Opposing effects of adenosine on the survival of glial cells exposed to chemical ischemia.
Extracellular adenosine (Ado) accumulates during brain ischemia. To investigate the pathophysiological role of Ado on glial cells under ischemic conditions, we examined the effect of Ado on the survival of C6 glial cells exposed to chemical ischemia (CI). Treatment with Ado during exposure to CI showed a marked protective effect, that was mediated via intracellular transport and conversion of Ado to inosine (Ino). In contrast, Ado exacerbated CI-mediated cell death when it was added during the recovery time after exposure to CI. Ado cytotoxicity was largely mediated via intracellular transport, but conversion of Ado to Ino abolished its toxicity. Ado-induced cell death was characteristic of apoptosis, and Ado increased the expression of a pro-apoptotic product Bax but decreased that of an anti-apoptotic product Bcl-2. Ado also suppressed the induction of two stress proteins HSC70 and HSP27. Furthermore, Ado induced cytochrome c release and increased caspase-3-like activity. These results indicate the dual opposing effects of Ado on glial cell survival. Intracellular accumulation of Ado can be both cytoprotective and cytotoxic, depending on its metabolic pathway.
Imura
T
T
Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Shimohama
S
S
D000241:Adenosine / Q000378:metabolism* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D051017:Apoptosis Regulatory Proteins; D002545:Brain Ischemia / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D002352:Carrier Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D002452:Cell Count / Q000706:statistics & numerical data; D002470:Cell Survival / Q000187:drug effects* / Q000502:physiology; D003574:Cytochrome c Group / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005910:Glioma; D006801:Humans; D009457:Neuroglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000378:metabolism* / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D051028:bcl-2-Associated X Protein
D051017:Apoptosis Regulatory Proteins; C494826:BAX protein, human; D002352:Carrier Proteins; D003574:Cytochrome c Group; D018696:Neuroprotective Agents; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C090468:TP53BP2 protein, human; D051028:bcl-2-Associated X Protein; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D000241:Adenosine