Tacrolimus, a Potential Neuroprotective Agent, Ameliorates Ischemic Brain Damage and Neurologic Deficits After Focal Cerebral Ischemia in Nonhuman Primates

• Published in: Journal of cerebral blood flow and metabolism Vol. 23; no. 10; pp. 1183 - 1194
• Main Authors: Furuichi, Yasuhisa, Maeda, Masashi, Moriguchi, Akira, Sawamoto, Taiji, Kawamura, Akio, Matsuoka, Nobuya, Mutoh, Seitaro, Yanagihara, Takehiko
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01.10.2003; Lippincott Williams & Wilkins; Sage Publications Ltd
• Subjects: Animals; Biological and medical sciences; Blood Pressure - drug effects; Brain Ischemia - drug therapy; Brain Ischemia - pathology; Brain Ischemia - physiopathology; Cerebrovascular Circulation - drug effects; Disease Models, Animal; Heart Rate - drug effects; Immunomodulators; Immunosuppressive Agents - blood; Immunosuppressive Agents - pharmacokinetics; Infarction, Middle Cerebral Artery - drug therapy; Infarction, Middle Cerebral Artery - pathology; Infarction, Middle Cerebral Artery - physiopathology; Macaca fascicularis; Male; Medical sciences; Neurologic Examination; Neurology; Neuroprotective Agents - blood; Neuroprotective Agents - pharmacokinetics; Pharmacology. Drug treatments; Recovery of Function - drug effects; Tacrolimus - blood; Tacrolimus - pharmacokinetics; Vascular diseases and vascular malformations of the nervous system; Focal cerebral ischemia; Neurologic deficits; Immunosuppressant; FK506; Long-term efficacy; Nonhuman primate; Animal model; Nervous system diseases; Treatment efficiency; Cardiovascular disease; Lactone; Neuroprotective agent; Long term; Cerebral disorder; Encephalon; Macrocycle; Vascular disease; Vertebrata; Chemotherapy; Mammalia; Immunosuppressant-FK506-Focal cerebral ischemia-Nonhuman primate-Neurologic deficits-Long-term efficacy; Ischemia; Tacrolimus; Animal; Central nervous system disease; Primates; Immunosuppressive agent; Cerebrovascular disease
• ISSN: 0271-678X; 1559-7016
• DOI: 10.1097/01.WCB.0000088761.02615.EB

Tacrolimus (FK506), an immunosuppressive drug, is known to have potent neuroprotective activity and attenuate cerebral infarction in experimental models of stroke. Here we assess the neuroprotective efficacy of tacrolimus in a nonhuman primate model of stroke, photochemically induced thrombotic occlusion of the middle cerebral artery (MCA) in cynomolgus monkeys. In the first experiment, tacrolimus (0.01, 0.032, or 0.1 mg/kg) was intravenously administered immediately after MCA occlusion, and neurologic deficits and cerebral infarction volumes were assessed 24 hours after the ischemic insult. Tacrolimus dose-dependently reduced neurologic deficits and infarction volume in the cerebral cortex, with statistically significant amelioration of neurologic deficits at 0.032 and 0.1 mg/kg and significant reduction of infarction at 0.1 mg/kg. In the second experiment, the long-term efficacy of tacrolimus on neurologic deficits and cerebral infarction was assessed. Vehicle-treated monkeys exhibited persistent and severe deficits in motor and sensory function for up to 28 days. A single intravenous bolus injection of tacrolimus (0.1 or 0.2 mg/kg) produced long-lasting amelioration of neurologic deficits and significant reduction of infarction volume. In conclusion, we have provided compelling evidence that a single dose of tacrolimus not only reduces brain infarction but also ameliorates long-term neurologic deficits in a nonhuman primate model of stroke, strengthening the view that tacrolimus might be beneficial in treating stroke patients.