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

Abstract

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.

• Authors: N Shioda, T Ishigami, F Han, S Moriguchi, M Shibuya, Y Iwabuchi, K Fukunaga
• Journal: Neuroscience (Neuroscience) Vol. 148 Issue 1 Pg. 221-9 (Aug 10 2007) ISSN: 0306-4522 [Print] United States
• PMID: 17629407 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apoptosis Regulatory Proteins
• Bcl-2-Like Protein 11
• Bcl2l11 protein, mouse
• Fas Ligand Protein
• Forkhead Transcription Factors
• Membrane Proteins
• Neuroprotective Agents
• Proto-Oncogene Proteins
• oxovanadium IV
• Vanadates
• Phosphatidylinositol 3-Kinases
• Proto-Oncogene Proteins c-akt
• Caspase 3

Topics

• Animals
• Apoptosis Regulatory Proteins (drug effects, metabolism)
• Bcl-2-Like Protein 11
• Brain (drug effects, enzymology, physiopathology)
• Brain Infarction (drug therapy, enzymology, physiopathology)
• Brain Ischemia (drug therapy, enzymology, physiopathology)
• Caspase 3 (drug effects, metabolism)
• Cell Death (drug effects, physiology)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Enzyme Activation (drug effects, physiology)
• Fas Ligand Protein (drug effects, metabolism)
• Forkhead Transcription Factors (drug effects, metabolism)
• Gene Expression Regulation, Enzymologic (drug effects)
• Male
• Membrane Proteins (drug effects, metabolism)
• Mice
• Mice, Inbred C57BL
• Neuroprotective Agents (pharmacology, therapeutic use)
• Phosphatidylinositol 3-Kinases (drug effects, metabolism)
• Phosphorylation (drug effects)
• Proto-Oncogene Proteins (drug effects, metabolism)
• Proto-Oncogene Proteins c-akt (drug effects, metabolism)
• Vanadates (pharmacology, therapeutic use)