NEUROPROTECTIVE ACTIONS OF FK506 IN EXPERIMENTAL STROKE - IN-VIVO EVIDENCE AGAINST AN ANTIEXCITOTOXIC MECHANISM

The cellular mechanisms underlying the neuroprotective action of the i mmunosuppressant FK506 in experimental stroke remain uncertain, althou gh in vitro studies have implicated an antiexcitotoxic action involvin g nitric oxide and calcineurin. The present in vivo study demonstrates that intraperitoneal pretreatment with 1 and 10 mg/kg FK506, doses th at reduced the volume of ischemic cortical damage by 56-58%, did not d ecrease excitotoxic damage induced by quinolinate, NMDA, and AMPA. Sim ilarly, intravenous FK506 did not reduce the volume of striatal quinol inate lesions at a dose (1 mg/kg) that decreased ischemic cortical dam age 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 an d excitotoxic damage. Histopathological data concerning striatal quino linate lesions were replicated in neurochemical experiments. MK801, bu t not FK506, attenuated the loss of glutamate decarboxylase and cholin e acetyltransferase activity induced by intrastriatal injection of qui nolinate. The contrasting efficacy of FK506 in ischemic and excitotoxi c lesion models cannot be explained by drug pharmacokinetics, because brain FK506 content rose rapidly using both treatment protocols and wa s sustained at a neuroprotective level for 3 d. Although these data in dicate that an antiexcitotoxic mechanism is unlikely to mediate the ne uroprotective action of FK506 in focal cerebral ischemia, the finding that intravenous cyclosporin A (20 mg/kg) reduced ischemic cortical da mage is consistent with the proposed role of calcineurin.