Neuroprotective effect of sodium orthovanadate on delayed neuronal death after transient forebrain ischemia in gerbil hippocampus.
In transient forebrain ischemia, sodium orthovanadate as well as insulinlike growth factor-1 (IGF-1) rescued cells from delayed neuronal death in the hippocampal CA1 region. Adult Mongolian gerbils were subjected to 5-minute forebrain ischemia. Immunoblotting analysis with anti-phospho-Akt/PKB (Akt) antibody showed that phosphorylation of Akt at serine-473 (Akt-Ser-473) in the CA1 region decreased immediately after reperfusion, and in turn transiently increased 6 hours after reperfusion. The decreased phosphorylation of Akt-Ser-473 was not observed in the CA3 region. The authors then tested effects of intraventricular injection of orthovanadate and IGF-1, which are known to activate Akt. Treatment with orthovanadate or IGF-1 30 minutes before ischemia blocked delayed neuronal death in the CA1 region. The neuroprotective effects of orthovanadate and IGF-1 were associated with preventing decreased Akt-Ser-473 phosphorylation in the CA1 region observed immediately after reperfusion. Immunohistochemical studies with the anti-phospho-Akt-Ser-473 antibody also demonstrated that Akt was predominantly in the nucleus and was moderately activated in the cell bodies and dendrites of pyramidal neurons after orthovanadate treatment. The orthovanadate treatment also prevented the decrease in phosphorylation of mitogen-activated protein kinase (MAPK). Pretreatment with combined blockade of phosphatidylinositol 3-kinase and MAPK pathways totally abolished the orthovanadate-induced neuroprotective effect. These results suggest that the activation of both Akt and MAPK activities underlie the neuroprotective effects of orthovanadate on the delayed neuronal death in the CA1 region after transient forebrain ischemia.
Kawano
T
T
Department of Pharmacology, Kumamoto University School of Medicine, Kumamoto, Japan.
Fukunaga
K
K
Takeuchi
Y
Y
Morioka
M
M
Yano
S
S
Hamada
J
J
Ushio
Y
Y
Miyamoto
E
E
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005849:Gerbillinae; D006624:Hippocampus / Q000201:enzymology / Q000473:pathology*; D007150:Immunohistochemistry; D007276:Injections, Intraventricular; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009474:Neurons / Q000166:cytology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D014638:Vanadates / Q000494:pharmacology*; D000077191:Wortmannin
D000730:Androstadienes; D002070:Butadienes; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D009570:Nitriles; D011518:Proto-Oncogene Proteins; C113580:U 0126; D014638:Vanadates; D007334:Insulin-Like Growth Factor I; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D000077191:Wortmannin