Therapeutic time window of tacrolimus (FK506) in a nonhuman primate stroke model: comparison with tissue plasminogen activator.

Abstract

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.

• Authors: Yasuhisa Furuichi, Masashi Maeda, Nobuya Matsuoka, Seitaro Mutoh, Takehiko Yanagihara
• Journal: Experimental neurology (Exp Neurol) Vol. 204 Issue 1 Pg. 138-46 (Mar 2007) ISSN: 0014-4886 [Print] United States
• PMID: 17169359 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Drug Combinations
• Fibrinolytic Agents
• Neuroprotective Agents
• Recombinant Proteins
• Tissue Plasminogen Activator
• Tacrolimus

Topics

• Animals
• Brain (pathology)
• Cerebrovascular Circulation (drug effects)
• Drug Administration Schedule
• Drug Combinations
• Fibrinolytic Agents (pharmacology)
• Injections, Intravenous
• Macaca fascicularis
• Male
• Nervous System (drug effects, physiopathology)
• Neuroprotective Agents (administration & dosage, pharmacology)
• Recombinant Proteins (administration & dosage, pharmacology)
• Stroke (pathology, physiopathology)
• Tacrolimus (administration & dosage, pharmacology)
• Tissue Plasminogen Activator (administration & dosage, pharmacology)