The phosphatase inhibitor, okadaic acid, strongly protects primary rat cortical neurons from lethal oxygen-glucose deprivation.
The protein kinase-mediated actions of peptide growth factors such as IGF-1 and bFGF protect cultured neurons from being killed by the oxygen and glucose deprivations (OGD) that prevail in the 'stroked brain'. Here, we show that neuroprotection by IGF-1 is mediated by PI-3K/Akt, whereas that of bFGF is mediated by MAPK. IGF-1 and bFGF together did not further increase protection suggesting a downstream convergence of their pathways. Since protein kinases mediated the protection, a phosphatase inhibitor such as okadaic acid (OA) might be as protective as the growth factors against OGD. Here, we show that OA is actually a much more effective protector. It increased the phosphorylation of both PI-3K/Akt and MAPK, and stimulated new protein synthesis. OA also acted independently of the CREB activation and FKHRL1 and GSK-3 inactivation which have been implicated in IGF-1 actions.
Atkinson
Trevor
T
Molecular Signalling Group, National Research Council, Institute for Biological Sciences, 1200 Montreal Rd., Bldg. M-54, Ottawa, Ont., Canada K1A 0R6.
Whitfield
James
J
Chakravarthy
Balu
B
D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D019610:Cytoprotection; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000201:enzymology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D019319:Okadaic Acid / Q000494:pharmacology*; D010100:Oxygen / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats
D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D019319:Okadaic Acid; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020929:Mitogen-Activated Protein Kinase Kinases; D010744:Phosphoric Monoester Hydrolases; D005947:Glucose; D010100:Oxygen