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
  • 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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