Astroglial cell death induced by excessive influx of sodium ions

Shinichi Takahashi, Mamoru Shibata, Jun Gotoh, Yasuo Fukuuchi

Research output: Contribution to journalArticlepeer-review

28 Citations (Scopus)

Abstract

Na+ influx has been implicated to play an important role in the mechanisms of neuronal cell damage under ischemia as well as in neurodegenerative disorders. Thus far, however, the effects of Na+ influx on astrocytic damage have not been studied extensively. In the present study, we have examined the effects of Na+ influx induced by veratridine (Na+ channel opener), monensin (Na+ ionophore), and glutamate (co-transportation with Na+) on rat cultured astroglial damage. Cells were incubated with bicarbonate buffer with 25 mM glucose containing either 100 μM veratridine, 10 μM monensin, or 1 mM glutamate with or without 1 mM ouabain for 20 h. Cellular damage was evaluated quantitatively by lactate dehydrogenase (LDH) release or 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction. Veratridine, monensin, or glutamate alone did not induce significant astroglial damage. Veratridine and monensin co-incubated with ouabain, which inhibits active extrusion of Na+ by Na+,K+-ATPase, thereby enhances intracellular Na+ accumulation, caused significant cell death (P < 0.001, approximately 50% cell damage), whereas glutamate did not. Na+-free solution substituted by choline (impermeable cation) attenuated cell damage induced by veratridine and monensin markedly, while Li+ substitution (permeable cation) rather exacerbated. Nifedipine (100 μM), a blocker of L-type Ca2+ channel, reduced veratridine-induced glial damage by 50%. Neither bepridil nor benzamil, a blocker of Na+-Ca2+ exchanger, had any protection. Cyclosporin A (1 or 10 μM), an inhibitor of mitochondrial permeability transition or 10 μM N-benzyloxycarbonyl-Val-Ala-Asp-(O-methyl)fluoromethyl ketone (zVAD-fmk), which inhibits a broad range of caspases, did not show protective effects. (C) 2000 Elsevier Science B.V.

Original languageEnglish
Pages (from-to)127-135
Number of pages9
JournalEuropean journal of pharmacology
Volume408
Issue number2
DOIs
Publication statusPublished - 2000 Nov 17

Keywords

  • Astrocyte
  • Ca
  • LDH (lactate dehydrogenase)
  • MTT
  • Mitochondrion
  • Na,K-ATPase
  • Ouabain

ASJC Scopus subject areas

  • Pharmacology

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