Projects per year
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 language | English |
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Pages (from-to) | 1266-1282 |
Number of pages | 17 |
Journal | Journal of Cerebral Blood Flow and Metabolism |
Volume | 39 |
Issue number | 7 |
DOIs | |
Publication status | Published - 29 Jan 2018 |
Keywords
- inflammation
- motor behaviour
- Photothrombotic stroke
- tonic inhibition
- γ-aminobutyric acid
Projects
- 1 Finished
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Delta-containing GABAA receptors as targets for neuroprotection
National Health and Medical Research Council (NHMRC) (Australia)
1/01/15 → 31/12/18
Project: Research