Differential neuroprotection by cyclosporin A and FK506 following ischemia corresponds with differing abilities to inhibit calcineurin and the mitochondrial permeability transition

被引:139
作者
Uchino, H
Minamikawa-Tachino, R
Kristián, T
Perkins, G
Narazaki, M
Siesjö, BK
Shibasaki, F
机构
[1] Tokyo Metropolitan Inst Med Sci, Dept Mol Cell Physiol, Bunkyo Ku, Tokyo 1138613, Japan
[2] Tokyo Med Univ, Hachioji Med Ctr, Dept Anesthesiol, Hachioji, Tokyo 1930998, Japan
[3] Univ Maryland, Dept Anesthesiol, Baltimore, MD 21201 USA
[4] Univ Calif San Diego, Natl Ctr Microscopy & Imaging Res, Dept Neurosci, La Jolla, CA 92093 USA
[5] Nihon Schering KK, Yodogawa Ku, Osaka 5320004, Japan
[6] Queens Med Ctr, Ctr Study Neurol Dis, Honolulu, HI 96813 USA
基金
美国国家卫生研究院;
关键词
ischemia; calcineurin; neuroprotection; cyclophilin D; mitochondria; CsA;
D O I
10.1006/nbdi.2002.0514
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Transient global or forebrain ischemia leads to severe brain damage following delayed neuronal cell death. We previously reported that cyclosporin A (CsA) provides near total suppression of brain damage in rat forebrain ischemia when allowed to pass the blood brain barrier, whereas Tacrolimus (FK506) is considerably less effective. We demonstrate herein that when administered prior to ischemic insult, both immunosuppressants equally block calcineurin, a type 2B Ser/Thr phosphatase, and efficiently inhibit dephosphorylation of pro-apoptotic protein Bad. CsA demonstrates more potent anti-ischemic effects than FK506, partially attributable to amelioration of mitochondrial damage as assayed in vivo and in vitro. These results suggest that pathways including calcineurin and cyclophilins, particularly mitochondrial cyclophilin D, play pivotal roles in ischemic brain damage. Since previous results have shown that CsA is efficacious also when administered after focal ischemia, the present findings give hints to clinical applications for new drugs for the treatment of ischemic damage in the brain as well as in the heart and liver. (C) 2002 Elsevier Science (USA).
引用
收藏
页码:219 / 233
页数:15
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