Hypoxia-induced ischemic tolerance in neonatal rat brain involves enhanced ERK1/2 signaling.
Hypoxic preconditioning (HP) 24 h before hypoxic-ischemic (HI) injury confers significant neuroprotection in neonatal rat brain. Recent studies have shown that the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K) intracellular signaling pathways play a role in the induction of tolerance to ischemic injury in heart and brain. To study the role of MAPK (ERK1/2, JNK, p38MAPK) and PI3K/Akt/GSK3beta signaling pathways in hypoxia-induced ischemic tolerance, we examined the brains of newborn rats at different time points after exposure to sublethal hypoxia (8% O(2) for 3 h). Immunoblot analysis showed that HP had no effect on the levels of phosphorylated Akt, GSK3beta, JNK and p38MAPK. In contrast, significantly increased levels of phosphorylated ERK1/2 were observed 0.5 h after HP. Double immunofluorescence staining showed that hypoxia-induced ERK1/2 phosphorylation was found mainly in microvessels throughout the brain and in astrocytes in white matter tracts. Inhibition of hypoxia-induced ERK1/2 pathway with intracerebral administration of U0126 significantly attenuated the neuroprotection afforded by HP against HI injury. These findings suggest that activation of ERK1/2 signaling may contribute to hypoxia-induced tolerance in neonatal rat brain in part by preserving vascular and white matter integrity after HI.
Jones
Nicole M
NM
Neuroscience Division, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA.
Bergeron
Marcelle
M
D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D001273:Atmosphere Exposure Chambers; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D002545:Brain Ischemia / Q000201:enzymology* / Q000517:prevention & control; D004791:Enzyme Inhibitors / Q000494:pharmacology; D002534:Hypoxia, Brain / Q000201:enzymology* / Q000473:pathology; D015151:Immunoblotting; D007150:Immunohistochemistry; D008833:Microcirculation / Q000187:drug effects; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009584:Nitrogen / Q000494:pharmacology; D010100:Oxygen / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D004791:Enzyme Inhibitors; C041364:nitrox; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D009584:Nitrogen; D010100:Oxygen