Journal
ACTA PHARMACOLOGICA SINICA
Volume 38, Issue 4, Pages 459-468Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/aps.2016.156
Keywords
cerebral ischemia; rosmarinic acid n-butyl ester; SH-SY5Y neuroblastoma cells; apoptosis; death-associated protein kinase; p53; microglia; inflammation
Funding
- National Natural Science Foundation of China [81522045, 81473113]
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China [SIMM1601KF-03]
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The discovery of efficacious anti-ischemic drugs remains a challenge. Recently we have found that rosmarinic acid n-butyl ester (RABE), a derivative of rosmarinic acid, significantly protects SH-SY5Y cells against oxygen glucose deprivation (OGD)-induced cell death. In the present study we simultaneously investigated the effects of RABE on the two key players in the pathophysiology of cerebral ischemia, ischemic neuronal damage and microglial inflammation. Pretreatment with RABE (1, 10 mu mol/L) dose-dependently attenuated OGD-or H2O2-induced reduction of the viability of SH-SY5Y neuroblastoma cells. RABE pretreatment concurrently reduced the apoptotic cell rate, down-regulated the expression of the pro-apoptotic proteins Bax and p53, and up-regulated the expression of the anti-apoptotic protein phosphorylated death-associated protein kinase (DAPK). Furthermore, pretreatment with RABE (3 mu mol/L) markedly inhibited lipopolysaccharide (LPS)-induced increases in the release of TNF-alpha, IL-1 beta, NO and PGE2, and the expression levels of iNOS, and COX-2 in cultured rat microglial cells. In conclusion, these results reveal for the first time the potential anti-ischemic effects of RABE on neuronal and glial cells and elucidate the molecular mechanisms involved in its dual beneficial profiles in vitro. RABE may be a promising drug lead/candidate for the treatment of ischemic stroke.
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