Abstract
THE immunosuppressive action of the drug FK506 involves inhibition of calcineurin in T-lymphocytes by a complex of FK506 and an FK506 binding protein, FKBP121,2, a member of the immunophilin protein family3,4. The functional role of brain immunophitins is, however, unclear5,6. We show here that FK506 is a powerful neuroprotective agent in an in vivo model of focal cerebral ischaemia when administered up to 60 min post-occlusion. The minimum effective neuroprotective dose is comparable with the immunosup-pressant dose in humans7, suggesting that FK506 may have clinical potential for the treatment of stroke. Although the related immunosuppressants rapamycin and cyclosporin failed to reduce brain damage, the finding that rapamycin pretreatment blocked the effect of FK506 confirms a role for immunophilins in the neuroprotective mechanism.
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References
Clipstone, N. A. & Crabtree, G. R. Nature 357, 695–697 (1992).
Liu, J. et al. Biochemistry 31, 3896–3901 (1992).
Schreiber, S. L. Science 251, 283–287 (1991).
Liu, J. Trends pharmac. Sci. 14, 182–188 (1993).
Steiner, J. P. et al. Nature 358, 584–587 (1992).
Asami, M. et al. Biochem. biophy. Res. Commun. 192, 1388–1394 (1993).
Fung, J. et al. Transplantn Proc. 23, 2977–2983.
Sharkey, J., Ritchie, I. M. & Kelly, P. A. T. J. cereb. Blood Flow Metab. 13, 865–871 (1993).
Park, C. K., Nehl, D. G., Graham, D. I., Teasdale, G. I. & McCulloch, J. M. Anns Neurol. 20, 150–157 (1989).
Sharkey, J., Butcher, S. P. & Kelly, J. S. J. autonom. Trans. (in the press).
Nagasawa, H. & Kogure, K. Stroke 20, 150–157 (1989).
Dumont, F. J. et al. J. immun. 144, 1418–1424 (1990).
Bierer, B. E. et al. Proc. Natn. Acad. Sci. U.S.A. 87, 9231–9235 (1990).
Dawson, T. M. et al. Proc. natn. Acad. Sci. U.S.A. 90, 9808–9812 (1993).
Siekuierka, J. J., Hung, S. H. Y., Poe, M., Lin, C. S. & Sigal, N. M. Nature 341, 755–757 (1989).
Harding, M. W., Galat, A., Uehling, D. E. & Schreiber, S. L. Nature 341, 758–760 (1989).
Standaert, R. F., Galat, A., Verdine, G. L. & Schreiber, S. L. Nature 346, 671–674 (1990).
Liu, J. et al. Cell 66, 807–815 (1991).
Fruman, D. A., Klee, C. B., Bierer, B. G. & Burakoff, S. J. Proc. natn. Acad. Sci. U.S.A. 89, 3686–3690 (1992).
Kuno, T. et al. J. Neurochem. 58, 1643–1651 (1992).
Makai, H., Kuno, J., Chang, C-D., Lane, B., Luly, J. R. & Tanaka, C. J. Biochem. 113, 292–298 (1993).
Shiga, Y., Onodera, H., Matsuo, Y. & Kogure, K. Brain Res. 595, 145–148 (1992).
Begley, D. J. et al. J. Neurochem. 55, 1222–1230 (1990).
Armstrong, D. A. Trends Neurosci. 12, 117–122 (1989).
Choi, D. W. Trends. Neurosci. 11, 465–468 (1988).
Nishinaka, Y., Sugiyama, S., Yokota, M., Saito, H. & Ozawa, T. J. cardiovasc. Pharmac. 21, 448–454 (1993).
Dawson, V. L., Daisso, T. M., London, G. D., Bredt, D. S. & Snyder, S. H. Proc. natn. Acad. Sci. U.S.A. 88, 6368–6371 (1991).
Choi, D. W. Science 258, 241–243 (1992).
Lipton, S. A. et al. Nature 364, 626–632 (1993).
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Sharkey, J., Butcher, S. Immunophilins mediate the neuroprotective effects of FK506 in focal cerebral ischaemia. Nature 371, 336–339 (1994). https://doi.org/10.1038/371336a0
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DOI: https://doi.org/10.1038/371336a0
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