6
177 ISSN 1756-8919 10.4155/FMC.10.296 © 2011 Future Science Ltd Future Med. Chem. (2011) 3(2), 177–182 The imbalance between synaptic inhibition and excitation still remains the mainstay for the development of antiepileptic drugs (AEDs). However, it is important to acknowledge that the final antiepileptic activity of a specific com- pound may derive from multiple complemen- tary mechanisms that target brain excitability systems. In fact, as is the case with other drug classes, AEDs have a diversity of actions on bio- logical systems, only some of which are related to the desired antiseizure effect. In general terms, AEDs can be categorized as those that modulate voltage-dependent ion channels, enhance synaptic inhibition or reduce synaptic excitation (TABLE 1) . Modulation of voltage-dependent ion channels (sodium, cal- cium and potassium channels) represents a key target for antiepileptic activity because these channels shape the electrical behavior of the neuron, regulating paroxysmal depolarization and responsiveness to synaptic signals [1] . In other cases, AEDs enhance inhibition mediated by GABA A receptor, and also possibly GABA B receptors, or through effects on the glycine system or regionally specific neurotransmitter system (catecholamines, serotonin, histamine and neuropeptides, including opioid peptides and neuropeptide Y and the inhibitory neuro- modulator adenosine) [2] . Finally, blockade of excitatory glutamate receptor, such as N-methyl- d-aspartate (NMDA), a-amino-3-hydroxy-5- methyl-4-isoxazole proprionate (AMPA) and also possibly kainate types, represent important antiseizure mechanisms [3] . Over the past 20 years, the treatment of epilepsies has made remarkable strides [4] . In parallel, there have been dramatic advances in the understanding of the pathophysiology of seizure disorders in terms of cellular physiology and genetics. Numerous new compounds have been licensed and introduced onto the market, namely oxcarbazepine, lamotrigine, felbamate, gabapentin, topiramate, tiagabine, vigabatrin, levetiracetam, pregabalin, zonisamide, esli- carbazepine and lacosamide. These drugs are regarded as second- or even third-generation compounds in comparison with older AEDs, such as phenobarbital, phenytoin, carbamaze- pine, ethosuximide and valproic acid. Although some of these new AEDs may be advantageous in terms of pharmacokinetics, tolerability and potential for drug interactions, improvements in clinical outcome have fallen short of expectations with no more than 15–20% of patients becom- ing seizure free in those refractory to older drugs and still, in at least some cases, having unaccept- able medication-related adverse effects [5] . The purpose of this article is to review the neurobiology and clinical relevance of AEDs with a well-known prominent GABAergic mechanism. The strengths and limitations of such compounds will be discussed in a clini- cal perspective, especially taking into account adverse effects on cognition and behavior. AEDs acting on GABA receptors Inhibitory GABAergic interneurons are found throughout the brain, but in any region they may comprise a wide range of morphological and functional types that participate in different cir- cuits. There are two known subtypes of GABA receptors: GABA A and GABA B . The GABA A receptor complex has several allosteric sites that modulate its function, such as the so-called ‘benzodiazepine binding site.’ In fact, the majority of compounds that act GABAergic drugs in the treatment of epilepsy: modern or outmoded? Antiepileptic drugs have a number of mechanisms of action that target brain excitability systems. The potentiation of GABAergic inhibitory neurotransmission represents a classic and well-known antiseizure effect. Currently available GABAergic antiepileptic drugs mainly target GABA A receptor-associated complexes, GABA reuptake or GABA catabolism. All these compounds, although generally effective, are limited by their deleterious effects on cognition and behavior. The challenge will be to find GABAergic drugs that exhibit the beneficial effects, without the adverse ones. Marco Mula Department of Clinical & Experimental Medicine, Division of Neurology, University Hospital Maggiore della Carità, C.so Mazzini 18, Italy Tel.: +39 032 137 33371 Fax: +39 032 137 33298 E-mail: [email protected] MINI-REVIEW SPECIAL FOCUS: GABAERGIC DRUGS For reprint orders, please contact [email protected]

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Page 1: GABAergic drugs in the treatment of epilepsy: modern or outmoded?

177ISSN 1756-891910.4155/FMC.10.296 © 2011 Future Science Ltd Future Med. Chem. (2011) 3(2), 177–182

The imbalance between synaptic inhibition and excitation still remains the mainstay for the development of antiepileptic drugs (AEDs). However, it is important to acknowledge that the final antiepileptic activity of a specific com-pound may derive from multiple complemen-tary mechanisms that target brain excitability systems. In fact, as is the case with other drug classes, AEDs have a diversity of actions on bio-logical systems, only some of which are related to the desired antiseizure effect.

In general terms, AEDs can be categorized as those that modulate voltage-dependent ion channels, enhance synaptic inhibition or reduce synaptic excitation (Table 1). Modulation of voltage-dependent ion channels (sodium, cal-cium and potassium channels) represents a key target for antiepileptic activity because these channels shape the electrical behavior of the neuron, regulating paroxysmal depolarization and responsiveness to synaptic signals [1]. In other cases, AEDs enhance inhibition mediated by GABA

A receptor, and also possibly GABA

B

receptors, or through effects on the glycine system or regionally specific neurotransmitter system (catecholamines, serotonin, histamine and neuropeptides, including opioid peptides and neuropeptide Y and the inhibitory neuro-modulator adenosine) [2]. Finally, blockade of excitatory glutamate receptor, such as N-methyl-d-aspartate (NMDA), a-amino-3-hydroxy-5-methyl-4-isoxazole proprionate (AMPA) and also possibly kainate types, represent important antiseizure mechanisms [3].

Over the past 20 years, the treatment of epilepsies has made remarkable strides [4]. In parallel, there have been dramatic advances in the understanding of the pathophysiology of

seizure disorders in terms of cellular physiology and genetics. Numerous new compounds have been licensed and introduced onto the market, namely oxcarbazepine, lamotrigine, felbamate, gabapentin, topiramate, tiagabine, vigabatrin, levetiracetam, pregabalin, zonisamide, esli-carbazepine and lacosamide. These drugs are regarded as second- or even third-generation compounds in comparison with older AEDs, such as phenobarbital, phenytoin, carbamaze-pine, ethosuximide and valproic acid. Although some of these new AEDs may be advantageous in terms of pharmacokinetics, tolerability and potential for drug interactions, improvements in clinical outcome have fallen short of expectations with no more than 15–20% of patients becom-ing seizure free in those refractory to older drugs and still, in at least some cases, having unaccept-able medication-related adverse effects [5].

The purpose of this article is to review the neurobiology and clinical relevance of AEDs with a well-known prominent GABAergic mechanism. The strengths and limitations of such compounds will be discussed in a clini-cal perspective, especially taking into account adverse effects on cognition and behavior.

AEDs acting on GABA receptorsInhibitory GABAergic interneurons are found throughout the brain, but in any region they may comprise a wide range of morphological and functional types that participate in different cir-cuits. There are two known subtypes of GABA receptors: GABA

A and GABA

B.

The GABAA receptor complex has several

allosteric sites that modulate its function, such as the so-called ‘benzodiazepine binding site.’ In fact, the majority of compounds that act

GABAergic drugs in the treatment of epilepsy: modern or outmoded?

Antiepileptic drugs have a number of mechanisms of action that target brain excitability systems. The potentiation of GABAergic inhibitory neurotransmission represents a classic and well-known antiseizure effect. Currently available GABAergic antiepileptic drugs mainly target GABAA receptor-associated complexes, GABA reuptake or GABA catabolism. All these compounds, although generally effective, are limited by their deleterious effects on cognition and behavior. The challenge will be to find GABAergic drugs that exhibit the beneficial effects, without the adverse ones.

Marco MulaDepartment of Clinical & Experimental Medicine, Division of Neurology, University Hospital Maggiore della Carità, C.so Mazzini 18, Italy Tel.: +39 032 137 33371 Fax: +39 032 137 33298 E-mail: [email protected]

Mini-Review

Special FocuS: GabaeRGic DRuGS

For reprint orders, please contact [email protected]

Page 2: GABAergic drugs in the treatment of epilepsy: modern or outmoded?

Mini-Review | Mula

Future Med. Chem. (2011) 3(2)178 future science group

on GABAA receptors do so at modulatory sites

distinct from the GABA recognition site. The benzodiazepine binding site is hypothesized to be responsible for mediating the wide range of CNS activities of benzodiazepines. However, GABA

A receptors have a number of different

subunit compositions and there is continuing debate about how differences in amino acid composition may lead to pharmacological dif-ferences in functional activity [6]. In particular, the sedative–hypnotic effect (and partially the antiseizure effect) appear to be caused by the allosteric positive modulation of GABA

A recep-

tors containing the a1 subunit, while the anx-iolytic effect seems to be related to those con-taining the a2 subunit [7]. Nonbenzodiazepine compounds, such as zolpidem, are often selec-tive for a1 and a5 subunits and are, therefore, sedative–hypnotic and partially antiseizure.

In the case of epilepsy, classical benzodiazepines are mainly used to treat status epilepticus but have limited utility in the chronic treatment because of the development of tolerance. A number of selec-tive agents could potentially be superior to ben-zodiazepines for chronic epilepsy but it remains to be demonstrated whether they are less suscep-tible to tolerance. The emerging understanding of different roles for phasic and tonic inhibition in epileptic phenomena may lead to the develop-ment of new drugs for epilepsy therapy targeting GABA

A receptors [8]. In fact, although mediated

by GABAA receptors, phasic and tonic inhibition

is modulated by different receptor subtypes whose most notable difference is in their subunit com-position (i.e., receptors mediating tonic inhibition contain the d-subunit, while the g-subunit char-acterizes receptors mediating synaptic or phasic inhibition) [9]. The concept of tonic inhibition mediated by extrasynaptic GABA

A receptors has

received special attention in recent literature. Neurosteroids target receptors containing a4 and a6 subunits [10], which are benzodiazepine insen-sitive and tend to activate d-containing GABA

A

receptors. Therefore, neurosteroids may have reduced liability to tolerance and may be use-ful in specific epilepsy syndromes (e.g., infantile spasms) or to treat hormone-dependent seizure exacerbations (e.g., catamenial epilepsy [11]).

The effects of phenytoin [12] and lamotrig-ine [13] on GABAergic neurotransmission are very controversial. However, it is interesting to note that both seem to increase tonic GABAergic neurotransmission and this mechanism may contribute to their antiseizure activity. Classic AEDs, such as phenobarbital, initially consid-ered as specific GABAergic drugs, are now seen as multiple-action drugs. In fact, the block-ade of voltage-gated sodium channels and the blockade of glutamate-mediated excitatory syn-apses appear to be as important as the GABA-receptor hypothesis for the mechanism of action of barbiturates [14].

Table 1. GABAergic effects of antiepileptic drugs.

GABA potentiation

GABAA receptor

GABAB receptor

Channel blockade Antiglutamate neurotransmission

Benzodiazepine ++ ++ – – –

Carbamazepine ? – – Na, Ca + (NMDA)

Ethosuximide – – – Na, Ca –

Felbamate + + – Na, Ca ++ (NMDA)

Gabapentin ? – – Ca –

Lacosamide – – – Na –

Lamotrigine + – – Na, Ca ++ (NMDA, AMPA)

Levetiracetam ? + – Ca ?

Oxcarbazepine ? – – Na, Ca + (NMDA)

Phenobarbital + + – Ca –

Phenytoin – – – Na ?

Pregabalin – – – Ca –

Tiagabine ++ – – – –

Topiramate + + – Na, Ca ++ (AMPA)

Valproic acid + ? – Na?, Ca? + (NMDA)

Vigabatrin ++ – – – –

Zonisamide ? – – Na, Ca –++: Primary action; +: Secondary action; –: No activity; ?: Controversial.AMPA: a-amino-3-hydroxy-5-methyl-4-isoxazole proprionate; NMDA: N-methyl-d-aspartate.

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GABAB receptors were originally identified

as those mediating the bicuculline-insensitive inhibitory GABAergic neurotransmission [15]. GABA

B receptors are expressed presynaptically

at GABAergic and glutamatergic synapses, and they act to decrease neurotransmitter release by reducing calcium influx. Baclofen is a clas-sic GABA

B receptor agonist because it is selec-

tive for GABAB receptors and does not activate

GABAA receptors. GABA

B-selective agonists

promote spike–wave discharges while antago-nists (e.g., phaclofen) suppress them in rodent models of absence epilepsy [16]. These factors suggest that GABA

B receptors might represent

a promising target for developing anti-absences agents. There are some compounds in develop-ment but none of the currently available AEDs showed significant activity on this receptor subtype [17].

AEDs acting on GABA transporters & GABA transaminaseGABA transporters remove synaptically released GABA, thus limiting or terminating its inhibi-tory activity. Neuronal GABA reuptake allows immediate recycling into synaptic vesicles while astrocytes reuptake leads to metabolism via GABA transaminase or succinic semialdehyde dehydrogenase [3].

At least four different GABA transporters have been identified in humans, namely GAT-1, GAT-2, GAT-3 and BGT-1 [18]. GAT-1 seems to shape phasic GABA neurotransmission and is thought to be an interesting molecular target for AEDs, especially glial GAT-1 [19]. Tiagabine is highly selective for GAT-1 and other isoforms expressed in the cortex and limbic structures [20]. It is of particular interest that GAT-1 inhibi-tion mediates a potentiation of tonic inhibi-tory effects of GABA rather than an enhance-ment of phasic inhibition. In fact, basic studies using hippo campal slices showed that tiagabine prolongs inhibitory synaptic potentials [21].

As stated earlier, GABA is metabolized by two main mitochondrial enzymes, namely GABA transaminase and succinic semialdehyde dehydro genase, the latter yielding to an acid cycle intermediate. Vigabatrin was initially identified as an irreversible GABA transaminase inhibi-tor [22]. This drug is a racemic mixture with only the S(+)-enantiomer possessing anticonvulsant activity. Subsequently, various studies suggested that the anticonvulsant activity of vigabatrin was not a consequence of enhanced GABAergic inhi-bition resulting from an augmented releasable

pool of neurotransmitter [23–26]. In fact, the increase in extracellular GABA concentrations does not seem to be dependent on vesicular release but rather on reverse transport of GABA by GAT-1 or GAT-3 [27]. These data have raised some doubts as to whether GABA-transaminase inhibition can be a useful molecular target for AEDs and future studies are needed to clarify this issue.

GABAergic AEDs & cognitionFirst of all, it is imperative to realize that, in clinical practice, many cognitive problems in patients with epilepsy have multiple causes, including, in some cases, adverse effects of AEDs [28]. However, the negative effect of GABA-potentiation on cognition has been clearly demonstrated. Studies in healthy vol-unteers show that the acute administration of benzodiazepine produce sedation, drowsiness, psychomotor slowing, anterograde amnesia and difficulties learning new materials [29]. Among the reported dysfunctions during long-term treatment, there are impairment of visuospatial and visuomotor abilities, decreased IQ, motor incoordination, slowing psychomotor speed, decreased speed of information processing, verbal learning and concentration, and delayed response times [29].

One interesting issue relates to the possibility that the selective modulation of GABA

A recep-

tors may impair cognition differently from the selective modulation of GABA

B receptors.

However, none of the currently available AEDs showed any significant activity on the GABA

B

receptor subtype, although some compounds are in development [1,30].

As far as the older drugs are concerned, major detrimental effects, in volunteer studies, have been shown for phenytoin and barbiturates in a wide spectrum of cognitive functions such as attention, memory and mental speed [28]. However, studies in patients with epilepsy have not replicated such differences in the case of phenytoin; for example, comparing phenytoin to other older agents such as carbamazepine and sodium valproate demonstrated no significant differences [31,32]. In fact, there seems to be gen-eral agreement that the major differentiation is between barbiturates and all other agents [28].

Among the newer AEDs, topiramate is probably the one associated with a significant negative impact on cognitive functions [28,32]. However, all of these studies evaluate short-term outcomes of the drug without considering

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Future Med. Chem. (2011) 3(2)180 future science group

the longer-term cognitive effects that are clini-cally relevant. In this regard, the so-called ‘posi-tive tolerance’ or habituation phenomenon has rarely been taken into consideration. For most drugs, side effects occur early and for a short period (i.e., during the first few days or weeks of drug exposure), after which normalization occurs. Little is known about how tolerance to the cognitive adverse effects of AEDs devel-ops and a failure to pay attention to this factor may lead to an over estimation of the negative effects of drugs on cognition. In fact, clinically, adverse effects that are of particular importance include those that persist during long-term treatment [33].

GABAergic AEDs & moodIt is notable that the AEDs associated with depression more than others (barbiturates, viga-batrin, tiagabine and topiramate), are those with prominent GABAergic properties [34].

In psychiatric practice, it is known that benzodiazepines can provoke depressive symp-toms, and that their withdrawal can also pro-voke depressive symptoms [35]. Furthermore, alterations of CSF GABA have been reported in patients with major depressive disorders [36]. Various clinical observations and experimen-tal studies have demonstrated that GABAergic mechanisms are involved in the pathogenesis of depression [37]. The evidence is not easy to explain, but is in keeping with the observation that a potentiation of the GABA neurotransmis-sion in patients with epilepsy may be detrimental to the patient’s mood.

As far as older generation anticonvulsants are concerned, a number of studies suggested a link between depression and treatment with barbi-turates (primidone or phenobarbital) [34]. An open study comparing primidone with carba-mazepine showed that, over time, patients tak-ing primidone displayed depressive symptoms more frequently than those taking carbamaze-pine [38]. Subsequently, other authors, using a double-blind crossover design, have replicated these findings using standardized clinical instru-ments [39]. Among new compounds, vigabatrin, tiagabine and topiramate have been linked with depression as a treatment-emergent adverse event [34]. Vigabatrin has been the most exten-sively studied, largely as a result of being the first of the new drugs to be introduced into clinical practice [40]. In some selected cases, the onset of depression was linked with a dramatic control of seizure frequency [41,42] (probably the so-called

‘forced normalization phenomenon’ [43]), while in others it was unrelated to that. However, in at least 50% of patients, treatment-emergent depressive symptoms appeared to be more com-mon in subjects with a past history of depres-sion [44], further confirming the importance of an underlying biological liability.

Topiramate has multiple mechanisms of action but among these mechanisms GABAergic potentiation is probably prominent, and data coming from functional neuroimaging stud-ies confirmed such a hypothesis [45]. Clinical studies have shown that depression is one of the main treatment-emergent adverse events during topiramate therapy with a rapid titration sched-ule, a past psychiatric history and probably a more severe form of epilepsy being major risk factors [46,47].

Numerous studies have pointed out that GABAergic potentiation is determinant in the development of depressive symptoms if it occurs in patients with hippocampal sclerosis [46,48,49]. Furthermore, it seems that functional abnor-malities in the limbic systems may be even more determinant than structural ones, repre-senting a major risk factor for the development of treatment-emergent psychiatric adverse event per se [47,50].

Future perspectiveGABAergic AEDs represented, and still repre-sent, an important class of compounds with anti-epileptic activity. However, they are burdened by a number of adverse effects on cognition and behavior that might not be so common with other classes, such as channels blockers. Tailored treatment strategies are needed according to specific patients’ needs and clinical character-istics. The challenge for the future will be to find GABAergic drugs that have the beneficial effects associated with this mechanism without the adverse effects.

Financial & competing interests disclosureThe author has received consultancy fees, speaker fees and travel grants from various pharmaceutical companies including Novartis, Pfizer, UCB, Janssen-Cilag, Sanofi-Aventis, who are involved in the manufacture of anti-epileptic drugs. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

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GABAergic drugs in the treatment of epilepsy: modern or outmoded? | Mini-Review

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Executive summary

� GABAergic neurotransmission still represents an important molecular target for the treatment of epilepsy.

� GABAergic antiepileptic drugs (AEDs) are burdened by detrimental effects on cognition and behavior compared with other classes of AEDs (i.e., channel blockers or antiglutamatergic drugs).

� Treatment-emergent adverse effects are multifactorial, depending on such factors as titration, dose and personal or family psychiatric history. This implies that AEDs, including those with a GABAergic mechanism, should be tailored to the clinical profile of the patients.

� New GABAergic AEDs with a better tolerability profile represent a major challenge.

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