The flavonoid, 2'-methoxy-6-methylflavone, affords neuroprotection following focal cerebral ischaemia
| Autor: | Navnath Gavande, Silke Neumann, Kimmo Jensen, Liang Jin, Emma K. Gowing, Petra S. van Nieuwenhuijzen, Andrew N. Clarkson, Raghavendra Y. Nagaraja, Mai Marie Holm, Lily Boothman-Burrell, Jane R. Hanrahan, Philip K. Ahring, Zita Dósa, Mary Chebib, Kim Parker, Joseph A. Nicolazzo |
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| Rok vydání: | 2018 |
| Předmět: |
Male
Flavonoid Inflammation Pharmacology Inhibitory postsynaptic potential Neuroprotection Tonic (physiology) Brain Ischemia 03 medical and health sciences Mice 0302 clinical medicine medicine Animals Receptor GABA Modulators chemistry.chemical_classification Mice Knockout Mice Inbred BALB C GABAA receptor business.industry Brain Synaptic Potentials Flavones Receptors GABA-A Stroke Disease Models Animal Neuroprotective Agents Neurology chemistry Cerebral ischaemia Original Article Neurology (clinical) medicine.symptom Cardiology and Cardiovascular Medicine business 030217 neurology & neurosurgery |
| Zdroj: | J Cereb Blood Flow Metab Clarkson, A N, Boothman-Burrell, L, Dósa, Z, Nagaraja, R Y, Jin, L, Parker, K, van Nieuwenhuijzen, P S, Neumann, S, Gowing, E K, Gavande, N, Ahring, P K, Holm, M M, Hanrahan, J R, Nicolazzo, J A, Jensen, K & Chebib, M 2019, ' The flavonoid, 2′-methoxy-6-methylflavone, affords neuroprotection following focal cerebral ischaemia ', Journal of Cerebral Blood Flow and Metabolism, vol. 39, no. 7, pp. 1266-1282 . https://doi.org/10.1177/0271678X18755628 |
| ISSN: | 1559-7016 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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