The flavonoid, 2′-methoxy-6-methylflavone, affords neuroprotection following focal cerebral ischaemia. Issue 7 (July 2019)

• Record Type: Journal Article
• Authors: Clarkson, Andrew N; Boothman-Burrell, Lily; Dósa, Zita; Nagaraja, Raghavendra Y; Jin, Liang; Parker, Kim; van Nieuwenhuijzen, Petra S; Neumann, Silke; Gowing, Emma K; Gavande, Navnath; Ahring, Philip K; Holm, Mai M; Hanrahan, Jane R; Nicolazzo, Joseph A; Jensen, Kimmo; Chebib, Mary
• Is Part Of: Journal of cerebral blood flow & metabolism. Volume 39:Issue 7(2019)
• Page Start: 1266
• Page End: 1282
• Publication Date: 2019-07
• Subjects: Photothrombotic stroke -- inflammation -- tonic inhibition -- motor behaviour -- γ-aminobutyric acid; Cerebral circulation -- Periodicals; Brain -- Metabolism -- Periodicals; Brain -- Blood-vessels -- Periodicals; Cerebrovascular disease -- Periodicals; 612.824
• DOI: 10.1177/0271678X18755628
• Languages: English
• ISSNs: 0271-678X

Abstract

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′-methoxy-6-methylflavone (0.1–10 µM; 2′MeO6MF), increases GABAA receptor tonic currents presumably via δ-containing GABAA receptors. Treatment with 2′MeO6MF 1–6 h post focal ischaemia dose dependently decreases infarct volume and improves functional recovery. The effect of 2′MeO6MF was attenuated in δ −/− mice, indicating that the effects of the flavonoid were mediated via δ-containing GABAA receptors. Further, as flavonoids have been shown to have multiple modes of action, we investigated the anti-inflammatory effects of 2′MeO6MF. Using a macrophage cell line, we show that 2′MeO6MF can dampen an LPS-induced elevation in NFkB activity. Assessment of vehicle-treated stroke animals revealed a significant increase in circulating IL1β, TNFα and IFγ levels. Treatment with 2′MeO6MF 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 δ-containing GABAA receptors soon after stroke can afford neuroprotection.