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2004 Fiscal Year Final Research Report Summary

Murine model of lidocaine-dependent neonatal epileptic encephalopathy with a SCN2A mutation

Research Project

Project/Area Number 15591083
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Pediatrics
Research InstitutionAkita University

Principal Investigator

SAWAISHI Yukio  Akita University, School of Medicine, Research Associate, 医学部, 講師 (90250894)

Co-Investigator(Kenkyū-buntansha) SUZUKI Akira  Akita University, School of Medicine, Professor, 医学部, 教授 (10311565)
Project Period (FY) 2003 – 2004
Keywordssodium channel / lidocaine / epilepsy
Research Abstract

We have previously reported a case of early infantile status epilepticus characterized by continual epileptic seizures with electroencephalogram patterns of long suppression with intermittent short burst activity. All the clinico-electrical findings consistently improved by lidocaine at a low serum concentration (10^<-6> M). Here we identify a de novo missence mutation (I1473M) of SCN2A gene just proximal to the III-IV linker. Patch-clamp analysis of the orthologous mutation of rat Na_v1.2 (rNa_v1.2) show negative shift of steady-state inactivation curve and slowing of recovery from fast inactivation, resulting in decreased channel availability. High concentration of lidocaine (0.5 mM) induces tonic block and use-dependent block with a similar magnitude between wild-type and I1473M mutant rNa_v1.2 channels. The low concentration of lidocaine (10^<-8> to 10^<-6> M), by contrast, shifts the steady-state activation curve towards the negative potentials and increases current amplitude at negative potentials in the mutant channels but not in the wild-type channels, when they are coexpressed with the auxiliary β subunit. The findings indicate that lidocaine effects lead not only to decrease in sodium channel currents but also to increase under certain circumstances.

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Published: 2006-07-11  

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