine [2,3]. A rationale for this use is the hypothesis that migraine and epilepsy share several pathogenetic mechanisms [1]. Here, we describe studies showing the efcacy of some AEDs in migraine prophylaxis, and we try to correlate these clinical results with existing knowledge concerning the cellular and molecular mechanisms of action of these drugs. In particular, we focus our attention on AEDs whose efcacy has been supported by clinical evidence [3]. Prophylactic therapy with AEDs in migraine Most AEDs target the glutamate-mediated and/or the GABA-mediated systems in conjunction with a modulation of voltage-gated sodium (Na+) and calcium (Ca2+) channels [4,5]. However, an imbalance between excitatory glutamate-mediated transmission and GABA-mediated inhibition has been postulated, not only in migraine and epilepsy (Figures 1,2), but also in several neurodegenerative diseases that do not seem to share clinical features and pathogenetic mechanisms with migraine. Similarly, an abnormal activation of voltage-gated ion channels has been implicated not only in migraine and epilepsy, but also in other distinct neurological diseases. Thus, it can be argued that the imbalance between excitatory and inhibitory transmission is selectively expressed in brain regions crucially involved in the pathophysiology of migraine, such as specic brainstem structures and cortical areas. Moreover, kindling, a pathological plastic change lowering the threshold for subsequent attacks, which occurs in experimental epilepsy, has some similarities with the process of sensitization postulated in pain, in addition to migraine [6,7]. These plastic changes require the longterm modulation of gene expression both in epilepsy and in migraine. Finally, cortical spreading depression (SD), a spreading neuroglial depolarization wave, is thought to be implicated in the neurological symptoms in migraine with aura, in addition to the pathophysiology of epilepsy [8,9] (Box 1). Although it is well known that AEDs exert their anticonvulsant action by targeting most of these pathogenetic steps [2,5,10,11] (Figures 13), the reasons why only a

0165-6147/$ see front matter 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.tips.2007.02.005

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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.

few compounds among the various AEDs are effective in the prophylactic treatment of migraine are still unknown. Interestingly, it is also worth noting that drugs other than AEDs, such as the b-blocker propranolol, the Ca2+ channel blocker unarizine and the tricyclic antidepressant amitriptyline, are also effective in migraine prevention [3]. Although these drugs do not exert a direct antiepileptic action, it has been shown for some of them, and for the AEDs effective in migraine prevention, that chronic treatment suppresses cortical SD in an experimental model [12]. This study raises the fascinating hypothesis that the AEDs effective in migraine prevention and also the other classes of drugs acting in migraine prophylaxis exert a therapeutic action in humans by inhibiting SD. Functional imaging and electrophysiological approaches could be used to test this hypothesis clinically in migraineurs. Among the primary headaches, migraine makes a major contribution to the high prevalence in the general population [3]. Several circumstances might warrant preventive treatment in migraine [3]. Timely use of prophylactic treatment might modify or prevent the transformation to chronic migraine and the extreme disability that characterizes a signicant subset of the migraine population [7]. Recently, research into the mechanisms of migraine and the progressive recognition that cortical hyperexcitability contributes to this condition have led to the identication of potential new therapies for the prevention of migraine attacks among the AED class of agents (Table 1).
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The effectiveness of valproic acid (VPA) in migraine prevention was rst reported in an open-label study [13]. The efcacy of VPA was also shown in a double-blind, randomized, crossover study [14]. The treatment was generally well tolerated, and most of the patients had a reduction in migraine frequency, severity and duration. A triple-blind, placebo- and dose-controlled crossover study showed the efcacy 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 were usually mild or moderate. In a multicenter, double-blind, randomized, placebo-controlled study, VPA was shown to be effective in the prophylaxis of episodic migraine [16]. The efcacy and safety of VPA as prophylactic monotherapy was established in a large, multicenter, double-blind, randomized, placebo-controlled study [17]. A more recent double-blind, randomized, placebo-controlled, parallelgroup study conrmed the efcacy of the extended-release version of VPA [18]. Results from an open-label study demonstrated a reduced severity and frequency of headaches in patients with migraine (with and without aura) after treatment with gabapentin (GPT) [19]. A double-blind, randomized, placebo-controlled trial showed that GPT caused a reduction in the frequency and intensity of migraine attacks. Adverse events were mild and no patients withdrew because of side effects [20]. A subsequent doubleblind, randomized, placebo-controlled, multicenter study

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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.

conrmed the efcacy and safety of GPT [21]. Similar results were reported in a prospective, open, multicenter, randomized clinical study using GPT over a 16-week period [22]. The efcacy of topiramate (TPM) in migraine prevention was rst investigated in a double-blind, placebo-controlled study [23]. TPM-treated patients experienced a signicantly lower migraine frequency, and TPM was well tolerated. The adverse effects that occurred more frequently in TPM-treated patients were paresthesia, weight loss, altered taste, anorexia and memory impairment. In a prospective trial, TPM was found to be effective as an adjunctive 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)
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prophylactic management had been less than satisfactory [24]. A large, multicenter, randomized, double-blind, controlled trial assigned patients to placebo and 50, 100 and 200 mg TPM. The mean migraine monthly frequency decreased signicantly for patients treated with 100 mg and 200 mg TPM compared with placebo [25]. Similar results were obtained by another randomized, doubleblind, placebo-controlled study [26]. In a recent study, 100 and 200 mg doses of TPM were compared with propranolol, and both drugs were found to have therapeutic efcacy [27]. To date, there has been no single placebo-controlled study that supports the use of lamotrigine (LTG) in migraine. The safety and efcacy of LTG versus placebo in migraine prophylaxis was evaluated in a double-blind, randomized, parallel-group trial. This study failed to show a signicant therapeutic effect of LTG and revealed adverse effects at a higher dose (200 mg/day) of LTG [28]. A possible interpretation of this negative result is that this drug selectively inuences a subpopulation of migraine patients, such as those showing aura. In accordance with this hypothesis, two small, open clinical studies found that LTG is effective in preventing migraine aura symptoms and in inuencing migraine headache frequency [29,30]. Recently, patients suffering from migraine with aura received LTG in a three-year, controlled, prospective, open study. LTG signicantly reduced both the frequency and duration of migraine aura [31].

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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 migraine The efcacy of AEDs in migraine seems to be mediated by an interaction with multiple sites of action. These AEDs target several molecular sites in the brain, altering voltage-gated ion channels and chemical transmission through an interaction with ion channels, and neurotransmitter receptors and metabolism [2,5]. Interaction with these multiple sites decreases abnormal brain excitability and protects vulnerable neurons in conditions with a high energy demand, such as neuronal hyperactivity and metabolic impairment [10,11]. Voltage-dependent Na+ channels AEDs function by modifying the excitability of nerves through effects on voltage-gated Na+ channels (Figure 1). The crucial role of Na+ channels in the pathogenesis of migraine has been recently supported by genetic studies on familial hemiplegic migraine (FHM). A heterozygous missense mutation in the neuronal voltage-gated Na+ channel gene SCN1A has been found in families with FHM and also in some forms of epilepsy. Interestingly, although this mutation gives rise to the rarest subtype of FHM, it is crucial for the inactivation of the channel and causes a gain of function [32]. Because this region of the channel is also targeted by several AEDs [2,5], it could be argued that the use of this class of drugs can limit the neuronal hyperexcitability also implicated in sporadic migraine.
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Sensitization of sensory neurons following the release of inammatory mediators is associated with an increase in Na+ conductance [33], and increases in the expression of Na+ channels occur in models of persistent inammation [34]. Findings from experimental models have shown that sterile neurogenic inammation occurs as a consequence of activation of the trigeminovascular system [35]. This mechanism might have a role in the pathophysiology of migraine. Modulation of the gating of brain Na+ channels accounts, at least in part, for the efcacy of most of the AEDs in epilepsy [5]. These drugs block the repetitive ring generated during the depolarized state but they are less effective in modulating single action potentials induced at a more hyperpolarized membrane potential. This use-dependent effect explains why these drugs selectively affect abnormal discharges induced by either epilepsy or pain [2]. A crucial question arises from the clinical experience of AED use in the various pathological conditions causing pain: why have drugs such as phenytoin, carbamazepine and oxcarbazepine, which have been shown to block some forms of neuropathic pain (i.e. trigeminal neuralgia and post-herpetic neuralgia) [2], not been reported to be effective in migraine? One possible answer could be that the selective and potent modulation of Na+ channels exerted by these AEDs

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Table 1. Clinical studies of antiepileptic drugs for the prophylactic treatment of migrainea
Study design and period of treatment VPA D-B, P-C (eight weeks) Multicenter, randomized, D-B, P-C (eight weeks) Multicenter, randomized, D-B, P-C (eight weeks) Randomized, D-B, P-C (17 weeks) Number of patients 32 107 Headache type Daily drug dosage Results Refs

MwoA and MwA Migraine, not specied MwoA and MwA

400 mg Adjusted to a serum level of 70120 mg/l 500 mg; 1000 mg; 1500 mg 5001000 mg extended release

171

237

MwoA and MwA

Reduction in migraine frequency, intensity and duration in 80% of the treated patients 50% or greater reduction in migraine headache frequency. No effect on headache intensity and duration Reduction in frequency of migraine attacks greater in patients receiving 1000 mg compared with those receiving placebo Signicant 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 Signicant reduction in the frequency and intensity of headache in 47.6% of GPT-treated patients Signicant 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 placebotreated patients) Signicant reduction in mean 28-day migraine frequency (36% of patients compared with 14% of placebo group) Signicant reduction in mean monthly migraine frequency with TPM at doses of 100 and 200 mg Signicant 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) Signicant reduction in monthly migraine frequency, overall 50% responder rate and monthly migraine days in TPM group. TPM 100 mg and propranolol exhibited similar efcacy proles

[14] [16]

[17]

[18]

GPT Randomized, D-B, P-C (three months) Randomized, D-B, P-C (eight weeks)

63 143

MwoA and MwA MwoA and MwA

1200 mg 1800 mg; 2400 mg

[20] [21]

TPM Single-center, randomized, D-B, P-C (8 weeks) Multicenter, randomized, D-B, P-C (18 weeks) Multicenter, randomized, D-B, P-C, parallel group (18 weeks) Multicenter, randomized versus propranolol or placebo, D-B (18 weeks)
a

35

MwoA and MwA

100200 mg

[23]

483 487

MwoA and MwA MwoA and MwA

50 mg; 100 mg; 200 mg 50 mg; 100 mg; 200 mg

[25] [26]

575

MwoA and MwA

100 mg; 200 mg; versus propranolol 160 mg

[27]

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

is sufcient to block forms of neuropathic pain generated by a simple ectopic electrical mechanism but is unable to counteract the complex mechanisms underlying migraine that also involves vascular and inammatory responses. Conversely, VPA, TPM, GPT and LTG, by targeting multiple channels and neurotransmitter functions, in addition to various intracellular metabolic and transcriptional cascades, could be more suitable to treat a complex pain condition such as migraine. A second explanation could relate to the modulation of a persistent Na+ current [5]. This current has a key role in regulating neuronal excitability near the ring threshold. Interestingly, VPA and TPM inhibit the persistent Na+ current at concentrations lower than those blocking the fast Na+ current [11]. Thus, the efcacy of certain AEDs in migraine could be related to their ability to counteract a persistent Na+ conductance. Voltage-dependent Ca2+ channels Abnormal neuronal activity of Ca2+ channels can represent an additional target of AEDs in migraine (Figure 1). Accordingly, recent genetic studies on FHM suggest that not only abnormalities in Na+, but also in Ca2+ channels have a crucial role in migraine pathogenesis. A missense mutation of the gene encoding the a1A subunit of the P/Q-type Ca2+ channel has been discovered in patients suffering from FHM [36]. This nding raises the possibility that sporadic
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forms of migraine could also be considered channelopathies. However, at present, there is no evidence supporting the involvement of this channel in the commonest forms of migraine. Ca2+ channels modulate neurogenic dural vasodilatation and calcitonin gene-related peptide-induced dilatation [37]. P/Q-, N- and L-type Ca2+ channels are presynaptically expressed on trigeminovascular neurons, and blockade of these channels prevents calcitonin gene-related peptide release and dural blood vessel dilatation. Ca2+ channels also have a key role in the physiology of periaqueductal gray (PAG), a structure that contributes to migraine pathophysiology [4,35,38]. P/Q-type Ca2+ channels in the PAG modulate trigeminal nociception, and dysfunctional activity of these channels inuences migraine [39]. GPT is the AED for which interaction with Ca2+ channels has been analyzed in the most detail. The main molecular target of GPT is an accessory subunit of Ca2+ channels, called a2d [2,5]. Regulation of the a2d subunit has a unique role in neuroplasticity after peripheral nerve injury causing allodynia. Allodynia represents a condition in which innocuous tactile stimulation elicits pain behavior [40]. Increased a2d subunit expression precedes the onset of allodynia and diminishes in animals recovering from tactile allodynia. Spinal administration of GPT suppresses experimental allodynia [40], a crucial mechanism in pain sensitization [41].

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The a2d subunit seems to be common to all Ca2+ channels. Thus, it is conceivable that GPT modulates the activity of more than one type of neuronal Ca2+ channel. This regulatory function can be exerted at both presynaptic and postsynaptic sites of action. Both P/Q- and N-type high voltage-activated channels are located at presynaptic levels and control neurotransmitter release [42]. At presynaptic levels, GPT reduces glutamate release by interacting with P/ Q-type, rather than N-type, Ca2+ channels [42]. The inhibition of L-type Ca2+ channels is a possible mechanism to explain the therapeutic action of TPM in migraine [2,5,43]. The reduction of intracellular Ca2+ levels by LTG during paroxysmal depolarizing events [44] and, possibly, during SD spreading, could account for the selective therapeutic effect of this AED in migraine with aura. Glutamate-mediated transmission AEDs target not only voltage-operated but also ligand-gated channels (Figure 1). Glutamate receptors are present at the trigeminal nucleus caudalis, where interneurons and descending inhibitory systems integrate afferent nociceptive signals involved in migraine [45]. Moreover, the injection of glutamate antagonists within the trigeminocervical complex causes an inhibition of neuronal ring triggered by stimulation of the superior sagittal sinus [46], suggesting that the modulation of glutamate receptors can be considered as one of the major mechanisms of action of AEDs in migraine prophylaxis. An enhancement of glutamatemediated neurotransmission might contribute to central sensitization, a phenomenon at the basis of chronic head pain. Nociceptive stimuli increase glutamate levels in the PAG, which, through ionotropic and metabotropic glutamate receptors, participates in modulating the hyperalgesia induced by peripheral noxious stimulation [47]. Cerebrospinal uid and plasma glutamate levels are increased in migraine [48]. An abnormal level of excitatory amino acids in specic migraine-related brain areas can be caused by an impaired activity of glutamate transporters. Accordingly, mutations in the gene encoding the excitatory amino acid transporter 1 contribute to glutamate-mediated hyperexcitability, inducing migraine attacks [49]. TPM inhibits excitatory synaptic currents mediated by AMPA receptors [2,5]. Similarly, VPA decreases the amplitude of AMPA-mediated postsynaptic currents recorded from pyramidal neurons [50]. However, VPA fails to modulate excitatory synaptic transmission in other neuronal subtypes [11]. A presynaptic mechanism of action seems to be involved in the glutamate-mediated modulation by GPT and LTG [10]. Glutamate release is inhibited by GPT in the caudal trigeminal nucleus following induction of tactile allodynia but not under normal conditions [51]. A new mechanism, involving astrocytes in epileptic activity, has also been implicated in migraine and might represent a target for AEDs that are effective in headache. Paroxysmal depolarizations can be initiated by the release of glutamate from extrasynaptic sources. VPA and GPT reduce the ability of astrocytes to transmit glutamate-mediated signaling [52]. Similarly, TPM reduces
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AMPA-induced Ca2+ transients and inhibits glutamate receptor GluR1 subunit phosphorylation in cortical astrocytes [53]. GABA-mediated transmission GABA-mediated inhibition is involved in the pathophysiological events that underlie migraine, and can represent a target for AEDs in migraine treatment (Figure 2). Clinical and genetic studies have provided evidence in favor of a possible relationship between GABAA receptor dysfunction and migraine [54]. GABAmediated transmission can also be altered in FHM. Accordingly, inhibitory GABA-containing synapses expressing FHM1 mutant P/Q-type Ca2+ channels are altered, leading to an impaired release of this inhibitory transmitter in specic brain areas implicated in migraine attacks [55]. In addition, GABA-mediated inhibition controls trigeminovascular nociception. Neurons recorded in the trigeminocervical complex and activated by stimulation of the superior sagittal sinus are inhibited by GABA receptor agonists [56]. TPM can reduce neuronal ring in the trigeminocervical complex through multiple GABA-mediated mechanisms [2,5,10,43]. GABA-mediated transmission is a main target for the antiepileptic and antimigraine actions of VPA. VPA is a GABA transaminase inhibitor and an activator of glutamic acid decarboxylase [2,5]. VPA, by enhancing GABAmediated inhibition, reduces the neurogenic inammation implicated in migraine [57]. VPA decreases dural plasma extravasation induced either by trigeminal stimulation or by intravenous substance P administration [57]. The same effect is caused by muscimol, a GABAA receptor agonist [57]. VPA reduces c-fos expression caused by intracisternal injection of capsaicin within the trigeminal nucleus caudalis through GABA-mediated mechanisms [58]. Also, GPT acts on GABA-mediated neurotransmission, although it has no effect on GABA receptors [2,5,10]. The modulation of GABA-mediated transmission by VPA, TPM and GPT is unlikely to represent the only mechanism of action of these AEDs in migraine prevention. Accordingly, no benecial action has been reported in migraine prophylaxis following treatment with drugs whose mechanism of action is limited to an interaction with the GABA transmission. Thus, it could be argued that these AEDs achieve their therapeutic effect in migraine prevention through modulation of the GABA system, in addition to an action at other crucial sites. SD Cortical SD has been associated with the induction of migraine, and in particular with migraine aura [4,9,12]. At present, there are no clear data about the pathophysiological similarity between migraine aura and epileptic aura. In fact, although these two clinical conditions might share some mechanisms, they also show differences in duration and in features of clinical presentation. SD is characterized by rapid and nearly complete depolarization of a massive population of brain cells, with an extensive redistribution of ions between intracellular and extracellular compartments [8]. This ionic alteration

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generates an all-or-none process that propagates slowly as a wave in brain tissue. AEDs might selectively increase the threshold for induction and reduce the progression of SD to counteract the frequency and intensity of migraine attacks. Agents blocking N-methyl-d-aspartate (NMDA) or Na+ channels reduce SD. In particular, it has been postulated that the cooperative action of the persistent Na+ current plus NMDA receptor-induced current is the major trigger of SD [8]. Similarly, the blockade of some Ca2+ channels can prevent SD [8]. Accordingly, an elevated threshold for cortical SD in mice with mutations in the a1A subunit of P/ Q-type calcium channels was found [59]. More recently, a genetic mouse model of FHM1 was also found to express an increased susceptibility to SD associated with functional abnormalities of these Ca2+ channels [60]. The Ca2+ channel subtypes that represent the best target in SD and migraine are still unclear. GPT and LTG function more selectively 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 on the initiation and propagation of cortical SD [61]. The observation that SD requires the activation of a persistent Na+ conductance [8] can also account for the specic therapeutic effect of VPA and TPM in migraine. As reported earlier, both of these AEDs inhibit a persistent Na+ conductance at concentrations that do not affect fast Na+ currents [2,5,10,11]. Because most AEDs effective in the treatment of migraine augment brain GABA levels, it is reasonable to assume that the modulation of GABA function represents an additional mechanism to limit the induction of SD. Glial cells have a crucial role in the initiation and propagation of SD [8]. Neurons are surrounded by restricted interstitial space and by a glia-buffering system regulating extracellular potassium and glutamate levels. Thus, when glial uptake is reduced, potassium and glutamate released from neurons accumulate in the extracellular space and induce SD. The recent nding that AEDs (in particular, VPA) target glial cells to block epileptic seizures [52] suggests that normalization of the functional activity of glial cells might contribute to the therapeutic effects of AEDs, limiting SD and migraine attacks. Accordingly, it has recently been shown that astrocytes might also be involved in the maintenance of central pain sensitization [62]. Chronic but not acute treatment with TPM and VPA blocks SD induced in vivo [12]. Interestingly, a similar effect is also achieved by chronic treatment with propranolol and amitriptyline, suggesting that the inhibition of SD is a common target for AEDs and for other classes of drugs currently used in migraine prophylaxis (Figure 3). Concluding remarks At present, controlled clinical studies indicate that VPA, TPM and GPT might be useful in migraine prevention. Conversely, for other AEDs, there is insufcient evidence of efcacy in treating migraine. The choice of a specic AED should take into account the characteristics of the individual patient; the spectrum of efcacy, tolerability and safety; the adverse events prole; comorbid conditions; concomitant drug interactions and cost.
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A general feature of the AEDs effective in the prevention of migraine attacks is the ability to target multiple pre- and postsynaptic mechanisms (Figures 1,2). In particular, the negative modulation of voltage-gated Na+ and Ca2+ channels is a common feature of these drugs. Moreover, these AEDs share the ability to inhibit, although through different mechanisms, glutamate-mediated transmission in specic brain areas selectively involved in migraine pathogenesis, such as the trigeminal nuclei and PAG. Finally, an increase in endogenous GABA tone and a modulation of GABA receptors represent an additional shared effect of the AEDs used in migraine prophylaxis. Modulation of these multiple molecular targets can interfere with gene regulation and increase the threshold for the activation of SD and pain sensitization, the two crucial pathophysiological mechanisms involved in migraine generation. Future clinical studies dealing with the efcacy and tolerability of AEDs in migraine prevention, in addition to pathogenetic studies, will lead to the identication of more-selective therapeutic targets.
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