Opposing effects of adenosine on survival of glial cells exposed to chemical ischemia

Extracellular adenosine (Ado) accumulates during brain ischemia. To investi gate the pathophysiological role of Ado on glial cells under ischemic condi tions, we examined the effect of Ado on the survival of C6 glial cells expo sed to chemical ischemia (CI). Treatment with Ado during exposure to CI sho wed a marked protective effect, that was mediated via intracellular transpo rt and conversion of Ado to inosine (Ino). In contrast, Ado exacerbated CI- mediated cell death when it was added during the recovery time after exposu re to CI. Ado cytotoxicity was largely mediated via intracellular transport , but conversion of Ado to Ino abolished its toxicity. Ado-induced cell dea th was characteristic of apoptosis, and Ado increased the expression of a p ro-apoptotic product Bar but decreased that of an anti-apoptotic product Bc l-2. Ado also suppressed the induction of two stress proteins HSC70 and HSP 27. Furthermore, Ado induced cytochrome c release and increased caspase-3-l ike activity. These results indicate the dual opposing effects of Ado on gl ial cell survival. Intracellular accumulation of Ado can be both cytoprotec tive and cytotoxic, depending on its metabolic pathway. (C) 2000 Wiley-Liss , Inc.