Skip to main content
SpringerLink
Log in

Suppressing Receptor-Interacting Protein 140: a New Sight for Salidroside to Treat Cerebral Ischemia

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. 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

    Article  PubMed  Google Scholar 

  2. 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

    PubMed  Google Scholar 

  3. Gupta YK, Briyal S, Gulati A (2010) Therapeutic potential of herbal drugs in cerebral ischemia. Indian J Physiol Pharmacol 54(2):99–122

    CAS  PubMed  Google Scholar 

  4. Carmichael ST (2005) Rodent models of focal stroke: size, mechanism, and purpose. NeuroRx 2(3):396–409. doi:10.1602/neurorx.2.3.396

    Article  PubMed  PubMed Central  Google Scholar 

  5. 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

    Article  CAS  PubMed  Google Scholar 

  6. 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

    Google Scholar 

  7. 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

    Article  PubMed  Google Scholar 

  8. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. 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

    Google Scholar 

  11. Wang J, Xiao 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

    Article  CAS  PubMed  Google Scholar 

  12. 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

    Article  CAS  PubMed  Google Scholar 

  13. 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

    Article  CAS  PubMed  Google Scholar 

  14. 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

    Google Scholar 

  15. 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

    Article  CAS  PubMed  Google Scholar 

  16. 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

    Article  Google Scholar 

  17. 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

    Article  CAS  PubMed  Google Scholar 

  18. 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

    Article  CAS  PubMed  Google Scholar 

  19. 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

    Article  CAS  PubMed  Google Scholar 

  20. 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

    Article  CAS  PubMed  Google Scholar 

  21. 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

    Article  CAS  PubMed  Google Scholar 

  22. 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

    Article  CAS  PubMed  Google Scholar 

  23. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. 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

    Article  PubMed  Google Scholar 

  25. 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

    Article  CAS  PubMed  Google Scholar 

  26. 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

    Article  CAS  PubMed  Google Scholar 

  27. 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

    Article  PubMed  Google Scholar 

  28. 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

    Article  PubMed  PubMed Central  Google Scholar 

  29. 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

    PubMed Central  Google Scholar 

  30. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. 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

    PubMed  PubMed Central  Google Scholar 

  32. 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

    Article  CAS  PubMed  Google Scholar 

  33. 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

    Article  CAS  PubMed  Google Scholar 

  34. 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

  35. Chen T, Mou Y, Tan J, Wei L, Qiao Y, Wei T, Xiang 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

    Article  CAS  PubMed  Google Scholar 

  36. 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

    Article  CAS  PubMed  Google Scholar 

  37. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. 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

    Article  PubMed  Google Scholar 

  39. 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

    Article  CAS  PubMed  Google Scholar 

Download references

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

Author notes

    Authors and Affiliations

    1. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China

      Tong Chen, Wenjiao Jiang, Tingting Wei & Tianhua Yan

    2. Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Nanjing, 210009, China

      Zhanqiang Ma, Kai Zhang & Qiang Fu

    3. Department of Physiology and Pharmacology, China Pharmaceutical University, Nanjing, 210009, China

      Lingpeng Zhu, Rui Zhou, Fen Luo, Chunhua Ma & Tianhua Yan

    Authors
    1. Tong Chen
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Zhanqiang Ma
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Lingpeng Zhu
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Wenjiao Jiang
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Tingting Wei
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Rui Zhou
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Fen Luo
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Kai Zhang
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. Qiang Fu
      View author publications

      You can also search for this author in PubMed Google Scholar

    10. Chunhua Ma
      View author publications

      You can also search for this author in PubMed Google Scholar

    11. Tianhua Yan
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding authors

    Correspondence to Chunhua Ma or Tianhua Yan.

    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

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    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

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s12035-015-9521-7

    Keywords

    Search

    Navigation