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  • Title: Role of sodium ion influx in depolarization-induced neuronal cell death by high KCI or veratridine.
    Author: Takahashi S, Shibata M, Fukuuchi Y.
    Journal: Eur J Pharmacol; 1999 May 21; 372(3):297-304. PubMed ID: 10395025.
    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 KCI 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 microM) 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 (approximately 50% at 25 mM, approximately 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 microM) did not. In contrast, veratridine (>10 microM) 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 approximately 100 microM), however, reduced percent cell damage induced by veratridine.
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