Differential Neuroprotection by Cyclosporin A and FK506 Following Ischemia Corresponds with Differing Abilities to Inhibit Calcineurin and the Mitochondrial Permeability Transition

Hiroyuki Uchino; Reiko Minamikawa-Tachino; Tibor Kristián; Guy Perkins; Michiko Narazaki; Bo K. Siesjö; Futoshi Shibasaki

Neurobiology of Disease (Aug 2002)

Differential Neuroprotection by Cyclosporin A and FK506 Following Ischemia Corresponds with Differing Abilities to Inhibit Calcineurin and the Mitochondrial Permeability Transition

Hiroyuki Uchino,
Reiko Minamikawa-Tachino,
Tibor Kristián,
Guy Perkins,
Michiko Narazaki,
Bo K. Siesjö,
Futoshi Shibasaki

Affiliations

Hiroyuki Uchino: Department of Molecular Cell Physiology, Tokyo Metropolitan Institute of Medical Science, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo, 113-8613, Japan; Department of Anesthesiology, Tokyo Medical University Hachioji Medical Center, 1163, Tatemachi, Hachioji, 193-0998, Japan; Department of Anesthesiology, University of Maryland, 685 W Baltimore St, MSTF 5-34, Baltimore, Maryland, 21201; National Center for Microscopy and Imaging Research, Department of Neurosciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California, 92093-0608; Nihon Schering K.K. 2-6-64 Nishimiyahara, Yodogawa-ku, Osaka, 532-0004, Japan; Center for the Study of Neurological Disease, The Queen's Medical Center, 1356 Lusitana Street, Honolulu, Hawaii, 96813
Reiko Minamikawa-Tachino: Department of Molecular Cell Physiology, Tokyo Metropolitan Institute of Medical Science, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo, 113-8613, Japan; Department of Anesthesiology, Tokyo Medical University Hachioji Medical Center, 1163, Tatemachi, Hachioji, 193-0998, Japan; Department of Anesthesiology, University of Maryland, 685 W Baltimore St, MSTF 5-34, Baltimore, Maryland, 21201; National Center for Microscopy and Imaging Research, Department of Neurosciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California, 92093-0608; Nihon Schering K.K. 2-6-64 Nishimiyahara, Yodogawa-ku, Osaka, 532-0004, Japan; Center for the Study of Neurological Disease, The Queen's Medical Center, 1356 Lusitana Street, Honolulu, Hawaii, 96813
Tibor Kristián: Department of Molecular Cell Physiology, Tokyo Metropolitan Institute of Medical Science, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo, 113-8613, Japan; Department of Anesthesiology, Tokyo Medical University Hachioji Medical Center, 1163, Tatemachi, Hachioji, 193-0998, Japan; Department of Anesthesiology, University of Maryland, 685 W Baltimore St, MSTF 5-34, Baltimore, Maryland, 21201; National Center for Microscopy and Imaging Research, Department of Neurosciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California, 92093-0608; Nihon Schering K.K. 2-6-64 Nishimiyahara, Yodogawa-ku, Osaka, 532-0004, Japan; Center for the Study of Neurological Disease, The Queen's Medical Center, 1356 Lusitana Street, Honolulu, Hawaii, 96813
Guy Perkins: Department of Molecular Cell Physiology, Tokyo Metropolitan Institute of Medical Science, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo, 113-8613, Japan; Department of Anesthesiology, Tokyo Medical University Hachioji Medical Center, 1163, Tatemachi, Hachioji, 193-0998, Japan; Department of Anesthesiology, University of Maryland, 685 W Baltimore St, MSTF 5-34, Baltimore, Maryland, 21201; National Center for Microscopy and Imaging Research, Department of Neurosciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California, 92093-0608; Nihon Schering K.K. 2-6-64 Nishimiyahara, Yodogawa-ku, Osaka, 532-0004, Japan; Center for the Study of Neurological Disease, The Queen's Medical Center, 1356 Lusitana Street, Honolulu, Hawaii, 96813
Michiko Narazaki: Department of Molecular Cell Physiology, Tokyo Metropolitan Institute of Medical Science, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo, 113-8613, Japan; Department of Anesthesiology, Tokyo Medical University Hachioji Medical Center, 1163, Tatemachi, Hachioji, 193-0998, Japan; Department of Anesthesiology, University of Maryland, 685 W Baltimore St, MSTF 5-34, Baltimore, Maryland, 21201; National Center for Microscopy and Imaging Research, Department of Neurosciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California, 92093-0608; Nihon Schering K.K. 2-6-64 Nishimiyahara, Yodogawa-ku, Osaka, 532-0004, Japan; Center for the Study of Neurological Disease, The Queen's Medical Center, 1356 Lusitana Street, Honolulu, Hawaii, 96813
Bo K. Siesjö: Department of Molecular Cell Physiology, Tokyo Metropolitan Institute of Medical Science, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo, 113-8613, Japan; Department of Anesthesiology, Tokyo Medical University Hachioji Medical Center, 1163, Tatemachi, Hachioji, 193-0998, Japan; Department of Anesthesiology, University of Maryland, 685 W Baltimore St, MSTF 5-34, Baltimore, Maryland, 21201; National Center for Microscopy and Imaging Research, Department of Neurosciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California, 92093-0608; Nihon Schering K.K. 2-6-64 Nishimiyahara, Yodogawa-ku, Osaka, 532-0004, Japan; Center for the Study of Neurological Disease, The Queen's Medical Center, 1356 Lusitana Street, Honolulu, Hawaii, 96813
Futoshi Shibasaki: Department of Molecular Cell Physiology, Tokyo Metropolitan Institute of Medical Science, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo, 113-8613, Japan; Department of Anesthesiology, Tokyo Medical University Hachioji Medical Center, 1163, Tatemachi, Hachioji, 193-0998, Japan; Department of Anesthesiology, University of Maryland, 685 W Baltimore St, MSTF 5-34, Baltimore, Maryland, 21201; National Center for Microscopy and Imaging Research, Department of Neurosciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California, 92093-0608; Nihon Schering K.K. 2-6-64 Nishimiyahara, Yodogawa-ku, Osaka, 532-0004, Japan; Center for the Study of Neurological Disease, The Queen's Medical Center, 1356 Lusitana Street, Honolulu, Hawaii, 96813

Journal volume & issue: Vol. 10, no. 3
pp. 219 – 233

Abstract

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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.

Published in Neurobiology of Disease

ISSN: 0969-9961 (Print); 1095-953X (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry
Website: https://www.journals.elsevier.com/neurobiology-of-disease

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