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Volume 17, Number 18, Issue of September 15, 1997 pp. 6939-6946
Copyright ©1997 Society for Neuroscience

Neuroprotective Actions of FK506 in Experimental Stroke: In Vivo Evidence against an Antiexcitotoxic Mechanism

Received March 4, 1997; revised June 25, 1997; accepted July 9, 1997.

Steven P. Butcher1, David C. Henshall2, Yoshinori Teramura3, Kazuhide Iwasaki3, and John Sharkey1

1 Fujisawa Institute of Neuroscience and 2 Department of Pharmacology, University of Edinburgh, United Kingdom EH8 9JZ, and 3 Pharmaceutical and Pharmacokinetic Research Laboratory, Fujisawa Pharmaceutical Company, Limited, Osaka, Japan

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.

Key words: FK506; tacrolimus; stroke; neuroprotection; excitotoxicity; ischemia; MK801; dizocilpine; cyclosporin A




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