The selective 5-HT1a receptor agonist repinotan HCL attenuates histopathology and spatial learning deficits following traumatic brain injury in rats

The selective 5-HT1A receptor agonist Repinotan HCl (BAY x3702) has been reported to attenuate cortical damage and improve functional performance in experimental models of cerebral ischemia and acute subdural hematoma. Using a clinically relevant contusion model of traumatic brain injury, we tested the hypothesis that a 4-h continuous infusion of Repinotan HCl (10 mug/kg/h i.v.) commencing 5 min post-injury would ameliorate functional outcome and attenuate histopathology. Forty isoflurane-anesthetized male adult rats were randomly assigned to receive either a controlled cortical impact (2.7 mm tissue deformation, 4 m/s) or sham injury (Injury/Vehicle = 10, Injury/MK-801 = 10, Injury/Repinotan HCl = 10, Sham/Vehicle = 10), then tested for vestibulomotor function on post-operative days 1-5 and for spatial learning on days 14-18. Neither Repinotan HCI nor the non-competitive N-methyl-D-aspartate receptor antagonist MK-801, which served as a positive control. improved vestibulomotor function on beam balance and beam walk tasks relative to the Injury/Vehicle group, but both did significantly attenuate spatial learning and memory deficits on a water maze task. Repinotan HCI also reduced hippocampal CAI and CA,,, neuronal loss, as welt as cortical tissue damage, compared to the Injury/Vehicle group at 4 weeks post-trauma. No significant difference in histological outcome was revealed between the Repinotan HCl- and MK-801-treated groups. These findings extend the therapeutic efficacy of Repinotan HCI to a contusion model of experimental brain injury and demonstrate for the first time that 5-HT1A receptor agonists confer neuroprotection and attenuate spatial learning deficits following controlled cortical impact injury. This treatment strategy may be beneficial in a clinical context where memory impairments are common following human traumatic brain injury. (C) 2001 IBRO. Published by Elsevier Science Ltd. All rights reserved.