Resveratrol reduces oxidative stress and cell death and increases mitochondrial antioxidants and XIAP in PC6.3-cells.

Resveratrol, a polyphenol derived e.g. from red grapes, has been shown to mediate several positive biological actions such as protection of cells against oxidative stress. It can also influence cell signaling, but the mechanisms behind its antioxidant properties are largely unknown. Here we show that RSV reduces oxidative stress and enhances cell survival in PC6.3 cells depending on the concentration. In these cells, RSV increased the levels of antioxidants, SOD2 and TRX2, and of X chromosome-linked inhibitor of apoptosis protein. RSV also activated NFκB signaling as shown using luciferase reporter constructs. These findings show that RSV regulates oxidative stress and mitochondrial antioxidants in neuronal cells. This may contribute to cell protection in various brain disorders

Activation of PGC-1 protect dopaminergic neurons in the MPTP mouse model of Parkinson’s disease

Peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC-1) is a transcriptional coactivator that is a master regulator of oxidative stress and mitochondrial metabolism. Mitochondrial dysfunction and oxidative stress occur in Parkinson’s disease (PD), but little is known about the molecular mechanisms controlling these events. We report that transgenic mice overexpressing PGC-1 in dopaminergic neurons are resistant against cell degeneration induced by the neurotoxin MPTP. The increase in neuronal viability was accompanied by elevated levels of mitochondrial antioxidants SOD2 and Trx2 in the substantia nigra of transgenic mice. To modulate PGC-1, we employed the small molecular compound resveratrol (RSV) that protected dopaminergic neurons against the MPTP-induced cell degeneration almost to the same extent as after PGC-1 overexpression. RSV also activated PGC-1 in dopaminergic SN4741 cells and enhanced PGC-1 gene transcription with increases in SOD2 and Trx2. Taken together the results reveal an important function of PGC-1 in dopaminergic neurons survival

Transgenic expression and activation of PGC-1\u3b1 protect dopaminergic neurons in the MPTP mouse model of Parkinson's disease

Mitochondrial dysfunction and oxidative stress occur in Parkinson\u2019s disease (PD), but little is known about the molecular mechanisms controlling these events. Peroxisome proliferator-activated receptor-gamma coactivator-1\u3b1 (PGC-1\u3b1) is a transcriptional coactivator that is a master regulator of oxidative stress and mitochondrial metabolism. We show here that transgenic mice overexpressing PGC-1\u3b1 in dopaminergic neurons are resistant against cell degeneration induced by the neurotoxin MPTP. The increase in neuronal viability was accompanied by elevated levels of mitochondrial antioxidants SOD2 and Trx2 in the substantia nigra of transgenic mice. PGC-1\u3b1 overexpression also protected against MPTP-induced striatal loss of dopamine, and mitochondria from PGC-1\u3b1 transgenic mice showed an increased respiratory control ratio compared with wild-type animals. To modulate PGC-1\u3b1, we employed the small molecular compound, resveratrol (RSV) that protected dopaminergic neurons against the MPTP-induced cell degeneration almost to the same extent as after PGC-1\u3b1 overexpression. As studied in vitro, RSV activated PGC-1\u3b1 in dopaminergic SN4741 cells via the deacetylase SIRT1, and enhanced PGC-1\u3b1 gene transcription with increases in SOD2 and Trx2. Taken together, the results reveal an important function of PGC-1\u3b1 in dopaminergic neurons to combat oxidative stress and increase neuronal viability. RSV and other compounds acting via SIRT1/PGC-1\u3b1 may prove useful as neuroprotective agents in PD and possibly in other neurological disorders