Polyphenols, present in fruits and vegetables, possess anti-oxidant, insulin-potentiating, anti-inflammatory, and anti- apoptotic properties. Oxidative stress, inflammation, and apoptosis are key characteristics of cerebral ischemia, caused by an interruption of cerebral blood flow, and polyphenols exert neuroprotective effects in ischemic injury. Brain edema is an important consequence of ischemia and oxidative stress and inflammation are implicated in its pathogenesis. Astrocyte swelling is a major component of cytotoxic brain edema and, along with vasogenic edema, may contribute to increased intracranial pressure, brain herniation, and additional ischemic injuries. We investigated the protective effects of several polyphenols in attenuating cell swelling using C6 glial cultures. Polyphenol extracts from cinnamon, green tea, as well as purified type-A polyphenols from cinnamon, myricetin, and quercetin, attenuated cell swelling following oxygen-glucose deprivation (OGD), an in vitro model of ischemic injury. To study the mechanisms underlying the protective effects of such polyphenols we examined their effects on increased ROS production, nitric oxide (NO), mitochondrial dysfunction, and intracellular calcium [Ca2+]i, key factors that contribute to cell swelling, and on the reduction in glutamate uptake. All the above-mentioned polyphenols significantly reduced the OGD-induced increase in ROS. However, cinnamon and green tea augmented the OGD-induced increase in NO and concentrations of type-A polyphenols, that did not block ROS, significantly attenuated cell swelling, indicating that polypehnols may have multiple actions in reducing cell swelling. Blockade of the mitochondrial permeability transition (mPT) pore generally blocks cell swelling. OGD-induced dissipation of the inner mitochondrial membrane potential (??m), a component of the mPT, was blocked by these polyphenols, but not by quercetin, even though quercetin blocked swelling. This indicated that the cellular mechanisms by which polyphenols reduce swelling are multi-factorial. OGD-induced [Ca2+]i was significantly attenuated by myricetin, quercetin, and a type-A polyphenol from cinnamon. Further, blockade of [Ca2+]i, using calcium channel blockers (nifedipine, nimodipine, verapamil), BAPTA-AM, a calcium chelator, and dantrolene, an inhibitor of Ca2+-release through RyR, significantly attenuated swelling indicating that one mechanism by which such polyphenols reduce swelling is through regulating [Ca2+]i, or a [Ca2+]i-mediated pathway. The type-A polyphenol component from cinnamon, as well as myricetin, but not quercetin, attenuated the decline in glutamate uptake after OGD, similar to cyclosporin A, a blocker of the mPT. These results indicate that polyphenols regulate [Ca2+]i, to exert their protective effects on cell swelling and some of the protective effects of polyphenols are mediated by mitochondria. In addition, given the differential effects of polyphenols on mitochondria, the neuroprotective effects of polyphenols may involve multiple intracellular signaling pathways that target diverse mechanisms.

Diverse cellular mechanisms underlying the neuroprotective effects of dietary polyphenols in ischemic injury in vitro

244th National Meeting (2012)

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