The flavonoid, 2′-methoxy-6-methylflavone, affords neuroprotection following focal cerebral ischaemia

Andrew N. Clarkson, Lily Boothman-Burrell, Zita Dósa, Raghavendra Y. Nagaraja, Liang Jin, Kim Parker, Petra S. van Nieuwenhuijzen, Silke Neumann, Emma K. Gowing, Navnath Gavande, Philip K. Ahring, Mai M. Holm, Jane R. Hanrahan, Joseph A. Nicolazzo, Kimmo Jensen, Mary Chebib

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4 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1266-1282
Number of pages17
JournalJournal of Cerebral Blood Flow and Metabolism
Volume39
Issue number7
DOIs
Publication statusPublished - 29 Jan 2018

Keywords

  • inflammation
  • motor behaviour
  • Photothrombotic stroke
  • tonic inhibition
  • γ-aminobutyric acid

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