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

Mantegazza, Massimo; Curia, Giulia; Biagini, Giuseppe; Ragsdale, David S.; Avoli, Massimo

doi:10.1016/s1474-4422(10)70059-4

Cited by 406 publications

(334 citation statements)

References 109 publications

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“…These show differential tissue distribution, different electrophysiological and pharmacological properties, and are linked to different physiological roles and pathologies (7,8). Drugs that selectively target Na v channel subtypes represent valuable pharmacological tools and have potential for development as medicines (7,8).…”

Section: Typically Acting On Ion Channels Implicated In Neurotransmismentioning

confidence: 99%

δ-Conotoxins Synthesized Using an Acid-cleavable Solubility Tag Approach Reveal Key Structural Determinants for NaV Subtype Selectivity

Peigneur

Paolini-Bertrand

Gaertner

et al. 2014

Journal of Biological Chemistry

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Background: Conotoxins are marine snail venom peptides of interest as pharmacological tools and potential medicines. Results: ␦-Conotoxins are poorly understood because they are difficult to synthesize. Using a new synthesis approach, we readily produced three ␦-conotoxins and two analogs, obtaining new pharmacological insights. Conclusion: Key structures on ␦-conotoxins determine Na V subtype selectivity. Significance: Our synthesis approach is applicable to other similarly challenging peptides.

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Section: Typically Acting On Ion Channels Implicated In Neurotransmismentioning

confidence: 99%

δ-Conotoxins Synthesized Using an Acid-cleavable Solubility Tag Approach Reveal Key Structural Determinants for NaV Subtype Selectivity

Peigneur

Paolini-Bertrand

Gaertner

et al. 2014

Journal of Biological Chemistry

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“…Volted-gated sodium channels as drug targets in CNS disorders were recently deeply reviewed by Mantegazza et al [2], Chahine et al [3] and Tarnawa et al [4]. In the current review we would like to summarize up to date information regarding their use in CNS disorders.…”

Section: Voltage-gated Sodium Channelsmentioning

confidence: 99%

“…Transient Na + current (I NaT ) is related with opening of the channel when sodium ions passively move through the channel on the basis of its electrochemical gradient [8]. On the other hand, persistent Na + current (I NaP ) is a small slowly inactivating sodium current with relatively long kinetics of inactivation (tens of seconds), which appears when inactivation of channels is incomplete [2]. It activates as potentials close to or slightly more negative than resting membrane potential and hardly inactivates.…”

Section: Voltage-gated Sodium Channelsmentioning

confidence: 99%

“…Names SCN1A-SCN5A and SCN8A-SCN11A refer to genes which code proteins building different -subunits of sodium channels, and SCN6A/SCN7A codifies Na x subunit [2]. SCN1B-SCN4B are genes responsible for encoding ofsubunit, 1-4, respectively [7].…”

Section: Voltage-gated Sodium Channelsmentioning

confidence: 99%

“…It is now known that abnormal expression or function of VGSCs may be involved in the pathophysiology of both acquired and inherited epilepsy [2]. Great evidence of the role of some [2], axon initial segments [13] Epilepsy NaV1.3 SCN3A Brain: neuronal somata, proximal dendrites; [2,12], upregulated expression in epileptic hippocampal neurons [14] Epilepsy, Central neuropathic pain [15] NaV1.4 SCN4A Skeletal muscle [2] NaV1.5 SCN5A Cardiac muscle; some neurons [2], microglial cells [16] Atrial fibrillation, ventricular fibrillation [10] NaV1.6 SCN8A Brain: axon initial segments, nodes of Ranvier, neuronal somata, dendrites of projection neurons [2] proximal dendrites [12], unmyelinated and myelinated axons [17] Ataxia NaV1.7 SCN9A NaV1.8 SCN10A NaV1.9 SCN11A…”

Section: Epilepsymentioning

confidence: 99%

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Ion Channels as Drug Targets in Central Nervous System Disorders

Waszkielewicz¹,

Gunia²,

Szkaradek³

et al. 2013

CMC

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Ion channel targeted drugs have always been related with either the central nervous system (CNS), the peripheral nervous system, or the cardiovascular system. Within the CNS, basic indications of drugs are: sleep disorders, anxiety, epilepsy, pain, etc. However, traditional channel blockers have multiple adverse events, mainly due to low specificity of mechanism of action. Lately, novel ion channel subtypes have been discovered, which gives premises to drug discovery process led towards specific channel subtypes. An example is Na + channels, whose subtypes 1.3 and 1.7-1.9 are responsible for pain, and 1.1 and 1.2 -for epilepsy. Moreover, new drug candidates have been recognized. This review is focusing on ion channels subtypes, which play a significant role in current drug discovery and development process. The knowledge on channel subtypes has developed rapidly, giving new nomenclatures of ion channels. For example, Ca 2+ channels are not any more divided to T, L, N, P/Q, and R, but they are described as Ca v 1.1-Ca v 3.3, with even newer nomenclature 1A-1I and 1S. Moreover, new channels such as P2X1-P2X7, as well as TRPA1-TRPV1 have been discovered, giving premises for new types of analgesic drugs.

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