Role of calcium in nitric oxide-induced cytotoxicity: EGTA protects mouse oligodendrocytes.
Active nitrogen species are overproduced in inflammatory brain lesions in multiple sclerosis (MS) and experimental allergic encephalomyelitis (EAE). NO has been shown to mediate the death of oligodendrocytes (OLs), a primary target of damage in MS. To develop strategies to protect OLs, we examined the mechanisms of cytotoxicity of two NO donors, S-nitroso-N-acetyl-penicillamine (SNAP) and sodium nitroprusside (SNP) on mature mouse OLs. Nitrosonium ion (NO+) rather than NO. mediates damage with both SNAP and SNP, as shown by significant protection with hemoglobin (HbO2), but not with the NO. scavenger PTIO. SNAP and SNP differ in time course and mechanisms of killing OLs. With SNAP, OL death is delayed for at least 6 hr, but with SNP, OL death is continuous over 18 hr with no delay. Relative to NO release, SNP is more toxic than SNAP, due to synergism of NO with cyanide released by SNP. SNAP elicits a Ca2+ influx in over half of the OLs within min. Further, OL death due to NO release from SNAP is Ca2+-dependent, because the Ca2+ chelator EGTA protects OLs from killing by SNAP, and also from killing by the NONOates NOC-9 and NOC-18, which spontaneously release NO. SNP does not elicit a Ca2+ influx, and EGTA is not protective. In comparison to the N20.1 OL cell line (Boullerne et al., [1999] J. Neurochem. 72:1050-1060), mature OLs are (1) more sensitive to SNAP, (2) much more resistant to SNP, (3) sensitive to cyanide, but not iron, and (4) exhibit a Ca2+ influx and EGTA protection in response to NO generated by SNAP.
Boullerne
A I
AI
Department of Neurology, Pritzker School of Medicine, University of Chicago, Chicago, Illinois, USA.
Nedelkoska
L
L
Benjamins
J A
JA
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D004533:Egtazic Acid / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D009498:Neurotoxins / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009836:Oligodendroglia / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
D009498:Neurotoxins; D020030:Nitric Oxide Donors; D009569:Nitric Oxide; D004533:Egtazic Acid; D002118:Calcium