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FK506 Attenuates Early Ischemic Neuronal Death in a Monkey Model of Stroke

The Medical and Pharmacological Research Center Foundation, Ishikawa; Central Research Laboratory, Hamamatsu Photonics, Shizuoka; and Department of Pharmacology, Hamamatsu University School of Medicine, Hamamatsu, Japan

FK506 is an immunosuppressive agent that has been reported to have neuroprotective effects in several kinds of rodent models of stroke. The purpose of this study was to evaluate the neuroprotective effects of FK506 in a monkey model of stroke. Methods: Cynomolgus monkeys underwent 3 h of occlusion followed by 5 h of reperfusion of the right middle cerebral artery (MCA) through a transorbital approach. A single bolus dose of FK506 (0.1 mg/kg) was injected intravenously 5 or 175 min after MCA occlusion. Eight hours after ischemia, a neuropathologic study was performed and the volume of ischemic damage was determined. To measure local cerebral blood flow (CBF), the cerebral metabolic rate of oxygen (CMRO₂), and the oxygen extraction fraction during the experiments, PET scans were obtained using a steady-state ¹⁵O continuous-inhalation method. Four consecutive PET scans (before and 2 h after ischemia and immediately and 3 h after reperfusion) were obtained on each monkey. Results: Treatment with FK506 (0.1 mg/kg) 5 or 175 min after ischemia significantly reduced cortical damage 8 h after ischemia by 82% (P < 0.05) and 73% (P < 0.05), respectively. In PET studies, FK506 did not affect CBF or physiologic parameters in any treatments. In the FK506-treated group, a volume of >40% CMRO₂ reduction 3 h after reperfusion decreased significantly (P < 0.05). Conclusion: This study showed that FK506 showed a powerful neuroprotective effect in a nonhuman primate model of stroke. The therapeutic time window of FK506 was at least 3 h after onset. PET studies detected neuroprotective effects only in areas with >40% CMRO₂ reduction 3 h after reperfusion.

Key Words: transient cerebral ischemia • middle cerebral artery occlusion • primates • emission CT • experimental stroke

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