Butcher S P, Henshall D C, Teramura Y, Iwasaki K, Sharkey J
Fujisawa Institute of Neuroscience, University of Edinburgh, United Kingdom EH8 9JZ.
J Neurosci. 1997 Sep 15;17(18):6939-46. doi: 10.1523/JNEUROSCI.17-18-06939.1997.
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.
免疫抑制剂FK506在实验性中风中发挥神经保护作用的细胞机制仍不明确，尽管体外研究表明其抗兴奋毒性作用涉及一氧化氮和钙调神经磷酸酶。目前的体内研究表明，腹腔注射1和10mg/kg FK506进行预处理，这两个剂量可使缺血性皮质损伤体积减少56 - 58%，但并未减少喹啉酸、N-甲基-D-天冬氨酸（NMDA）和α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）诱导的兴奋毒性损伤。同样，静脉注射FK506在剂量为1mg/kg时，虽可使缺血性皮质损伤减少63%，但并未减少纹状体喹啉酸损伤的体积。在大脑中动脉闭塞后120分钟而非180分钟静脉给药的研究中确定了FK506神经保护的时间窗。非竞争性NMDA受体拮抗剂MK801可减少缺血性和兴奋毒性损伤。关于纹状体喹啉酸损伤的组织病理学数据在神经化学实验中得到了重复。MK801而非FK506可减轻纹状体内注射喹啉酸诱导的谷氨酸脱羧酶和胆碱乙酰转移酶活性的丧失。FK506在缺血性和兴奋毒性损伤模型中的不同疗效无法用药物药代动力学来解释，因为使用两种治疗方案时脑内FK506含量均迅速升高，并在神经保护水平维持3天。尽管这些数据表明抗兴奋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（20mg/kg）可减少缺血性皮质损伤这一发现与钙调神经磷酸酶的假定作用一致。
