Repinotan is a highly potent
5-HT1A receptor agonist with strong neuroprotective efficacy in animal models of
middle cerebral artery occlusion and
traumatic brain injury. In this study, we characterized the time window for
neuroprotective effects of
repinotan in animal models. In the permanent
middle cerebral artery occlusion model,
repinotan showed neuroprotective efficacy when administered as a triple bolus injection (0.3-100 microg/kg) or an
intravenous infusion (0.3-100 microg/kg per hour). A 73% reduction in
infarct volume was observed with a 3 microg/kg intravenous bolus, and a 65% reduction was observed with a 3 and 10 microg/kg per hour
intravenous infusion. When delayed until 5 hours after occlusion,
repinotan (10 microg/kg per hour) reduced
infarct volume by 43%. In the transient
middle cerebral artery occlusion model,
repinotan (10 microg/kg per hour) administered immediately after occlusion reduced
infarct volume by 97%, and a delay to 5 hours reduced
infarct volume by 81%. In the
acute subdural hematoma model,
repinotan (3 and 10 microg/kg per hour) reduced
infarct volume by 65%. In this model,
repinotan (3 microg/kg per hour) administered 5 hours after occlusion reduced
infarct volume by 54%. The favorable neuroprotective efficacy, broad dose-response curve, and prolonged therapeutic window observed in all models strongly suggest that
repinotan is a promising candidate for treating
acute ischemic stroke in humans.