Therapeutic time window of tacrolimus (FK506) in a nonhuman primate stroke model: comparison with tissue plasminogen activator.
Tacrolimus (FK506), an immunosuppressive drug, has been shown to exert a potent neuroprotective activity when administered immediately after occlusion of the middle cerebral artery (MCA) in a nonhuman primate model of stroke. Here, we assessed the neuroprotective efficacy of tacrolimus with delayed treatment using the same model and compared with that of recombinant tissue plasminogen activator (rt-PA). Ischemic insult was induced by photochemically induced thrombotic occlusion of MCA in cynomolgus monkeys, and tacrolimus (0.2 mg/kg) and/or rt-PA (1.0 mg/kg) was intravenously administered 2 h after MCA occlusion. In another experiment, tacrolimus (0.1 mg/kg) was administered 4 h after MCA occlusion. Neurological deficits were monitored for 28 days after the ischemic insult and cerebral infarct volumes were measured with brain slices. With drug administration 2 h after the ischemic insult, tacrolimus significantly reduced neurological deficits and infarct volumes in the cerebral cortex without affecting the recanalization pattern in the MCA, however, rt-PA did not significantly improve neurological deficits or infarct volumes, even though it increased the recanalization rate of the occluded MCA. Combined treatment with tacrolimus and rt-PA exerted additional protection. Administration of tacrolimus 4 h after the ischemic insult still showed significant amelioration of neurological deficits. These results suggested that tacrolimus had a wider therapeutic time window than rt-PA in the nonhuman primate stroke model.
Furuichi
Yasuhisa
Y
Pharmacology Research Labs, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki, Japan. yasuhisa.furuichi@jp.astellas.com
Maeda
Masashi
M
Matsuoka
Nobuya
N
Mutoh
Seitaro
S
Yanagihara
Takehiko
T
D000818:Animals; D001921:Brain / Q000473:pathology; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004334:Drug Administration Schedule; D004338:Drug Combinations; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D007275:Injections, Intravenous; D008252:Macaca fascicularis; D008297:Male; D009420:Nervous System / Q000187:drug effects / Q000503:physiopathology; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D020521:Stroke / Q000473:pathology* / Q000503:physiopathology*; D016559:Tacrolimus / Q000008:administration & dosage / Q000494:pharmacology*; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000494:pharmacology*
D004338:Drug Combinations; D005343:Fibrinolytic Agents; D018696:Neuroprotective Agents; D011994:Recombinant Proteins; D010959:Tissue Plasminogen Activator; D016559:Tacrolimus