References for this Review were identified through searches of PubMed with the search terms “amyotrophic lateral sclerosis”, “antiepileptic drugs”, “epilepsy”, “inflammation”, “migraine”, “multiple sclerosis”, “mutation”, “neurodegenerative”, “pain”, “sodium channels”, and “stroke” from June, 1963, up to October, 2009. Further references were identified from those cited in articles. The final reference list was generated from papers that were relevant to the topics covered in the Review.
ReviewVoltage-gated sodium channels as therapeutic targets in epilepsy and other neurological disorders
Introduction
Many of the most common neurological disorders, such as epilepsy, migraine, neurodegenerative diseases, and neuropathic pain, involve abnormalities of neuronal excitability. There is a growing body of data that implicates abnormal expression and function of voltage-gated sodium channels (VGSCs) in these disorders. Pharmacological inhibitors of VGSCs have been used for decades to treat epileptic seizures, the most common disease of neuronal excitability, and it is becoming increasingly evident that these antiepileptic VGSC blockers might also be efficacious against a broad range of neurological disorders. In this Review, we summarise the emerging evidence for a central role of VGSCs in the pathophysiology of epilepsy, migraine, neurodegeneration, and neuropathic pain, and examine the efficacy of antiepileptic VGSC blockers in the treatment of these neurological diseases. We also outline future developments that might extend the therapeutic use of compounds that target VGSCs.
Section snippets
Biophysical and molecular properties of VGSCs
Most neuroscientists and neurologists are familiar with the textbook description of VGSC function1 (figure 1A). VGSCs are closed at resting membrane potentials characteristic of quiescent neurons. In response to membrane depolarisation, they open within a few hundred microseconds (a process termed activation), resulting in an inward sodium ion (Na+) current, and then convert within a few milliseconds to a non-conducting inactivated state through a process called fast inactivation. Transient Na+
VGSCs and epileptic seizures
Epilepsy is a disorder of neuronal excitability, characterised by episodes of excessive synchronised neuronal activity. Electroencephalographic recordings from patients with partial epileptic disorders reveal two types of abnormal activity: interictal events, which are short asymptomatic episodes recurring periodically between seizures, and ictal discharges, which are more prolonged abnormalities in neuronal activity associated with behavioural manifestations.23 Both ictal and interictal
Migraine
In addition to causing epilepsy, mutations of Nav1.1 are also associated with familial hemiplegic migraine type 3,56, 57, 58, 59 a severe autosomal dominant inherited subtype of migraine with visual aura and hemiparesis during attacks. Data from studies in patients with migraine indicate that the aura coincides with cortical spreading depression (CSD), a wave of neuronal depolarisation that spreads across the cerebral cortex and generates transient intense firing followed by a long-lasting
VGSC blockers as AEDs
The widely used AEDs phenytoin and carbamazepine inhibit VGSCs at therapeutic concentrations, and this attenuation of Na+ current is thought to be the main mechanism of their therapeutic efficacy.77 These drugs are effective in the maximal electroshock seizure test, a model of tonic-clonic seizures that assesses the ability of AEDs to suppress hindlimb flexion/extension induced in normal rodents by electrical stimuli delivered through corneal electrodes. In contrast, these drugs are ineffective
VGSC blockers and treatment of other neurological disorders
VGSC blockers might be clinically effective in several neurological disorders, including migraine, neurodegeneration, and neuropathic pain;93, 94 their potential uses in the treatment of these disorders is described in the next sections.
Conclusions and future directions
An emerging theme that unifies many supposedly diverse neurological disorders is altered neuronal excitability, caused by abnormal expression and function of membrane ion channels. VGSCs, as the main determinants of intrinsic neuronal excitability, are implicated in many of these inherited and acquired channelopathies and, thus, they are particularly appealing targets for pharmacological intervention. VGSC blockers, including AEDs and local anaesthetics, have been used for decades to treat
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