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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 – 0.1–3mg/kg, RTM – 1–3mg/kg p.o.) significantly reduced the effect of rUCO. Long-term treatment with S44819 (1–10mg/kg twice daily p.o. for 14 days), that was initiated 24h 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 30min caused a significantly diminished performance in the OR. This was prevented by S44819 given p.o. 15mg/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 development of cognitive impairment after mild stroke. In conclusion, as longer-term administration led to a persistent reversal of the cognitive deficits, it appears that S44819 may have symptomatic, as well as disease-modifying effects in models of VCI. Proof of concept is therefore provided for testing S44819 in the therapy of VCI and post-stroke dementia in humans.