Technical Abstract: Astrocyte swelling is an integral component of cytotoxic brain edema in ischemic injury. While mechanisms underlying astrocyte swelling are likely multifactorial, oxidative stress and mitochondrial dysfunction are hypothesized to contribute to such swelling. We investigated the protective effects of cinnamon polyphenol extract (CPE) that has anti-oxidant and insulin-potentiating effects on cell swelling and depolarization of the inner mitochondrial membrane potential (delta psi m) during simulated ischemic injury in vitro. C6 glial cells were subjected to oxygen-glucose deprivation (OGD) and cell volume determined using the 3-O-methyl-[3H]-glucose method at 90 min after the end of OGD. When compared with controls, OGD increased cell volume by 34%. This increase was blocked by CPE or insulin, but not by blockers of oxidative/nitrosative stress including vitamin E, resveratrol, N-nitro-L-arginine methyl ester (L-NAME), and uric acid. Mitochondrial dysfunction, a key component of ischemic injury, contributes to cell swelling. Changes in delta psi were assessed at the end of OGD with tetramethylrhodamine ethyl ester (TMRE), a potentiometric dye. OGD induced a 39% decline in delta psi and this decline was blocked by CPE, as well as insulin. To test the involvement of the mitochondrial permeability transition (mPT), we used Cyclosporin A (CsA), an immunosuppressant and a blocker of the mPT pore. CsA blocked cell swelling and the decline in delta psi. FK506, an immunosuppressant that does not block the mPT pore, did not block cell swelling or delta psi. Our results show that CPE reduces OGD-induced cell swelling, as well as the decline in delta psi in C6 glial cells, and some of its protective effects may be through inhibiting the mPT.