p42/44 MAPK is an essential effector for purine nucleoside-mediated neuroprotection of hypoxic PC12 cells and primary cerebellar granule neurons.
Purine nucleosides protect neurons against hypoxic insult, but the signaling mechanisms have not yet been fully elucidated. We studied the role of the p42/44 MAPK pathway in purine nucleoside-mediated protection of cultured PC12 cells and primary cerebellar granule neurons from hypoxia-induced cell death. Incubation with adenosine reduced hypoxia-evoked cell death morphology, and increased the activity of the MAPK pathway. Inosine, a metabolic derivative of adenosine was generally less potent in PC12 cells. Pharmacological inhibition of the MAPK pathways severely hampered adenosine-mediated induction of cell viability and neurite outgrowth. Consistently, siRNA-mediated knockdown of p42 and p44 MAPK completely blocked adenosine-mediated rescue of hypoxic PC12 cells. The role of MAPK activation was further studied in primary neurons. Cells were significantly rescued by adenosine and inosine and siRNA-mediated knockdown severely affected purine-mediated rescue of neuronal viability after hypoxic insult. Results point to the important role of p42/44 MAPK for adenosine receptor-mediated neuroprotection.
Tomaselli
Bettina
B
Biocenter, Division of Neurobiochemistry, Medical University of Innsbruck, Fritz Pregl Str.3, A-6020 Innsbruck, Austria.
Nedden
Stephanie Zur
SZ
Podhraski
Valerie
V
Baier-Bitterlich
Gabriele
G
D000818:Animals; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002531:Cerebellum / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D003594:Cytoplasmic Granules / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016716:PC12 Cells; D011684:Purine Nucleosides / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D018696:Neuroprotective Agents; D011684:Purine Nucleosides; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3