Activation of phosphatidylinositol 3-kinase/protein kinase B pathway by a vanadyl compound mediates its neuroprotective effect in mouse brain ischemia.
We previously reported that orthovanadate composed of vanadate (V(5+)) activates phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling through inhibition of protein tyrosine phosphatases, thereby eliciting neuroprotection in brain ischemia/reperfusion injury. However, therapeutic doses of orthovanadate are associated with diarrhea due to inhibition of ATPase. By contrast, vanadyl (V(4+)) organic compounds show low cytotoxicity. Since both vanadate and vanadyl inhibit protein tyrosine phosphatases, we tested whether bis(1-oxy-2-pyridinethiolato)oxovanadium(IV) [VO(OPT)] in a vanadyl form elicits a neuroprotection in brain ischemia. In a mouse transient middle cerebral artery occlusion (MCAO) model, pre- and post-treatments with VO(OPT) significantly reduced infarct volume in a dose-dependent manner. Like orthovanadate, activation of the PI3K/Akt pathway mediated neuroprotective action. VO(OPT) treatment inhibited reduced Akt phosphorylation at Ser-473 following brain ischemia and restored decreased phosphorylation of forkhead box class O (FOXO) family members such as FKHR, FKHRL1, and AFX. Consistent with inhibition of FOXO dephosphorylation, VO(OPT) treatment blocked elevated expression of Fas-ligand, Bim and active caspase-3 24 h after ischemia/reperfusion. Taken together, a vanadyl compound, VO(OPT) elicits neuroprotective effects on brain ischemia/reperfusion injury without apparent side effects.
Shioda
N
N
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aramaki-Aoba Aoba-ku, Sendai 980-8578, Japan.
Ishigami
T
T
Han
F
F
Moriguchi
S
S
Shibuya
M
M
Iwabuchi
Y
Y
Fukunaga
K
K
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000187:drug effects / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D020520:Brain Infarction / Q000188:drug therapy / Q000201:enzymology / Q000503:physiopathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D053148:Caspase 3 / Q000187:drug effects / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D053222:Fas Ligand Protein / Q000187:drug effects / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000187:drug effects / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D008297:Male; D008565:Membrane Proteins / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects* / Q000378:metabolism; D014638:Vanadates / Q000494:pharmacology* / Q000627:therapeutic use
D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D053222:Fas Ligand Protein; D051858:Forkhead Transcription Factors; D008565:Membrane Proteins; D018696:Neuroprotective Agents; D011518:Proto-Oncogene Proteins; C075743:oxovanadium IV; D014638:Vanadates; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3