Persistent therapeutic effect of a novel α5-GABAA receptor antagonist in rodent preclinical models of vascular cognitive impairment

European Journal of Pharmacology
István GacsályiFerenc A Antoni

Abstract

This study examined the potential of the selective extra-synaptic α5-GABAA receptor inhibitor S44819 (Egis-13529) to improve cognitive performance in preclinical models of vascular cognitive impairment (VCI). Chronic hypoperfusion of the brain in mice was induced by permanent occlusion of the right common carotid artery (rUCO). rUCO induced impairments of cognitive function in the object recognition test (OR) and the rewarded T-maze (RTM). In both tests, a single oral treatment with S44819 (OR - 0.1-3 mg/kg, RTM - 1-3 mg/kg p.o.) significantly reduced the effect of rUCO. Long-term treatment with S44819 (1-10 mg/kg twice daily p.o. for 14 days), that was initiated 24 h after surgery and was followed by a 10- or 13-day wash-out period, fully prevented the decline of cognitive performance of rUCO mice. In rats, occlusion of the middle cerebral artery (MCA) for 30 min caused a significantly diminished performance in the OR. This was prevented by S44819 given p.o. 15 mg/kg twice daily for 8 days, starting 7 days after surgery and tested following a 7-day wash-out period. Taken together, S44819 markedly and stably improved reference and working memory impaired by rUCO in mice. In rats, the compound effectively suppressed the developm...Continue Reading

Citations

Jan 28, 2021·Brain Communications·Colm J McGinnityAlexander Hammers
Feb 13, 2021·Seminars in Cell & Developmental Biology·Joan Jiménez-Balado, Teal S Eich

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