%0 Journal Article
%T The flavonoid, 2¡ä
%A Andrew N Clarkson
%A Emma K Gowing
%A Jane R Hanrahan
%A Joseph A Nicolazzo
%A Kim Parker
%A Kimmo Jensen
%A Liang Jin
%A Lily Boothman-Burrell
%A Mai M Holm
%A Mary Chebib
%A Navnath Gavande
%A Petra S van Nieuwenhuijzen
%A Philip K Ahring
%A Raghavendra Y Nagaraja
%A Silke Neumann
%A Zita D¨®sa
%J Journal of Cerebral Blood Flow & Metabolism
%@ 1559-7016
%D 2019
%R 10.1177/0271678X18755628
%X Tonic inhibitory currents, mediated by extrasynaptic GABAA receptors, are elevated at a delay following stroke. Flavonoids minimise the extent of cellular damage following stroke, but little is known about their mode of action. We demonstrate that the flavonoid, 2¡ä-methoxy-6-methylflavone (0.1¨C10£¿¦ÌM; 2¡äMeO6MF), increases GABAA receptor tonic currents presumably via ¦Ä-containing GABAA receptors. Treatment with 2¡äMeO6MF 1¨C6£¿h post focal ischaemia dose dependently decreases infarct volume and improves functional recovery. The effect of 2¡äMeO6MF was attenuated in ¦Ä£¿/£¿ mice, indicating that the effects of the flavonoid were mediated via ¦Ä-containing GABAA receptors. Further, as flavonoids have been shown to have multiple modes of action, we investigated the anti-inflammatory effects of 2¡äMeO6MF. Using a macrophage cell line, we show that 2¡äMeO6MF can dampen an LPS-induced elevation in NFkB activity. Assessment of vehicle-treated stroke animals revealed a significant increase in circulating IL1¦Â, TNF¦Á and IF¦Ã levels. Treatment with 2¡äMeO6MF dampened the stroke-induced increase in circulating cytokines, which was blocked in the presence of the pan-AKT inhibitor, GSK690693. These studies support the hypothesis that compounds that potentiate tonic inhibition via ¦Ä-containing GABAA receptors soon after stroke can afford neuroprotection
%K Photothrombotic stroke
%K inflammation
%K tonic inhibition
%K motor behaviour
%K ¦Ã-aminobutyric acid
%U https://journals.sagepub.com/doi/full/10.1177/0271678X18755628