2. Academic Validation
  3. The flavonoid, 2'-methoxy-6-methylflavone, affords neuroprotection following focal cerebral ischaemia

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

  • J Cereb Blood Flow Metab. 2019 Jul;39(7):1266-1282. doi: 10.1177/0271678X18755628.
Andrew N Clarkson 1 2,  Lily Boothman-Burrell 1,  Zita Dósa 3,  Raghavendra Y Nagaraja 1,  Liang Jin 4,  Kim Parker 1,  Petra S van Nieuwenhuijzen 2,  Silke Neumann 1 5,  Emma K Gowing 1,  Navnath Gavande 2,  Philip K Ahring 2,  Mai M Holm 3,  Jane R Hanrahan 2,  Joseph A Nicolazzo 4,  Kimmo Jensen 3,  Mary Chebib 2
Affiliations

Affiliations

  • 1 1 Department of Anatomy, Brain Health Research Centre and Brain Research New Zealand, University of Otago, Dunedin, New Zealand.
  • 2 2 Faculty of Pharmacy, The University of Sydney, Sydney, Australia.
  • 3 3 Department of Biomedicine, Aarhus University, Aarhus, Denmark.
  • 4 4 Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia.
  • 5 5 Department of Pathology, University of Otago, Dunedin, New Zealand.
PMID: 29376464 DOI: 10.1177/0271678X18755628
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.

Keywords

Photothrombotic stroke; inflammation; motor behaviour; tonic inhibition; γ-aminobutyric acid.

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