Abstract
The purpose of the current study was to detect the effect of salidroside (Sal) on cerebral ischemia and explore its potential mechanism. Middle cerebral artery occlusion (MCAO) was performed to investigate the effects of Sal on cerebral ischemia. The rats were randomly divided into five groups: sham group, vehicle group, clopidogrel (7.5 mg/kg) group, Sal (20 mg/kg) group, and Sal (40 mg/kg) group. SH-SY5Y cells were exposed to ischemia–reperfusion (I/R) injury to verify the protective effect of Sal in vitro. We also built the stable receptor-interacting protein 140 (RIP140)-overexpressing SH-SY5Y cells. The results showed that Sal significantly reduces brain infarct size and cerebral edema. Sal could effectively decrease the levels of interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) in serum of the MCAO rats and supernatant of I/R-induced SH-SY5Y cells. Immunohistochemical and Western blot results demonstrated that Sal inhibited RIP140-mediated inflammation and apoptosis in the MCAO rats and SH-SY5Y cells. In addition, we further confirmed that RIP140/NF-κB signaling plays a crucial role by evaluating the protein expression in RIP140-overexpressing SH-SY5Y cells. Our findings suggested that Sal could be used as an effective neuroprotective agent for cerebral ischemia due to its significant effect on preventing neuronal cell injury after cerebral ischemia both in vivo and in vitro by the inhibitions of RIP140-mediated inflammation and apoptosis.
Similar content being viewed by others
References
Bramlett HM, Dietrich WD (2004) Pathophysiology of cerebral ischemia and brain trauma: similarities and differences. J Cereb Blood Flow Metab 24(2):133–150. doi:10.1097/01.wcb.0000111614.19196.04
Behravan E, Razavi BM, Hosseinzadeh H (2014) Review of plants and their constituents in the therapy of cerebral ischemia. PTR 28(9):1265–1274. doi:10.1002/ptr.5187
Gupta YK, Briyal S, Gulati A (2010) Therapeutic potential of herbal drugs in cerebral ischemia. Indian J Physiol Pharmacol 54(2):99–122
Carmichael ST (2005) Rodent models of focal stroke: size, mechanism, and purpose. NeuroRx 2(3):396–409. doi:10.1602/neurorx.2.3.396
Vieira M, Fernandes J, Carreto L, Anuncibay-Soto B, Santos M, Han J, Fernandez-Lopez A, Duarte CB et al (2014) Ischemic insults induce necroptotic cell death in hippocampal neurons through the up-regulation of endogenous RIP3. Neurobiol Dis 68:26–36. doi:10.1016/j.nbd.2014.04.002
Hua K, Sheng X, Li TT, Wang LN, Zhang YH, Huang ZJ, Ji H (2015) The edaravone and 3-n-butylphthalide ring-opening derivative 10b effectively attenuates cerebral ischemia injury in rats. Acta Pharmacol Sin. doi:10.1038/aps.2015.31
Lin Z, Zhu D, Yan Y, Yu B (2008) Herbal formula FBD extracts prevented brain injury and inflammation induced by cerebral ischemia-reperfusion. J Ethnopharmacol 118(1):140–147. doi:10.1016/j.jep.2008.03.023
Flaisher-Grinberg S, Tsai HC, Feng X, Wei LN (2014) Emotional regulatory function of receptor interacting protein 140 revealed in the ventromedial hypothalamus. Brain Behav Immun 40:226–234. doi:10.1016/j.bbi.2014.03.019
Fang DL, Chen Y, Xu B, Ren K, He ZY, He LL, Lei Y, Fan CM et al (2014) Development of lipid-shell and polymer core nanoparticles with water-soluble salidroside for anti-cancer therapy. Int J Mol Sci 15(3):3373–3388. doi:10.3390/ijms15033373
Zhu L, Wei T, Gao J, Chang X, He H, Miao M, Yan T (2015) Salidroside attenuates lipopolysaccharide (LPS) induced serum cytokines and depressive-like behavior in mice. Neurosci Lett. doi:10.1016/j.neulet.2015.08.025
Wang J, **ao L, Zhu L, Hu M, Wang Q, Yan T (2015) The effect of synthetic salidroside on cytokines and airway inflammation of asthma induced by diisocyanate (TDI) in mice by regulating GATA3/T-bet. Inflammation 38(2):697–704. doi:10.1007/s10753-014-9979-x
Gao J, He H, Jiang W, Chang X, Zhu L, Luo F, Zhou R, Ma C et al (2015) Salidroside ameliorates cognitive impairment in a d-galactose-induced rat model of Alzheimer’s disease. Behav Brain Res 293:27–33. doi:10.1016/j.bbr.2015.06.045
Chang X, Luo F, Jiang W, Zhu L, Gao J, He H, Wei T, Gong S et al (2015) Protective activity of salidroside against ethanol-induced gastric ulcer via the MAPK/NF-kappaB pathway in vivo and in vitro. Int Immunopharmacol 28(1):604–615. doi:10.1016/j.intimp.2015.07.031
He H, Chang X, Gao J, Zhu L, Miao M, Yan T (2015) Salidroside mitigates sepsis-induced myocarditis in rats by regulating IGF-1/PI3K/Akt/GSK-3beta signaling. Inflammation. doi:10.1007/s10753-015-0200-7
Zhu L, Wei T, Chang X, He H, Gao J, Wen Z, Yan T (2015) Effects of salidroside on myocardial injury in vivo in vitro via regulation of Nox/NF-kappaB/AP1 pathway. Inflammation 38(4):1589–1598. doi:10.1007/s10753-015-0134-0
Fu B, Zhang J, Zhang X, Zhang C, Li Y, Zhang Y, He T, Li P et al (2014) Alpha-lipoic acid upregulates SIRT1-dependent PGC-1alpha expression and protects mouse brain against focal ischemia. Neuroscience 281c:251–257. doi:10.1016/j.neuroscience.2014.09.058
Mdzinarishvili A, Kiewert C, Kumar V, Hillert M, Klein J (2007) Bilobalide prevents ischemia-induced edema formation in vitro and in vivo. Neuroscience 144(1):217–222. doi:10.1016/j.neuroscience.2006.08.037
Li J, Han B, Ma X, Qi S (2010) The effects of propofol on hippocampal caspase-3 and Bcl-2 expression following forebrain ischemia-reperfusion in rats. Brain Res 1356:11–23. doi:10.1016/j.brainres.2010.08.012
Lai W, Zheng Z, Zhang X, Wei Y, Chu K, Brown J, Hong G, Chen L (2015) Salidroside-mediated neuroprotection is associated with induction of early growth response genes (EGRS) across a wide therapeutic window. Neurotox Res 28(2):108–121. doi:10.1007/s12640-015-9529-9
Tao T, Zhao M, Yang W, Bo Y, Li W (2014) Neuroprotective effects of therapeutic hypercapnia on spatial memory and sensorimotor impairment via anti-apoptotic mechanisms after focal cerebral ischemia/reperfusion. Neurosci Lett 573:1–6. doi:10.1016/j.neulet.2014.04.051
Liang H, Liu P, Wang Y, Song S, Ji A (2011) Protective effects of alkaloid extract from Leonurus heterophyllus on cerebral ischemia reperfusion injury by middle cerebral ischemic injury (MCAO) in rats. Phytomedicine 18(10):811–818. doi:10.1016/j.phymed.2011.01.020
Zador Z, Bloch O, Yao X, Manley GT (2007) Aquaporins: role in cerebral edema and brain water balance. Prog Brain Res 161:185–194. doi:10.1016/s0079-6123(06)61012-1
Simard JM, Kent TA, Chen M, Tarasov KV, Gerzanich V (2007) Brain oedema in focal ischaemia: molecular pathophysiology and theoretical implications. Lancet Neurol 6(3):258–268. doi:10.1016/s1474-4422(07)70055-8
Bu Y, Lee K, Jung HS, Moon SK (2013) Therapeutic effects of traditional herbal medicine on cerebral ischemia: a perspective of vascular protection. Chin J Integr Med 19(11):804–814. doi:10.1007/s11655-013-1341-2
Dong P, Zhao J, Zhang Y, Dong J, Zhang L, Li D, Li L, Zhang X et al (2014) Aging causes exacerbated ischemic brain injury and failure of sevoflurane post-conditioning: role of B-cell lymphoma-2. Neuroscience 275:2–11. doi:10.1016/j.neuroscience.2014.05.064
Okuno S, Saito A, Hayashi T, Chan PH (2004) The c-Jun N-terminal protein kinase signaling pathway mediates Bax activation and subsequent neuronal apoptosis through interaction with Bim after transient focal cerebral ischemia. J Neurosci 24(36):7879–7887. doi:10.1523/jneurosci.1745-04.2004
Huang J, Upadhyay UM, Tamargo RJ (2006) Inflammation in stroke and focal cerebral ischemia. Surg Neurol 66(3):232–245. doi:10.1016/j.surneu.2005.12.028
Shichita T, Sakaguchi R, Suzuki M, Yoshimura A (2012) Post-ischemic inflammation in the brain. Front Immunol 3:132. doi:10.3389/fimmu.2012.00132
Wang YS, Li YX, Zhao P, Wang HB, Zhou R, Hao YJ, Wang J, Wang SJ et al (2015) Anti-inflammation effects of oxysophoridine on cerebral ischemia-reperfusion injury in mice. Inflammation. doi:10.1007/s10753-015-0211-4
Adibhatla RM, Hatcher JF (2007) Secretory phospholipase A2 IIA is up-regulated by TNF-alpha and IL-1alpha/beta after transient focal cerebral ischemia in rat. Brain Res 1134(1):199–205. doi:10.1016/j.brainres.2006.11.080
Feng Q, Wang YI, Yang Y (2015) Neuroprotective effect of interleukin-6 in a rat model of cerebral ischemia. Exp Ther Med 9(5):1695–1701. doi:10.3892/etm.2015.2363
Clemens JA, Stephenson DT, Smalstig EB, Dixon EP, Little SP (1997) Global ischemia activates nuclear factor-kappa B in forebrain neurons of rats. Stroke 28(5):1073–1080, discussion 1080–1071
Qu Y, Zhang X, Wu R (2015) Knockdown of NF-kappaB p65 subunit expression suppresses growth of nude mouse lung tumor cell xenografts by activation of Bax apoptotic pathway. Neoplasma 62(1):34–40
Chen T, Guo Q, Wang H, Zhang H, Wang C, Zhang P, Meng S, Li Y, Ji H, Yan T (2015) Effects of esculetin on lipopolysaccharide(LPS)-induced acute lung injury via regulation of RhoA/Rho kinase/NF-кB pathways in vivo and in vitro. Free Radical Res:1–21. doi:10.3109/10715762.2015.1087643
Chen T, Mou Y, Tan J, Wei L, Qiao Y, Wei T, **ang P, Peng S et al (2015) The protective effect of CDDO-Me on lipopolysaccharide-induced acute lung injury in mice. Int Immunopharmacol 25(1):55–64. doi:10.1016/j.intimp.2015.01.011
Duclot F, Lapierre M, Fritsch S, White R, Parker MG, Maurice T, Cavailles V (2012) Cognitive impairments in adult mice with constitutive inactivation of RIP140 gene expression. Genes Brain Behav 11(1):69–78. doi:10.1111/j.1601-183X.2011.00731.x
Lee CH, Chinpaisal C, Wei LN (1998) Cloning and characterization of mouse RIP140, a corepressor for nuclear orphan receptor TR2. Mol Cell Biol 18(11):6745–6755
Gardiner K (2006) Transcriptional dysregulation in Down syndrome: predictions for altered protein complex stoichiometries and post-translational modifications, and consequences for learning/behavior genes ELK, CREB, and the estrogen and glucocorticoid receptors. Behav Genet 36(3):439–453. doi:10.1007/s10519-006-9051-1
Zhang L, Chen Y, Yue Z, He Y, Zou J, Chen S, Liu M, Chen X et al (2014) The p65 subunit of NF-kappaB involves in RIP140-mediated inflammatory and metabolic dysregulation in cardiomyocytes. Arch Biochem Biophys 554:22–27. doi:10.1016/j.abb.2014.05.005
Acknowledgments
The study was supported by the Foundation for Science of Chinese Medicine, the Foundation for Science of Integrated Chinese and Western Medicine, the National Natural Science Foundation of China (81403041), the Natural Science Foundation of Jiangsu Province (BK20140961), the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), and the National Twelve Five Major Drug Discovery Project (no. 2011ZX09102-002-01).
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of Interest
The authors declare that they have no competing interests.
Additional information
Tong Chen and Zhanqiang Ma contributed equally to this work.
Rights and permissions
About this article
Cite this article
Chen, T., Ma, Z., Zhu, L. et al. Suppressing Receptor-Interacting Protein 140: a New Sight for Salidroside to Treat Cerebral Ischemia. Mol Neurobiol 53, 6240–6250 (2016). https://doi.org/10.1007/s12035-015-9521-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12035-015-9521-7