The selective 5-HT(1A) receptor agonist repinotan HCl attenuates histopathology and spatial learning deficits following traumatic brain injury in rats.

Abstract

The selective 5-HT(1A) 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 microg/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 HCl 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 HCl also reduced hippocampal CA(1) and CA(3) neuronal loss, as well 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 HCl to a contusion model of experimental brain injury and demonstrate for the first time that 5-HT(1A) 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.

• Authors: A E Kline, J Yu, E Horváth, D W Marion, C E Dixon
• Journal: Neuroscience (Neuroscience) Vol. 106 Issue 3 Pg. 547-55 ( 2001) ISSN: 0306-4522 [Print] United States
• PMID: 11591455 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Benzopyrans
• Excitatory Amino Acid Antagonists
• Neuroprotective Agents
• Receptors, Serotonin
• Receptors, Serotonin, 5-HT1
• Serotonin Receptor Agonists
• Thiazoles
• repinotan hydrochloride
• Dizocilpine Maleate

Topics

• Animals
• Benzopyrans (pharmacology)
• Body Temperature (drug effects, physiology)
• Brain (drug effects, pathology, physiopathology)
• Brain Injuries (drug therapy, pathology, physiopathology)
• Cognition (drug effects, physiology)
• Cognition Disorders (drug therapy, etiology, physiopathology)
• Dizocilpine Maleate (pharmacology)
• Drug Administration Schedule
• Excitatory Amino Acid Antagonists (pharmacology)
• Hippocampus (drug effects, pathology, physiopathology)
• Male
• Maze Learning (drug effects, physiology)
• Nerve Degeneration (drug therapy, pathology, physiopathology)
• Neurons (drug effects, metabolism, pathology)
• Neuroprotective Agents (pharmacology)
• Postural Balance (drug effects, physiology)
• Rats
• Rats, Sprague-Dawley
• Receptors, Serotonin (drug effects, metabolism)
• Receptors, Serotonin, 5-HT1
• Serotonin Receptor Agonists (pharmacology)
• Thiazoles (pharmacology)
• Vestibular Nuclei (drug effects, pathology, physiopathology)