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

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.

[1]  C. Stafstrom.  Persistent Sodium Current and Its Role in Epilepsy , 2007, Epilepsy currents.

[2]  J Brown,et al.  Molecular Determinants of Voltage-dependent Gating and Binding of Pore-blocking Drugs in Transmembrane Segment IIIS6 of the Na+ Channel α Subunit* , 2001, The Journal of Biological Chemistry.

[3]  I. Scheffer,et al.  Generalized epilepsy with febrile seizures plus. A genetic disorder with heterogeneous clinical phenotypes. , 1997, Brain : a journal of neurology.

[4]  William A. Catterall,et al.  International Union of Pharmacology. XLVII. Nomenclature and Structure-Function Relationships of Voltage-Gated Sodium Channels , 2005, Pharmacological Reviews.

[5]  W. Löscher,et al.  The neurobiology of antiepileptic drugs for the treatment of nonepileptic conditions , 2004, Nature Medicine.

[6]  W. Catterall,et al.  Frequency and voltage-dependent inhibition of type IIA Na+ channels, expressed in a mammalian cell line, by local anesthetic, antiarrhythmic, and anticonvulsant drugs. , 1991, Molecular pharmacology.

[7]  M. Gold,et al.  Voltage-gated sodium channels and hyperalgesia. , 2004, Annual review of pharmacology and toxicology.

[8]  Harald Sontheimer,et al.  Voltage-gated Na+ channels in glia: properties and possible functions , 1996, Trends in Neurosciences.

[9]  W. Catterall,et al.  Molecular determinants of state-dependent block of Na+ channels by local anesthetics. , 1994, Science.

[10]  F. L. D. Silva,et al.  Excitatory ionic currents and calcium extrusion in hippocampal neurons in epilepsy , 2007 .

[11]  A. M. Rush,et al.  Voltage-gated sodium channel blockers for the treatment of neuropathic pain , 2007, Expert review of neurotherapeutics.

[12]  R. Kass,et al.  Regulation of the voltage-gated cardiac sodium channel Nav1.5 by interacting proteins. , 2005, Trends in cardiovascular medicine.

[13]  T. Stöhr,et al.  Lacosamide: a review of preclinical properties. , 2007, CNS drug reviews.

[14]  J. Krystal,et al.  Riluzole in the Treatment of Mood and Anxiety Disorders , 2008, CNS drugs.

[15]  N. Mercuri,et al.  Increased persistent sodium current determines cortical hyperexcitability in a genetic model of amyotrophic lateral sclerosis , 2009, Experimental Neurology.

[16]  G. Avanzini,et al.  Epileptogenic Channelopathies: Experimental Models of Human Pathologies , 2007, Epilepsia.

[17]  M. Rogawski,et al.  Selective Antagonism of GluR5 Kainate-Receptor-Mediated Synaptic Currents by Topiramate in Rat Basolateral Amygdala Neurons , 2003, The Journal of Neuroscience.

[18]  Melinda S. Martin,et al.  The voltage-gated sodium channel Scn8a is a genetic modifier of severe myoclonic epilepsy of infancy. , 2007, Human molecular genetics.

[19]  Peter K. Stys,et al.  General mechanisms of axonal damage and its prevention , 2005, Journal of the Neurological Sciences.

[20]  C. Steinhäuser,et al.  Glial membrane channels and receptors in epilepsy: impact for generation and spread of seizure activity. , 2002, European journal of pharmacology.

[21]  W. Löscher.  Basic Pharmacology of Valproate , 2002 .

[22]  I. Scheffer,et al.  Benign familial neonatal‐infantile seizures: Characterization of a new sodium channelopathy , 2004, Annals of neurology.

[23]  Steven Petrou,et al.  SCN1A mutations and epilepsy , 2005, Human mutation.

[24]  C. Heckman,et al.  Increased persistent Na+ current and its effect on excitability in motoneurones cultured from mutant SOD1 mice , 2005, The Journal of physiology.

[25]  H R Parri,et al.  On the Action of the Anti-Absence Drug Ethosuximide in the Rat and Cat Thalamus , 1998, The Journal of Neuroscience.

[26]  M. Avoli,et al.  Neocortical Potassium Currents Are Enhanced by the Antiepileptic Drug Lamotrigine , 2002, Epilepsia.

[27]  A. L. Goldin,et al.  A BAC transgenic mouse model reveals neuron subtype-specific effects of a Generalized Epilepsy with Febrile Seizures Plus (GEFS+) mutation , 2009, Neurobiology of Disease.

[28]  Vladimir Yarov-Yarovoy,et al.  Role of Amino Acid Residues in Transmembrane Segments IS6 and IIS6 of the Na+ Channel α Subunit in Voltage-dependent Gating and Drug Block* , 2002, The Journal of Biological Chemistry.

[29]  David John Adams,et al.  μO-conotoxin MrVIB selectively blocks Nav1.8 sensory neuron specific sodium channels and chronic pain behavior without motor deficits , 2006, Proceedings of the National Academy of Sciences.

[30]  Alfred L George,et al.  Inherited disorders of voltage-gated sodium channels. , 2005, The Journal of clinical investigation.

[31]  Sulayman D. Dib-Hajj,et al.  Electrophysiological Properties of Mutant Nav1.7 Sodium Channels in a Painful Inherited Neuropathy , 2004, The Journal of Neuroscience.

[32]  T. Strom,et al.  Mutation in the neuronal voltage-gated sodium channel SCN1A in familial hemiplegic migraine , 2005, The Lancet.

[33]  G. Lees,et al.  The Investigational Anticonvulsant Lacosamide Selectively Enhances Slow Inactivation of Voltage-Gated Sodium Channels , 2008, Molecular Pharmacology.

[34]  E. Kimchi,et al.  Dysregulation of sodium channel expression in cortical neurons in a rodent model of absence epilepsy , 2004, Brain Research.

[35]  I. Chessell,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 , 2008, European journal of pain.

[36]  M. Avoli,et al.  Lacosamide: a new approach to target voltage-gated sodium currents in epileptic disorders. , 2009, CNS drugs.

[37]  S. Waxman,et al.  Fire and phantoms after spinal cord injury: Na+ channels and central pain , 2006, Trends in Neurosciences.

[38]  M. Meisler,et al.  Mutation of sodium channel SCN3A in a patient with cryptogenic pediatric partial epilepsy , 2008, Neuroscience Letters.

[39]  A. Alonso,et al.  High Conductance Sustained Single-Channel Activity Responsible for the Low-Threshold Persistent Na+ Current in Entorhinal Cortex Neurons , 1999, The Journal of Neuroscience.

[40]  C. Fertleman,et al.  Paroxysmal extreme pain disorder (previously familial rectal pain syndrome) , 2007, Neurology.

[41]  G Bernardi,et al.  Lamotrigine inhibits Ca2+ currents in cortical neurons: functional implications. , 1996, European journal of pharmacology.

[42]  D. Ragsdale.  How do mutant Nav1.1 sodium channels cause epilepsy? , 2008, Brain Research Reviews.

[43]  A. Urbani,et al.  Riluzole inhibits the persistent sodium current in mammalian CNS neurons , 2000, The European journal of neuroscience.

[44]  D. Prince,et al.  Characterization of ethosuximide reduction of low‐threshold calcium current in thalamic neurons , 1989, Annals of neurology.

[45]  Christoph Lossin.  A catalog of SCN1A variants , 2009, Brain and Development.

[46]  Aldo Quattrone,et al.  Identification of an Nav1.1 sodium channel (SCN1A) loss-of-function mutation associated with familial simple febrile seizures. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[47]  Darrell R. Abernethy,et al.  International Union of Pharmacology: Approaches to the Nomenclature of Voltage-Gated Ion Channels , 2003, Pharmacological Reviews.

[48]  G. Avanzini,et al.  Effects in Neocortical Neurons of Mutations of the Nav1.2 Na+ Channel causing Benign Familial Neonatal-Infantile Seizures , 2006, The Journal of Neuroscience.

[49]  V. Warren,et al.  Imidazopyridines: a novel class of hNav1.7 channel blockers. , 2008, Bioorganic & medicinal chemistry letters.

[50]  H. Fozzard,et al.  Molecular Modeling of Local Anesthetic Drug Binding by Voltage-Gated Sodium Channels , 2005, Molecular Pharmacology.

[51]  A. Alonso,et al.  Increased Persistent Sodium Currents in Rat Entorhinal Cortex Layer V Neurons in a Post–Status Epilepticus Model of Temporal Lobe Epilepsy , 2003, Epilepsia.

[52]  I. Scheffer,et al.  Temporal lobe epilepsy and GEFS+ phenotypes associated with SCN1B mutations. , 2006, Brain : a journal of neurology.

[53]  I. Scheffer,et al.  Generalized epilepsy with febrile seizures plus–associated sodium channel β1 subunit mutations severely reduce beta subunit–mediated modulation of sodium channel function , 2007, Neuroscience.

[54]  M. Kiernan.  Hyperexcitability, persistent Na+ conductances and neurodegeneration in amyotrophic lateral sclerosis , 2009, Experimental Neurology.

[55]  A. L. Goldin.  Mechanisms of sodium channel inactivation , 2003, Current Opinion in Neurobiology.

[56]  P. Emson,et al.  Changes in the mRNAs encoding voltage-gated sodium channel types II and III in human epileptic hippocampus , 2001, Neuroscience.

[57]  A. L. Goldin,et al.  A gain-of-function mutation in the sodium channel gene Scn2a results in seizures and behavioral abnormalities , 2001, Neuroscience.

[58]  H. Gould,et al.  Ibuprofen blocks changes in Na v 1.7 and 1.8 sodium channels associated with complete Freund's adjuvant-induced inflammation in rat. , 2004, The journal of pain : official journal of the American Pain Society.

[59]  R. Shank,et al.  Molecular Pharmacodynamics, Clinical Therapeutics, and Pharmacokinetics of Topiramate , 2008, CNS neuroscience & therapeutics.

[60]  William A Catterall,et al.  Temperature- and age-dependent seizures in a mouse model of severe myoclonic epilepsy in infancy , 2009, Proceedings of the National Academy of Sciences.

[61]  David F Meaney,et al.  Traumatic Axonal Injury Induces Proteolytic Cleavage of the Voltage-Gated Sodium Channels Modulated by Tetrodotoxin and Protease Inhibitors , 2004, The Journal of Neuroscience.

[62]  J J Clare,et al.  Cloning, distribution and functional analysis of the type III sodium channel from human brain , 2000, The European journal of neuroscience.

[63]  J. Gargus,et al.  Novel mutation confirms seizure locus SCN1A is also familial hemiplegic migraine locus FHM3. , 2007, Pediatric neurology.

[64]  G. Cruccu.  Treatment of painful neuropathy , 2007, Current opinion in neurology.

[65]  Massimo Mantegazza,et al.  Self-Limited Hyperexcitability: Functional Effect of a Familial Hemiplegic Migraine Mutation of the Nav1.1 (SCN1A) Na+ Channel , 2008, The Journal of Neuroscience.

[66]  Samuel F. Berkovic,et al.  A childhood epilepsy mutation reveals a role for developmentally regulated splicing of a sodium channel , 2007, Molecular and Cellular Neuroscience.

[67]  W. Catterall,et al.  Molecular Determinants for Modulation of Persistent Sodium Current by G-Protein βγ Subunits , 2005, The Journal of Neuroscience.

[68]  Hussain Jafri,et al.  An SCN9A channelopathy causes congenital inability to experience pain , 2006, Nature.

[69]  Hal Blumenfeld,et al.  Role of hippocampal sodium channel Nav1.6 in kindling epileptogenesis , 2009, Epilepsia.

[70]  A. Lo,et al.  Sodium channels contribute to microglia/macrophage activation and function in EAE and MS , 2005, Glia.

[71]  B. Ding,et al.  Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia , 2004, Journal of Medical Genetics.

[72]  J. Noebels,et al.  Topiramate alters excitatory synaptic transmission in mouse hippocampus , 2003, Epilepsy Research.

[73]  L. Lagae,et al.  De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy. , 2001, American journal of human genetics.

[74]  R. Kapoor.  Sodium channel blockers and neuroprotection in multiple sclerosis using lamotrigine , 2008, Journal of the Neurological Sciences.

[75]  M. Leppert,et al.  A Role of SCN9A in Human Epilepsies, As a Cause of Febrile Seizures and As a Potential Modifier of Dravet Syndrome , 2009, PLoS genetics.

[76]  Govert Hoogland,et al.  Persistent sodium current in subicular neurons isolated from patients with temporal lobe epilepsy , 2004, The European journal of neuroscience.

[77]  M. Ferrari,et al.  Divergent sodium channel defects in familial hemiplegic migraine , 2008, Proceedings of the National Academy of Sciences.

[78]  P. Calabresi,et al.  Antiepileptic drugs in migraine: from clinical aspects to cellular mechanisms. , 2007, Trends in pharmacological sciences.

[79]  S. Waxman.  Mechanisms of Disease: sodium channels and neuroprotection in multiple sclerosis—current status , 2008, Nature Clinical Practice Neurology.

[80]  W. Catterall,et al.  Voltage-gated ion channels and gating modifier toxins. , 2007, Toxicon : official journal of the International Society on Toxinology.

[81]  Sulayman D. Dib-Hajj,et al.  From genes to pain: Nav1.7 and human pain disorders , 2007, Trends in Neurosciences.

[82]  V. Crunelli,et al.  Childhood absence epilepsy: Genes, channels, neurons and networks , 2002, Nature Reviews Neuroscience.

[83]  W. Löscher.  Basic pharmacology of valproate: a review after 35 years of clinical use for the treatment of epilepsy. , 2002, CNS drugs.

[84]  S. Dib-Hajj,et al.  A novel Nav1.7 mutation producing carbamazepine‐responsive erythromelalgia , 2009, Annals of neurology.

[85]  M. Meisler,et al.  Sodium channel mutations in epilepsy and other neurological disorders. , 2005, The Journal of clinical investigation.

[86]  Andrew K. Dunn,et al.  Intrinsic brain activity triggers trigeminal meningeal afferents in a migraine model , 2002, Nature Medicine.

[87]  S. Waxman,et al.  Sodium channel activity modulates multiple functions in microglia , 2009, Glia.

[88]  Wolfgang Löscher,et al.  The neurobiology of antiepileptic drugs , 2004, Nature Reviews Neuroscience.

[89]  D. Johnston,et al.  Pharmacological upregulation of h-channels reduces the excitability of pyramidal neuron dendrites , 2002, Nature Neuroscience.

[90]  Clifford J. Woolf,et al.  Upregulation of the Voltage-Gated Sodium Channel β2 Subunit in Neuropathic Pain Models: Characterization of Expression in Injured and Non-Injured Primary Sensory Neurons , 2005, The Journal of Neuroscience.

[91]  Dirk Troost,et al.  Induction of neonatal sodium channel II and III α‐isoform mRNAs in neurons and microglia after status epilepticus in the rat hippocampus , 2001, The European journal of neuroscience.

[92]  I. Scheffer,et al.  The spectrum of SCN1A-related infantile epileptic encephalopathies. , 2007, Brain : a journal of neurology.

[93]  Hiroyuki Miyamoto,et al.  Nav1.1 Localizes to Axons of Parvalbumin-Positive Inhibitory Interneurons: A Circuit Basis for Epileptic Seizures in Mice Carrying an Scn1a Gene Mutation , 2007, The Journal of Neuroscience.

[94]  Paolo Calabresi,et al.  Antiepileptic drugs as a possible neuroprotective strategy in brain ischemia , 2003, Annals of neurology.

[95]  D. McCormick,et al.  On the cellular and network bases of epileptic seizures. , 2001, Annual review of physiology.

[96]  B. Rosen,et al.  Mechanisms of migraine aura revealed by functional MRI in human visual cortex , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[97]  H. Oguni,et al.  Severe myoclonic epilepsy in infancy: Dravet syndrome. , 2005, Advances in neurology.

[98]  D. Pietrobon,et al.  Familial hemiplegic migraine , 2007, Neurotherapeutics.

[99]  B. Hille.  Ionic channels of excitable membranes , 2001 .

[100]  S. Franceschetti,et al.  Modulatory Proteins Can Rescue a Trafficking Defective Epileptogenic Nav1.1 Na+ Channel Mutant , 2007, The Journal of Neuroscience.

[101]  M. Meisler,et al.  Heterozygosity for a protein truncation mutation of sodium channel SCN8A in a patient with cerebellar atrophy, ataxia, and mental retardation , 2005, Journal of Medical Genetics.

[102]  N. Nukina,et al.  A Functional Null Mutation of SCN1B in a Patient with Dravet Syndrome , 2009, The Journal of Neuroscience.

[103]  W. Catterall,et al.  Role of the C-terminal domain in inactivation of brain and cardiac sodium channels , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[104]  S. Franceschetti,et al.  A rescuable folding defective Nav1.1 (SCN1A) sodium channel mutant causes GEFS+: Common mechanism in Nav1.1 related epilepsies? , 2009, Human mutation.

[105]  D. Yoshikami,et al.  Synthetic muO-conotoxin MrVIB blocks TTX-resistant sodium channel NaV1.8 and has a long-lasting analgesic activity. , 2006, Biochemistry.

[106]  C. Argoff,et al.  Use of antiepileptic drugs for nonepileptic conditions: Psychiatric disorders and chronic pain , 2011, Neurotherapeutics.

[107]  R. Spain,et al.  Recent developments in multiple sclerosis therapeutics , 2009, BMC medicine.

[108]  A. Pitkänen.  Efficacy of current antiepileptics to prevent neurodegeneration in epilepsy models , 2002, Epilepsy Research.

[109]  G. Lees,et al.  Seeking a mechanism of action for the novel anticonvulsant lacosamide , 2006, Neuropharmacology.

[110]  John N. Wood,et al.  SCN9A Mutations in Paroxysmal Extreme Pain Disorder: Allelic Variants Underlie Distinct Channel Defects and Phenotypes , 2006, Neuron.

[111]  W. Crill,et al.  Persistent sodium current in mammalian central neurons. , 1996, Annual review of physiology.

[112]  M. Gutnick,et al.  Endogenous polyamines regulate cortical neuronal excitability by blocking voltage-gated Na+ channels , 2008, Proceedings of the National Academy of Sciences.