Neuroprotective Efficacy of Repinotan HCl, a 5-HT_1A Receptor Agonist, in Animal Models of Stroke and Traumatic Brain Injury

Abstract

Repinotan is a highly potent 5-HT 1A 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 lg/kg) or an intravenous infusion (0.3-100 lg/ kg per hour). A 73% reduction in infarct volume was observed with a 3 lg/kg intravenous bolus, and a 65% reduction was observed with a 3 and 10 lg/kg per hour intravenous infusion. When delayed until 5 hours after occlusion, repinotan (10 lg/kg per hour) reduced infarct volume by 43%. In the transient middle cerebral artery occlusion model, repinotan (10 lg/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 lg/kg per hour) reduced infarct volume by 65%. In this model, repinotan (3 lg/kg per hour) administered 5 hours after occlusion reduced infarct volume by 54%. The favorable neuroprotective efficacy, broad doseresponse curve, and prolonged therapeutic window observed in all models strongly suggest that repinotan is a promising candidate for treating acute ischemic stroke in humans.

Cardiac glycosides provide neuroprotection against ischemic stroke: Discovery by a brain slice-based compound screening platform

“…pounds have been found to be efficacious in the middle cerebral artery occlusion (MCAO) model for ischemic stroke (12)(13)(14).…”

Membrane Neovascularization and Drainage of Subdural Hematoma in a Rat Model

“…Clinical and laboratory studies have so far been largely focused on the short-term effects of SDH on such changes as regional CBF, intracranial pressure, brain water content, and sensorimotor deficiencies (R. Bullock et al, 1991;Jussen et al, 2008;Mauler and Horváth, 2005;Timaru-Kast et al, 2008). The cognitive dysfunctions and secondary performance deficiencies that accompany the increase in acute phase astrocyte reactivity have also been reported in patients and in animal models of experimental SDH (Eijkenboom et al, 2000(Eijkenboom et al, , 2004.…”

A comparison of in vivo and in vitro neuroimaging of 5-HT1A receptor binding sites in the cat brain

“…The 5-HT 1A receptor has been implicated in different pathologies (Jones and Blackburn, 2002) and is thought to play a central role in the action of antidepressants/anxiolytics such as selective serotonin reuptake inhibitors and azapirones (Blier and de Montigny, 1999;Hensler, 2003;Riad et al, 2004;www.elsevier.com/locate/jchemneu Journal of Chemical Neuroanatomy 31 (2006) 226-232 Zimmer et al, 2004). It has also recently been shown that 5-HT 1A receptor agonists possess a strong neuroprotective efficacy in brain ischemia (Mauler and Horvath, 2005).…”