Neuroprotection against Aß25-35-induced apoptosis by Salvia miltiorrhiza extract in SH-SY5Y cells.

The neurotoxicity of ß-amyloid protein (Aß) contributes significantly to the pathogenesis of Alzheimer's disease (AD), and hence the attractive therapeutic strategies focusing on the modulation of Aß-induced neurotoxicity are warranted. The present study aims to investigate the neuroprotection and underlying mechanisms by which Salvia miltiorrhiza Bunge (Lamiaceae) extract (SME) protects against Aß25-35-induced apoptosis in SH-SY5Y cells. 2h Pre-treatment of SH-SY5Y cells with SME (0.01, 0.1 or 0.2mg raw herb/ml) concentration-dependently attenuated Aß25-35-induced cell death, as evidenced by the increase in cell viability and decrease in neuronal apoptosis. In addition, SME suppressed the increased intracellular reactive oxygen species levels, decreased the protein expression of cleaved caspase-3, cytosolic cytochrome c, and Bax/Bcl-2 ratio. These findings taken together suggest that SME provides substantial neuroprotection against Aß25-35-induced neurotoxicity in SH-SY5Y cells, at least in part, via inhibiting oxidative stress and attenuating the mitochondria-dependent apoptotic pathway. The approach used in this study may also be useful for the screening of therapeutic agents for AD and other related neurodegenerative disease.

JAK-STAT pathway modulates the roles of iNOS and COX-2 in the cytoprotection of early phase of hydrogen peroxide preconditioning against apoptosis induced by oxidative stress.

Our previous studies have demonstrated that preconditioning with hydrogen peroxide (H(2)O(2)) activated the JAK-STAT pathway that played an important role in the cytoprotection, and inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) mediated the late phase of cytoprotection induced by high concentration of H(2)O(2) after preconditioning. Here we sought to identify the downstream targets of the JAK-STAT axis that mediated H(2)O(2) preconditioning and the expression of iNOS and COX-2 in the early phase of H(2)O(2) preconditioning. It was shown that (1) Preconditioning with H(2)O(2) at 100 µmol/L for 90 min in PC12 cells induced significant expression of iNOS and COX-2. (2) Pretreatment with the iNOS inhibitor AG (10 µmol/L) or the COX-2 inhibitor NS-398 (10 µmol/L) respectively 20min before H(2)O(2) preconditioning not only inhibits the increased expression of iNOS or COX-2 but also abrogates the protective effects of H(2)O(2) preconditioning against apoptosis induced by oxidative stress. (3) Pretreatment with the JAK inhibitor AG-490 (10 µmol/L) 20 min before H(2)O(2) preconditioning obviously inhibits the up-regulation of iNOS or COX-2 induced by H(2)O(2) preconditioning. These results suggested that JAK-STAT pathway modulates the roles of iNOS and COX-2 in the cytoprotection of early phase of H(2)O(2) preconditioning.