Mechanism of neuroprotective effect of tacrolimus (FK506) for cerebral ischemia in gerbils

他克莫司（FK506）对沙鼠脑缺血的神经保护作用机制

• 批准号: 15591531
• 负责人: KUMON Yoshiaki
• 金额: $ 1.41万
• 依托单位: Ehime University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15591531/
• 关键词: delayed neuronal death; tacrolimus : FK506; FKBP 12; CA1; Gerbil; Neuroprotection; eIF2; Protein synthesis; Neuroprotection; protein synthesis

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.

为了评估克莫司（FK506）在瞬时前脑缺血模型中的神经保护作用，在再融合后腹膜内注射10.0 mg/kg的FK506，并以1,3,6,9,9和12小时的间隔和12小时的间隔注射。缺血5分钟后，FK506产生了长达6小时的明显神经保护作用。免疫印迹和免疫组织化学表明，在再灌注后12小时之前，在细胞质中，FKBP12（12-kDa FK506结合蛋白）的量一直保持不变。直到再灌注后24小时，FKBP 12从细胞核转移到细胞质。 FK506的施用似乎并未引起FKBP 12的胞质增加。在这项研究中，FK506的缺血后治疗功效与胞质胞质后的缺血后变化之间没有明显的相关性。 因素。免疫印迹表明，与简单局部缺血组的磷酸化EIF2的磷酸化EIF2量减少了30分钟，1和3小时（在局部缺血后注射）的量减少了30分钟，1和3 h。蛋白质合成通过 ^<14> c-达氨酸放射率评估，在缺血组中3小时后CA1神经元中的恢复（在缺血组中注射后注射）在CA1神经元中恢复，尽管并未在简单的缺血组中。缺血后6小时的施用FK506 3也诱导了磷酸化EIF2的量减少。缺血性损伤后注射FK506的治疗功效的机制可能是EIF2的去磷酸化和蛋白质合成的恢复。

项目成果

Hippocampal CA1 neuron survival and cytosolic FKBP12, the 12 kDa FK506-binding protein, after ischemia and tacrolimus treatment in gerbil

沙鼠缺血和他克莫司治疗后海马 CA1 神经元存活和胞质 FKBP12（12 kDa FK506 结合蛋白）

• 发表时间: 2003
• 期刊: Neuroscience Letters 339
• 作者: Fumoto N;Nakatsuka H;Ohta S;Kumon Y;Ohnishi T
• 通讯作者: Ohnishi T

Fumoto N, Nakatsuka H, Ohta S, Kumon Y, Ohnishi T: "Hippocampal CA1 neuron survival and cytosolic FKBP12, the 12 kDa FK506-binding protein, after ischemia and tacrolimus treatment in gerbils"Neuroscience Letters. 339. 219-222 (2003)

Fumoto N、Nakatsuka H、Ohta S、Kumon Y、Ohnishi T：“沙鼠缺血和他克莫司治疗后海马 CA1 神经元存活和胞质 FKBP12（12 kDa FK506 结合蛋白）”神经科学快报。