Abstract
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 μmol/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 μmol/L) markedly inhibited lipopolysaccharide (LPS)-induced increases in the release of TNF-α, IL-1β, 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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Acknowledgements
This work was supported by the National Natural Science Foundation of China (No 81522045 and 81473113) and the State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China (SIMM1601KF-03).
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Supplementary Chart S1 (download PDF )
Structures of rosmarinic acid (1) and its analogues. (PDF 332 kb)
Supplementary Figure S1 (download PDF )
Effect of rosmarinic acid (1) and its analogues (2-12) on SH-SY5Y cells subjected to OGD. (PDF 273 kb)
Supplementary Figure S2 (download PDF )
RABE had no effect on cell viability in SH-SY5Y cells. (PDF 273 kb)
Supplementary Figure S3 (download PDF )
Effect of RABE or LPS on cell viability in primary microglia. (PDF 264 kb)
Supplementary Figure S4 (download PDF )
RABE protected primary neurons from primary microglia-condition medium (CM) injury. (PDF 389 kb)
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Wu, L., Wang, Hm., Li, Jl. et al. Dual anti-ischemic effects of rosmarinic acid n-butyl ester via alleviation of DAPK-p53-mediated neuronal damage and microglial inflammation. Acta Pharmacol Sin 38, 459–468 (2017). https://doi.org/10.1038/aps.2016.156
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DOI: https://doi.org/10.1038/aps.2016.156
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