Akt is a molecular target for signal transduction therapy in brain ischemic insult.
Growth factors including insulin-like growth factor-1 (IGF-1) promote cell survival in ischemic brain injury. Stimulation of IGF-1 receptor coupled with tyrosine kinase activates phosphatidylinositol 3-kinase and subsequently, protein kinase B (Akt) in hippocampal neurons. Here we introduce a new approach of signal transduction therapy for brain damage occurring in ischemic insult. As has been shown for IGF-1, intracerebroventricular injection of sodium orthovanadate, a protein tyrosine phosphatase inhibitor, prior to ischemic insult blocked delayed neuronal death in the CA1 region. The neuroprotective effects of orthovanadate and IGF-1 were associated with an increased Akt activity in the CA1 region. We discuss here potential targets for Akt relevant to such neuroprotective activity. Our findings lead to the conclusion that Akt activity is a potential target for neuroprotective drugs in brain ischemic insult and other episodes of excitotoxic neuronal apoptosis such as seizure and Huntington's and Parkinson's diseases.
Fukunaga
Kohji
K
Department of Pharmacology, Tohoku University Graduate School of Pharmaceutical Sciences, Sendai, Japan. fukunaga@mail.pharma.tohoku.ac.jp
Kawano
Takayuki
T
D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism*; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014638:Vanadates / Q000494:pharmacology / Q000627:therapeutic use
D011518:Proto-Oncogene Proteins; D014638:Vanadates; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt