| Budget Amount *help |
¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 2004: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2003: ¥1,200,000 (Direct Cost: ¥1,200,000)
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| Research Abstract |
To assess the neuroprotective effect of tacrolimus (FK506) in transient forebrain ischemia models in gerbils, 10.0 mg/kg of FK506 was injected intraperitoneally immediately following reperfusion and at intervals of 1,3,6,9, and 12 h after reperfusion. FK506 produced a significant neuroprotective effect for up to 6 h after 5 min of ischemia. Immunoblot and immunohistochemistry revealed that the amount of FKBP12, the 12-kDa FK506-binding protein, in the cytosol remained unchanged until 12 h after reperfusion. Translocation of FKBP 12 from the nucleus to the cytosol was not observed until 24 h after reperfusion. Administration of FK506 did not appear to induce the cytosolic increase in FKBP 12. In this study, no correlation was apparent between the post-ischemic therapeutic efficacy of FK506 and the post-ischemic changes in the cytosolic FKBP12.
Then, we studied the effect of FK506 for the protein synthesis and eukaryonic intiation factor 2 (eIF2) known as protein synthesis initiation factor. Immunoblot revealed that the amount of phosphorylated eIF2 decreased 30 min, 1, and 3 h after reperfusion in the FK506-treated group (injected just after ischemia), in comparison with those in the simple ischemia group. The protein synthesis, which was evaluated by ^<14>C-Leucine autoradiography, showed recovery in CA1 neurons 3 h after ischemia in the FK506-treated group (injected just after ischemia), although did not in the simple ischemia group. Administration of FK506 3, and 6 h after ischemia also induced the decrease in the amount of phosphrylated eIF2. The mechanism of therapeutic efficacy of FK506 injected after ischemic insult may be de-phosphorylation of eIF2 and recovery of protein synthesis.
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