title: Neuroprotective efficacy of repinotan HCl, a 5-HT1A receptor agonist, in animal models of stroke and traumatic brain injury.
abstract: 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.
authors.affiliation: Global Drug Safety, Bayer Health Care, PH-R-EU-CNS, Wuppertal, Germany. frank.mauler@bayerhealthcare.com
authors.forename: Frank
authors.initials: F
authors.lastname: Mauler
authors.forename: Ervin
authors.initials: E
authors.lastname: Horváth
mesh_terms: D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D015415:Biomarkers; D001921:Brain / Q000473:pathology; D001930:Brain Injuries / Q000188:drug therapy* / Q000473:pathology; D020199:Hematoma, Subdural, Acute / Q000473:pathology; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology; D008297:Male; D018696:Neuroprotective Agents; D051381:Rats; D020318:Rats, Long-Evans; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D020521:Stroke / Q000188:drug therapy* / Q000473:pathology; D013385:Succinate Dehydrogenase / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: D001578:Benzopyrans; D015415:Biomarkers; D018696:Neuroprotective Agents; D017366:Serotonin Receptor Agonists; D013844:Thiazoles; D044282:Receptor, Serotonin, 5-HT1A; C111221:repinotan hydrochloride; D013385:Succinate Dehydrogenase