The relationship between sodium channel inhibition and anticonvulsant activity in a model of generalised seizure in the rat

Large, Charles H.; Kalinichev, Mikhail; Lucas, A.; Carignani, Corrado; Bradford, Andrea M.; Garbati, Nicoletta; Sartori, Ilaria; Austin, Nigel; Ruffo, Alberto; Jones, Declan N.C.; Alvaro, Giuseppe; Read, Kevin D.

doi:10.1016/j.eplepsyres.2009.02.018

Cited by 44 publications

(42 citation statements)

References 25 publications

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“…Blood samples were taken at 60 min (GSK2 or GSK3) or 90 min (lamotrigine) after drug treatment (at the end of the test period). Blood samples were analyzed for drug concentration using a method based on protein precipitation followed by liquid chromatography/mass spectrometry; plasma concentrations were calculated based on the plasma protein binding for each drug determined from equilibrium dialysis studies (described in Large et al, 2009b), and corrected for the blood/plasma ratio as appropriate.…”

Section: Neurochemistrymentioning

confidence: 99%

“…We have developed two novel use-dependent sodium channel blockers, (5R)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-L-prolinamide (GSK2) and (2R,5R)-2-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-7-methyl-1,7-diazaspiro [4.4]nonan-6-one (GSK3). Like lamotrigine, the two compounds are effective anticonvulsant agents in animal models of seizure, but have notably higher affinities for the channels (Large et al, 2009b), and are structurally distinct from the older drug and thus have a reduced risk of inducing rash. We therefore wished to examine their potential as agents for the treatment of cognitive deficits associated with schizophrenia.…”

Section: Introductionmentioning

confidence: 99%

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The Efficacy of Sodium Channel Blockers to Prevent Phencyclidine-Induced Cognitive Dysfunction in the Rat: Potential for Novel Treatments for Schizophrenia

Large¹,

Bison²,

Sartori³

et al. 2011

J Pharmacol Exp Ther

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Sodium channel inhibition is a well precedented mechanism used to treat epilepsy and other hyperexcitability disorders. The established sodium channel blocker and broad-spectrum anticonvulsant lamotrigine is also effective in the treatment of bipolar disorder and has been evaluated in patients with schizophrenia. Double-blind placebo-controlled clinical trials found that the drug has potential to reduce cognitive symptoms of the disorder. However, because of compound-related side-effects and the need for dose titration, a conclusive evaluation of the drug's efficacy in patients with schizophrenia has not been possible. In this series of studies in the rat, we compared the efficacy of the two new molecules to prevent a cognitive deficit induced by the N-methyl-D-aspartic acid receptor antagonist phencyclidine (PCP) in the reversal-learning paradigm in the rat. We also explored the effects of the drugs to prevent brain activation and neurochemical effects of PCP. We found that, like lamotrigine, both GSK2 and GSK3 were able to prevent the deficit in reversal learning produced by PCP, thus confirming their potential in the treatment of cognitive symptoms of schizophrenia. However, higher doses than those required for anticonvulsant efficacy of the drugs were needed for activity in the reversal-learning model, suggesting a lower therapeutic window relative to mechanism-dependent central side effects for this indication.

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Section: Neurochemistrymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Efficacy of Sodium Channel Blockers to Prevent Phencyclidine-Induced Cognitive Dysfunction in the Rat: Potential for Novel Treatments for Schizophrenia

Large¹,

Bison²,

Sartori³

et al. 2011

J Pharmacol Exp Ther

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“…It is well established that deficiency of VGSC function causes epilepsy and pain, however, growing evidence of the channel's role have shown in other conditions too, including autism, neurodegeneration, multiple sclerosis, muscle, and immune disorders, as well as, cardiovascular complications (52)(53)(54)(55)(56). Hopefully, in the near future, we can design subtype-specific blockers of these or improve the existing agents in term of subtype-selectivity.…”

Section: Voltage-gated Sodium Channelmentioning

confidence: 99%

A Short Guide to Electrophysiology and Ion Channels

Rubaiy

2017

J Pharm Pharm Sci

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ABSTRACT:The birth and discovery of electrophysiological science took place in the 18 th century laying the path for our understanding of nerve membrane ionic currents. The pore-forming proteins, ion channels, are involved and play critical roles in very important physiological and pathological processes, such as neuronal signaling and cardiac excitability, therefore, they serve as therapeutic drug targets. The study of physiological, pharmacological and biophysical properties of ion channels can be done by patch clamp, a gold standard and powerful electrophysiological technique. The current review, in addition to highlight and cover the history of electrophysiology, patch clamp (conventional and automated) technique, and different types of ion channels, will also discuss the importance of ion channels in different neurological diseases and disorders. As the field of neuroscience is growing, this manuscript is intended as a guide to help in understanding the importance of ion channels, particularly in neuroscience, and also in using the patch clamp technique for the study of molecular physiology, pathophysiology, and pharmacology of neuronal ion channels. Importantly, this review will spotlight on the therapeutic aspect of neuronal ion channels.

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“…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%

“…It is a one of the most widely used AEDs in the treatment of generalized and partial seizures both in adults and children [27]. Several studies reported its possibility of reducing sodium currents in neocortical rat neurons (at concentration 0.2-2mM) [28], and especially persistent Na + current (with high potency IC 50 of 13.87±0.36 M) [24] as well as in recombinant human Na V 1.2 channels (IC 50 514 M) [12]. The proposed mechanism of VGSCs alteration is that valproate, being a fatty acid, may modulate the channels by influencing the biophysical properties of the channel's membrane but it does not explain the whole activity [27,29].…”

Section: Scn1bmentioning

confidence: 99%

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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The relationship between sodium channel inhibition and anticonvulsant activity in a model of generalised seizure in the rat

Cited by 44 publications

References 25 publications

The Efficacy of Sodium Channel Blockers to Prevent Phencyclidine-Induced Cognitive Dysfunction in the Rat: Potential for Novel Treatments for Schizophrenia

The Efficacy of Sodium Channel Blockers to Prevent Phencyclidine-Induced Cognitive Dysfunction in the Rat: Potential for Novel Treatments for Schizophrenia

A Short Guide to Electrophysiology and Ion Channels

Ion Channels as Drug Targets in Central Nervous System Disorders

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