Neuroprotective Actions of FK506 in Experimental Stroke: In Vivo Evidence against an Antiexcitotoxic Mechanism-猫眼课题宝

FK506 在实验性中风中的神经保护作用：针对抗兴奋毒性机制的体内证据

DOI：

发表时间：

1997

期刊：

Journal of Neuroscience

影响因子：

5.3

通讯作者：

中科院分区：

医学1区

文献类型：

作者：

S. Butcher;D. Henshall;Y. Teramura;K. Iwasaki;J. Sharkey

免疫抑制剂FK506在实验性中风中的神经保护作用的细胞机制仍不确定，尽管体外研究表明其具有涉及一氧化氮和钙调神经磷酸酶的抗兴奋性毒性作用。目前的体内研究表明，1和10 mg/kg FK 506腹腔内预处理（使缺血性皮质损伤体积减少56 - 58%的剂量）并未减少喹啉酸盐、NMDA和AMPA诱导的兴奋性毒性损伤。同样，在缺血性皮质损伤降低63%的剂量（1 mg/kg）下，静脉注射FK506未减少纹状体喹啉酸损伤的体积。在证明大脑中动脉闭塞后120 min（而非180 min）静脉给药有效性的研究中，定义了FK 506神经保护的时间窗。非竞争性NMDA受体拮抗剂MK 801减少缺血性和兴奋性毒性损伤。在神经化学实验中复制了有关纹状体喹啉损伤的组织学数据。MK 801，而不是FK506，减弱谷氨酸脱羧酶和胆碱乙酰转移酶活性的损失引起的纹状体注射喹啉。FK506在缺血性和兴奋性毒性损伤模型中的对比有效性不能用药物药代动力学解释，因为使用两种治疗方案时，脑FK506含量迅速升高，并维持在神经保护水平3 d。尽管这些数据表明，抗兴奋性毒性机制不太可能介导FK506在局灶性脑缺血中的神经保护作用，但静脉注射环孢素A（20 mg/kg）减少缺血性皮质损伤的发现与钙调神经磷酸酶的拟议作用一致。

The cellular mechanisms underlying the neuroprotective action of the immunosuppressant FK506 in experimental stroke remain uncertain, although in vitro studies have implicated an antiexcitotoxic action involving nitric oxide and calcineurin. The present in vivo study demonstrates that intraperitoneal pretreatment with 1 and 10 mg/kg FK506, doses that reduced the volume of ischemic cortical damage by 56–58%, did not decrease excitotoxic damage induced by quinolinate, NMDA, and AMPA. Similarly, intravenous FK506 did not reduce the volume of striatal quinolinate lesions at a dose (1 mg/kg) that decreased ischemic cortical damage by 63%. The temporal window for FK506 neuroprotection was defined in studies demonstrating efficacy using intravenous administration at 120 min, but not 180 min, after middle cerebral artery occlusion. The noncompetitive NMDA receptor antagonist MK801 reduced both ischemic and excitotoxic damage. Histopathological data concerning striatal quinolinate lesions were replicated in neurochemical experiments. MK801, but not FK506, attenuated the loss of glutamate decarboxylase and choline acetyltransferase activity induced by intrastriatal injection of quinolinate. The contrasting efficacy of FK506 in ischemic and excitotoxic lesion models cannot be explained by drug pharmacokinetics, because brain FK506 content rose rapidly using both treatment protocols and was sustained at a neuroprotective level for 3 d. Although these data indicate that an antiexcitotoxic mechanism is unlikely to mediate the neuroprotective action of FK506 in focal cerebral ischemia, the finding that intravenous cyclosporin A (20 mg/kg) reduced ischemic cortical damage is consistent with the proposed role of calcineurin.