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

Research output: Contribution to journalArticleResearchpeer-review

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 languageEnglish
Pages (from-to)1266-1282
Number of pages17
JournalJournal of Cerebral Blood Flow and Metabolism
Volume39
Issue number7
DOIs
Publication statusPublished - 29 Jan 2018

Keywords

  • inflammation
  • motor behaviour
  • Photothrombotic stroke
  • tonic inhibition
  • γ-aminobutyric acid

Cite this

Clarkson, Andrew N. ; Boothman-Burrell, Lily ; Dósa, Zita ; Nagaraja, Raghavendra Y. ; Jin, Liang ; Parker, Kim ; van Nieuwenhuijzen, Petra S. ; Neumann, Silke ; Gowing, Emma K. ; Gavande, Navnath ; Ahring, Philip K. ; Holm, Mai M. ; Hanrahan, Jane R. ; Nicolazzo, Joseph A. ; Jensen, Kimmo ; Chebib, Mary. / The flavonoid, 2′-methoxy-6-methylflavone, affords neuroprotection following focal cerebral ischaemia. In: Journal of Cerebral Blood Flow and Metabolism. 2018 ; Vol. 39, No. 7. pp. 1266-1282.
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title = "The flavonoid, 2′-methoxy-6-methylflavone, affords neuroprotection following focal cerebral ischaemia",
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 = "inflammation, motor behaviour, Photothrombotic stroke, tonic inhibition, γ-aminobutyric acid",
author = "Clarkson, {Andrew N.} and Lily Boothman-Burrell and Zita D{\'o}sa and Nagaraja, {Raghavendra Y.} and Liang Jin and Kim Parker and {van Nieuwenhuijzen}, {Petra S.} and Silke Neumann and Gowing, {Emma K.} and Navnath Gavande and Ahring, {Philip K.} and Holm, {Mai M.} and Hanrahan, {Jane R.} and Nicolazzo, {Joseph A.} and Kimmo Jensen and Mary Chebib",
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Clarkson, AN, Boothman-Burrell, L, Dósa, Z, Nagaraja, RY, Jin, L, Parker, K, van Nieuwenhuijzen, PS, Neumann, S, Gowing, EK, Gavande, N, Ahring, PK, Holm, MM, Hanrahan, JR, Nicolazzo, JA, Jensen, K & Chebib, M 2018, '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

The flavonoid, 2′-methoxy-6-methylflavone, affords neuroprotection following focal cerebral ischaemia. / Clarkson, Andrew N.; Boothman-Burrell, Lily; Dósa, Zita; Nagaraja, Raghavendra Y.; Jin, Liang; Parker, Kim; van Nieuwenhuijzen, Petra S.; Neumann, Silke; Gowing, Emma K.; Gavande, Navnath; Ahring, Philip K.; Holm, Mai M.; Hanrahan, Jane R.; Nicolazzo, Joseph A.; Jensen, Kimmo; Chebib, Mary.

In: Journal of Cerebral Blood Flow and Metabolism, Vol. 39, No. 7, 29.01.2018, p. 1266-1282.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - The flavonoid, 2′-methoxy-6-methylflavone, affords neuroprotection following focal cerebral ischaemia

AU - Clarkson, Andrew N.

AU - Boothman-Burrell, Lily

AU - Dósa, Zita

AU - Nagaraja, Raghavendra Y.

AU - Jin, Liang

AU - Parker, Kim

AU - van Nieuwenhuijzen, Petra S.

AU - Neumann, Silke

AU - Gowing, Emma K.

AU - Gavande, Navnath

AU - Ahring, Philip K.

AU - Holm, Mai M.

AU - Hanrahan, Jane R.

AU - Nicolazzo, Joseph A.

AU - Jensen, Kimmo

AU - Chebib, Mary

PY - 2018/1/29

Y1 - 2018/1/29

N2 - 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.

AB - 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.

KW - inflammation

KW - motor behaviour

KW - Photothrombotic stroke

KW - tonic inhibition

KW - γ-aminobutyric acid

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DO - 10.1177/0271678X18755628

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