Role of sodium ion influx in depolarization-induced neuronal cell death by high KCl or veratridine

S. Takahashi, M. Shibata, Y. Fukuuchi

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Intracellular Na+ concentration plays an important role in the regulation of cellular energy metabolism; i.e., increased intracellular Na+ concentration stimulates glucose utilization both in cultured neurons and astrocytes. Both high KCl and veratridine, which have been known to cause neuronal damage, elicit increased glucose utilization, presumably via increased intracellular Na+ concentration. In the present study, we examined the role of intracellular Na+ influx in the mechanisms of neuronal cell damage induced by high KCl or veratridine assayed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric method. Rat primary cultures of striatal neurons were incubated with high KCl (final concentrations: 25, 50 mM) or veratridine (0.1-100 μM) with or without various inhibitors. High KCl depolarizes cell membrane, thus, leading to Na+ influx through an activation of voltage-sensitive Na+ channels, while veratridine elicits Na+ influx by directly opening these channels. After 24-h incubation with elevated [K+](o) or veratridine, glucose contents in the medium decreased significantly (approximately by 7 mM), but remained higher than 18 mM. High [K+](o) reduced percent cell viability significantly (~50% at 25 mM, ~40% at 50 mM [K+](o), P<0.01), but tetrodotoxin (100 nM) had no protective effect, indicating that Na+ influx was not essential to high K+-induced cell death. dl-2-Amino-5-phosponovaleric acid (APV) (1 mM) completely blocked cell death induced by elevated [K+](o), while 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) (10 μM) did not. In contrast, veratridine (>10 μM) caused cell damage in a dose-dependent and tetrodotoxin-sensitive manner, but none of APV, CNQX, or bepridil (Na+-Ca2+ exchanger blocker) had any protective effect. Nifedipine (50~100 μM), however, reduced percent cell damage induced by veratridine. Copyright (C) 1999 Elsevier Science B.V.

Original languageEnglish
Pages (from-to)297-304
Number of pages8
JournalEuropean journal of pharmacology
Volume372
Issue number3
DOIs
Publication statusPublished - 1999 Jun 12

Keywords

  • Ca
  • K, extracellular
  • MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide)
  • Na channel, voltage-sensitive
  • Tetrodotoxin
  • Veratridine

ASJC Scopus subject areas

  • Pharmacology

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