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

doi:10.1177/0271678X18755628

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. Epub 2018 Jan 29.

Authors

Andrew N Clarkson^{1

2}, Lily Boothman-Burrell¹, Zita Dósa³, Raghavendra Y Nagaraja¹, Liang Jin⁴, Kim Parker¹, Petra S van Nieuwenhuijzen², Silke Neumann^{1

5}, Emma K Gowing¹, Navnath Gavande², Philip K Ahring², Mai M Holm³, Jane R Hanrahan², Joseph A Nicolazzo⁴, Kimmo Jensen³, Mary Chebib²

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.

Abstract

Tonic inhibitory currents, mediated by extrasynaptic GABA_A 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 GABA_A receptor tonic currents presumably via δ-containing GABA_A 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 GABA_A 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 GABA_A receptors soon after stroke can afford neuroprotection.

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

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Brain / metabolism
Brain Ischemia / drug therapy*
Disease Models, Animal
Flavones / administration & dosage*
Flavones / pharmacokinetics
GABA Modulators / administration & dosage*
Male
Mice
Mice, Inbred BALB C
Mice, Knockout
Neuroprotective Agents / administration & dosage*
Receptors, GABA-A / drug effects
Receptors, GABA-A / genetics
Receptors, GABA-A / physiology
Stroke / drug therapy
Synaptic Potentials / drug effects
Synaptic Potentials / physiology

Substances

2'-methoxy-6-methylflavone
Flavones
GABA Modulators
Neuroprotective Agents
Receptors, GABA-A