Activation of phosphatidylinositol 3-kinase/protein kinase B pathway by a vanadyl compound mediates its neuroprotective effect in mouse brain ischemia

N. Shioda, T. Ishigami, F. Han, S. Moriguchi, M. Shibuya, Y. Iwabuchi, K. Fukunaga

Research output: Contribution to journalArticlepeer-review

59 Citations (Scopus)

Abstract

We previously reported that orthovanadate composed of vanadate (V5+) 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 (V4+) 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.

Original languageEnglish
Pages (from-to)221-229
Number of pages9
JournalNeuroscience
Volume148
Issue number1
DOIs
Publication statusPublished - 2007 Aug 10

Keywords

  • Akt
  • FOXO
  • Fas-ligand
  • brain ischemia
  • neuronal death
  • vanadyl compound

ASJC Scopus subject areas

  • Neuroscience(all)

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