Non-N-methyl-D-aspartate glutamate receptors mediate oxygen-glucose deprivation-induced oligodendroglial injury

Cells of oligodendroglial lineage are susceptible to oxygen and glucose dep rivation. When oligodendrocyte-like cells differentiated from CG-4-immortal ized rat O-2A progenitor cells were exposed to hypoxia alone or glucose dep rivation alone for 48 h, release of lactate dehydrogenase (LDH) into the cu lture medium did not increase. However, when cells were deprived of both ox ygen and glucose for 6 or 12 h preceding reoxygenation for 2 h, LDH release increased. Adding glucose to the medium protected against cell death and i ncreased lactate production in a concentration-dependent manner. Cell damag e induced by deprivation of oxygen and glucose was prevented by calcium-fre e medium or by non-N-methyl-D-aspartate glutamate receptor (GluR) antagonis ts, such as 6-cyano-7-nitroquinoxaline-2,3-dione or LY293558, but not by th e voltage-dependent calcium channel blocker, nimodipine, or by the N-methyl -D-aspartate GluR antagonist, MK-801. The glutamate concentration in the me dium from cells exposed to oxygen-glucose deprivation for 12 h was 49.70 +/ - 3.04 mu M/I, which is sufficient to activate GluRs during deprivation of oxygen and glucose. Apoptotic cells detected by terminal deoxynucleotidyl t ransferase (TdT)-mediated dUTP-biotin nick end-labeling (TUNEL) or Hoechst 33258 staining did not increase in cells exposed to oxygen-glucose deprivat ion for 12 h and subsequent reoxygenation for 2 h. No DNA laddering was det ected by agarose gel electrophoresis from cells exposed to deprivation of o xygen and glucose. Neither acetyl-YVAD-CHO, an inhibitor of caspase-1-like proteases, nor acetyl-DEVD-CHO, an inhibitor of caspase-3-like proteases, p revented oxygen-glucose deprivation-induced injury. Thus, oxygen and glucos e deprivation causes calcium-influx-induced necrotic cell damage in cells o f oligodendroglial lineage via non-N-methyl-D-aspartate GluR channels. (C) 2000 Elsevier Science B.V. All rights reserved.