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 language | English |
|---|---|
| Pages (from-to) | 1266-1282 |
| Number of pages | 17 |
| Journal | Journal of Cerebral Blood Flow and Metabolism |
| Volume | 39 |
| Issue number | 7 |
| DOIs | |
| Publication status | Published - 29 Jan 2018 |
Keywords
- inflammation
- motor behaviour
- Photothrombotic stroke
- tonic inhibition
- γ-aminobutyric acid
Cite this
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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 journal › Article › Research › peer-review
TY - JOUR
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
UR - http://www.scopus.com/inward/record.url?scp=85045027391&partnerID=8YFLogxK
U2 - 10.1177/0271678X18755628
DO - 10.1177/0271678X18755628
M3 - Article
VL - 39
SP - 1266
EP - 1282
JO - Journal of Cerebral Blood Flow and Metabolism
JF - Journal of Cerebral Blood Flow and Metabolism
SN - 0271-678X
IS - 7
ER -