Elsevier

The Lancet Neurology

Volume 9, Issue 4, April 2010, Pages 413-424
The Lancet Neurology

Review
Voltage-gated sodium channels as therapeutic targets in epilepsy and other neurological disorders

https://doi.org/10.1016/S1474-4422(10)70059-4Get rights and content

Summary

Voltage-gated sodium channels (VGSCs) are key mediators of intrinsic neuronal and muscle excitability. Abnormal VGSC activity is central to the pathophysiology of epileptic seizures, and many of the most widely used antiepileptic drugs, including phenytoin, carbamazepine, and lamotrigine, are inhibitors of VGSC function. These antiepileptic drugs might also be efficacious in the treatment of other nervous system disorders, such as migraine, multiple sclerosis, neurodegenerative diseases, and neuropathic pain. In this Review, we summarise the structure and function of VGSCs and their involvement in the pathophysiology of several neurological disorders. We also describe the biophysical and molecular bases for the mechanisms of action of antiepileptic VGSC blockers and discuss the efficacy of these drugs in the treatment of epileptic and non-epileptic disorders. Overall, clinical and experimental data indicate that these drugs are efficacious for a range of diseases, and that the development of drugs with enhanced selectivity for specific VGSC isoforms might be an effective and novel approach for the treatment of several neurological diseases.

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

Search strategy and selection criteria

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.

References (113)

  • JA Kearney et al.

    A gain-of-function mutation in the sodium channel gene Scn2a results in seizures and behavioral abnormalities

    Neuroscience

    (2001)
  • L Claes et al.

    De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy

    Am J Hum Genet

    (2001)
  • R Xu et al.

    Generalized epilepsy with febrile seizures plus-associated sodium channel β1 subunit mutations severely reduce beta subunit-mediated modulation of sodium channel function

    Neuroscience

    (2007)
  • C Lossin

    A catalog of SCN1A variants

    Brain Dev

    (2009)
  • DS Ragsdale

    How do mutant Nav1.1 sodium channels cause epilepsy?

    Brain Res Rev

    (2008)
  • B Tang et al.

    A BAC transgenic mouse model reveals neuron subtype-specific effects of a generalized epilepsy with febrile seizures plus (GEFS+) mutation

    Neurobiol Dis

    (2009)
  • R Xu et al.

    A childhood epilepsy mutation reveals a role for developmentally regulated splicing of a sodium channel

    Mol Cell Neurosci

    (2007)
  • M Dichgans et al.

    Mutation in the neuronal voltage-gated sodium channel SCN1A in familial hemiplegic migraine

    Lancet

    (2005)
  • JJ Gargus et al.

    Novel mutation confirms seizure locus SCN1A is also familial hemiplegic migraine locus FHM3

    Pediatr Neurol

    (2007)
  • D Pietrobon

    Familial hemiplegic migraine

    Neurotherapeutics

    (2007)
  • M Pieri et al.

    Increased persistent sodium current determines cortical hyperexcitability in a genetic model of amyotrophic lateral sclerosis

    Exp Neurol

    (2009)
  • MC Kiernan

    Hyperexcitability, persistent Na+ conductances and neurodegeneration in amyotrophic lateral sclerosis

    Exp Neurol

    (2009)
  • CR Fertleman et al.

    SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes

    Neuron

    (2006)
  • SG Waxman et al.

    Fire and phantoms after spinal cord injury: Na+ channels and central pain

    Trends Neurosci

    (2006)
  • HJ Gould et al.

    Ibuprofen blocks changes in Nav 1.7 and 1.8 sodium channels associated with complete Freund's adjuvant-induced inflammation in rat

    J Pain

    (2004)
  • IT Strickland et al.

    Changes in the expression of NaV1.7, NaV1.8 and NaV1.9 in a distinct population of dorsal root ganglia innervating the rat knee joint in a model of chronic inflammatory joint pain

    Eur J Pain

    (2008)
  • A Stefani et al.

    Lamotrigine inhibits Ca2+ currents in cortical neurons: functional implications

    Eur J Pharmacol

    (1996)
  • J Qian et al.

    Topiramate alters excitatory synaptic transmission in mouse hippocampus

    Epilepsy Res

    (2003)
  • AC Errington et al.

    Seeking a mechanism of action for the novel anticonvulsant lacosamide

    Neuropharmacology

    (2006)
  • AB Ettinger et al.

    Use of antiepileptic drugs for nonepileptic conditions: psychiatric disorders and chronic pain

    Neurotherapeutics

    (2007)
  • P Calabresi et al.

    Antiepileptic drugs in migraine: from clinical aspects to cellular mechanisms

    Trends Pharmacol Sci

    (2007)
  • A Pitkanen

    Efficacy of current antiepileptics to prevent neurodegeneration in epilepsy models

    Epilepsy Res

    (2002)
  • R Kapoor

    Sodium channel blockers and neuroprotection in multiple sclerosis using lamotrigine

    J Neurol Sci

    (2008)
  • B Hille

    Ionic channels of excitable membranes

    (2001)
  • J Magistretti et al.

    High conductance, sustained single channel activity responsible for the low-threshold persistent Na+ current in entorhinal cortex neurons

    J Neurosci

    (1999)
  • WE Crill

    Persistent sodium current in mammalian central neurons

    Annu Rev Physiol

    (1996)
  • CE Stafstrom

    Persistent sodium current and its role in epilepsy

    Epilepsy Curr

    (2007)
  • M Mantegazza et al.

    Molecular determinants for modulation of persistent sodium current by G-protein βγ subunits

    J Neurosci

    (2005)
  • IA Fleidervish et al.

    Endogenous polyamines regulate cortical neuronal excitability by blocking voltage-gated Na+ channels

    Proc Natl Acad Sci USA

    (2008)
  • SG Waxman

    Mechanisms of disease: sodium channels and neuroprotection in multiple sclerosis-current status

    Nat Clin Pract Neurol

    (2008)
  • WA Catterall et al.

    International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels

    Pharmacol Rev

    (2005)
  • DS Ragsdale et al.

    Molecular determinants of state-dependent block of Na+ channels by local anesthetics

    Science

    (1994)
  • GM Lipkind et al.

    Molecular modeling of local anesthetic drug binding by voltage-gated sodium channels

    Mol Pharmacol

    (2005)
  • M Mantegazza et al.

    Role of the C-terminal domain in inactivation of brain and cardiac sodium channels

    Proc Natl Acad Sci USA

    (2001)
  • YH Chen et al.

    Cloning, distribution and functional analysis of the type III sodium channel from human brain

    Eur J Neurosci

    (2000)
  • JA Black et al.

    Sodium channel activity modulates multiple functions in microglia

    Glia

    (2009)
  • R Káradóttir et al.

    Spiking and nonspiking classes of oligodendrocyte precursor glia in CNS white matter

    Nat Neurosci

    (2008)
  • C Steihhäuser et al.

    Glial membrane channels and receptors in epilepsy: impact for generation and spread of seizure activity

    Eur J Pharmacol

    (2002)
  • DA McCormick et al.

    On the cellular and network bases of epileptic seizures

    Annu Rev Physiol

    (2001)
  • E Aronica et al.

    Induction of neonatal sodium channel II and III α-isoform mRNAs in neurons and microglia after status epilepticus in the rat hippocampus

    Eur J Neurosci

    (2001)
  • Cited by (365)

    View all citing articles on Scopus
    View full text