Molecular mechanisms and therapeutic approach for ischemic brain damages

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In this research project, we pursued clarifying mechanisms by which calcineurin and cyclophilin D, specifically expressed in mitochondria, playes an important role in delayed neuronal cell death of CA1 sector of rat forebrain ischemic model. The series of results from this model with 10 min ischemia and reperfusion showed the drastic neuroprotective effect of an immunosuppressant cyclosporin A. These results clearly demonstrated that the mechams of the neuroprotection of cyclosporin A to ischemic brain damages were due to the inhibition of both calcineurin activity and cyclophilin D specifically expressed in mitochondrial matrix. The inhibition of cyclophilin D by CsA suppressed the assembly of MPT (mitochondrial permeability transition) pores through which cell death inducers such as cytochrome c and caspases were released. MPT pores were reported to be consisted of three components ; VDAC (voltage dependent anion channel), ANT (adenine nucleotide translocase), and cyclophilin D. We d … More emonstrated that cyclophilin D directly bind to ANT and/or VDAC using affinity colomn bound to cyclophilin D.Under these information, we succeeded in development of the new anti-ischemic drug, FR901459 in collabaration with Fujisawa Pharm. CO. LTD., Japan. This new drug shows ideal characterization as an anti-ischemic drug, such as lower anti-immunosuppressive effect and a strong anti-isomerase activity. We are now developing this drug for a clinical use.Furthermore, we focused on the critical event of hypoxia or anoxia during ischemic insult, and found hypoxic inducible factor HIF, which was a transcription factor and involved in the metabolic, angiogenetic, and erythropoietic pathway, played an critical role in regulatingneuronal cell deatrh. First, we have demonstrated that mRNA of HIF3, a subtype of the HIF family, mainly expressed in CA1 of hippocumpus 24 hours after ischemia, eventhough mRNA of HIF1 was responsive but much lower expressed than that of HIF3. In culture cells, calcineurin activity was suggested to be important in the HIF1 regulation by its dephosphorylatio.These results prompt us to investigate the role of hypoxic pathway involving HIF as well as calcineurin/immunophilins. We plane to cralify the hypothesis that HIF family members would be critical factors in the pathway under calcium/calcineuin in ischemic events. Less