Drug development by signal transduction therapy in the ischemic brain injury.

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The apoptotic signal is believed to account for delayed neuronal death in the neurodegenerative disorders. We here proposed novel therapeutic strategies for sub-acute therapy in the ischemic injury. The novel drugs have been developing for molecular-target therapy up-regulating the survival signals during apoptosis. Vanadium and its derivatives are general protein tyrosine phosphatase inhibitors, having anti-diabetic action. Like insulin growth factor-1(IGF-1), administration of orthovanadate activated PI3-kinase/Akt and MAP kinase signaling in the brain. We have defined the potent neuroprotective effect of orthovanadate in gerbil transient forebrain ischemia, in the rat middle artery occlusion (MCAO) model and in myocardial ischemia. Consistent with our hypothesis, phosphorylation of forkhead transcription factors, Bad and glycogen synthase kinase 3β by Akt contributed to the cytoprotective action of orthovanadate.In addition, neuronal death after ischemia, trauma and numerous neurodegenerative disorders has been attributed to excessive elevation of intracellular Ca^<2+> concentration, thereby leading toxic nitric oxide (NO) production and activation of calcium-activated protease, calpains. We recently documented powerful cytoprotective actions of a novel calmodulin antagonist, DY-9760e, on brain and heart ischemia. Expectedly, DY-9760e rescued neurons and cardiomyocytes from ischemic injury through inhibition NO production and calpain/caspase activation. We also found that DY-9760e inhibited blood-brain barrier disruption and brain edema formation associated with a worse clinical outcome. Our novel strategy focused on inhibition of brain edema will provide novel therapeutic strategy for sub-acute or chronic treatments in the neurodegenerative disorders.