DOSE-DEPENDENT, PROTECTIVE EFFECT OF FK506 AGAINST WHITE-MATTER CHANGES IN THE RAT-BRAIN AFTER CHRONIC CEREBRAL-ISCHEMIA

Neuroprotective effects of immunosuppressive agents have been shown in cerebral ischemia. To investigate the role of immunosuppressive agent s in chronic cerebral ischemia and to design a drug protocol with safe therapeutic windows, we examined the effects of FK506, a potent immun osuppressive agent, on chronic cerebral ischemia. Both common carotid arteries were ligated in 73 male Wistar rats. Fifty-eight of these rat s received a chronic injection of FK506 (0.2, 0.5, 1.0 mg/kg) and the remaining 15 received a vehicle solution injection. Microglia/macropha ge was investigated with immunohistochemistry for leukocyte common ant igen and major histocompatibility complex, and astroglia was examined with glial fibrillary acidic protein as markers. White matter rarefact ion and the number of immunopositive glial cells were assessed from 7 to 30 days after the ligation. In the vehicle-treated animals, there w as persistent and extensive activation of the microglia/macrophages an d astroglia in the white matter, including the optic nerve, optic trac t, corpus callosum, internal capsule, anterior commissure and traversi ng fiber bundles of the caudoputamen. In the FK506-treated rats, the n umber of activated microglia/macrophages was significantly reduced in a dose-dependent manner(p < 0.01) as compared to the vehicle-treated r ats. Rarefaction of the white matter was also inhibited by FK506 in a dose-dependent manner (p < 0.01). Thus, a clinically-relevant dosage o f FK506 attenuated both glial activation and white matter changes in c hronic cerebral ischemia in the rat. These results indicate a potentia l use for FK506 in cerebrovascular diseases. (C) 1998 Elsevier Science B.V.