Mechanisms underlying the protective effects of myricetin and quercetin following oxygen/glucose deprivation-induced cell swelling and the reduction in glutamate uptake in glial cells

Authors: Panickar, Kiran; Anderson, Richard

Submitted to: Journal of Neuroscience
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/29/2011
Publication Date: 6/2/2011
Citation: Panickar, K.S., Anderson, R.A. 2011. Mechanisms underlying the protective effects of myricetin and quercetin following oxygen/glucose deprivation-induced cell swelling and the reduction in glutamate uptake in glial cells. Journal of Neuroscience. 183:1-14.

Interpretive Summary: This article describes the protective role of myricetin and quercetin, dietary flavonoid polyphenols, in a cell culture model of ischemia/stroke. A major feature of cerebral ischemia is the swelling of cells that are responsible for the development of brain edema. Our results suggested that swelling of glial cells, when deprived of oxygen and glucose, can be significantly prevented by these flavonoids, although the mechanisms by which they do it appear to be different. One common mechanism by which myricetin and quercetin exert such protective effects is possibly through regulating intracellular calcium. This article also describes that even though the chemical structures of myricetin and quercetin are very similar, their biological actions can be different, indicating that dietary polyphenols even from the same family (flavanoids) may have different neurobiological actions. This article should be useful for lay people as well as scientists who are interested in the role of dietary polyphenols on neural function.

Technical Abstract: C6 glial cells were exposed to oxygen-glucose deprivation (OGD) in cell culture for 5 hr and cell swelling was determined 90 min after the end of OGD. The OGD-induced increase in swelling was significantly blocked by the two flavonoids studied, quercetin and myricetin. The OGD-induced increase in free radical production, a contributing factor in cell swelling, was significantly reduced by both myricetin and quercetin. However, depolarization of the inner mitochondrial membrane potential, the blockade of which generally reduces swelling, was significantly diminished by myricetin, but not quercetin. Increased intracellular calcium ([Ca2+]i) is an important characteristic of ischemic injury and is implicated in swelling. Both flavonoids attenuated the increase in [Ca2+]i, indicating that one possible mechanism by which these flavonoids attenuate cell swelling may be through regulating [Ca2+]i. The OGD-induced decrease in glutamate uptake was also attenuated by myricetin, but not quercetin. Cyclosporin A, a blocker of the mitochondrial permeability transition (mPT) pore, but not FK506, attenuated the decline in glutamate uptake after OGD, indicating the involvement of the mPT in glutamate uptake. Our results indicate that while blockade of the inner mitochondrial membrane potential may be sufficient to reduce swelling, it may not be a necessary factor, and that flavonoids reduce cell swelling by regulating [Ca2+]i. The differential effects of myricetin and quercetin on the OGD-induced reduction on glutamate uptake may be due to their differential effects on mitochondria.