Despite success in preclinical studies, the GABAA α5 receptor antagonist S44819 does not improve outcomes in patients with ischaemic stroke, a trial recently published in The Lancet Neurology indicates. Previous research in rodent models of stroke showed that S44819 reversed tonic inhibition in the peri-infarct tissue, which resulted in improvements in motor recovery. The RESTORE BRAIN trial tested two different doses of S44819 (150 mg and 300 mg, administered twice daily) against placebo in 585 patients with ischaemic stroke, starting 3–8 days after stroke onset. Over a follow-up period of 90 days, no differences in clinical outcomes were observed between the S44819-treated patients and the placebo group. These findings raise questions about the influence of tonic inhibition on post-stroke recovery in humans versus rodents.
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Chabriat, H. et al. Safety and efficacy of GABAA α5 antagonist S44819 in patients with ischaemic stroke: a multicentre, double-blind, randomised, placebo-controlled trial. Lancet Neurol. 19, 226–233 (2020)
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Wood, H. Trial casts doubt on tonic inhibition as a target in stroke treatment. Nat Rev Neurol 16, 184 (2020). https://doi.org/10.1038/s41582-020-0338-2
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DOI: https://doi.org/10.1038/s41582-020-0338-2
