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Ursolic Acid Ameliorates Early Brain Injury After Experimental Traumatic Brain Injury in Mice by Activating the Nrf2 Pathway

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Abstract

Previous studies have indicated oxidative stress and inflammatory injury as significant contributors to the secondary damage associated with traumatic brain injury (TBI). Ursolic acid (UA) has been demonstrated to exert anti-oxidative and anti-inflammatory effects on cerebral ischemia by activating the nuclear factor-erythroid 2-related factor 2 (Nrf2) pathway. However, the effects of UA on TBI remain unclear. The aim of this study is to evaluate the potential roles of UA in the activation of the Nrf2 pathway using an experimental TBI model and the underlying mechanism. Wild-type (WT) and Nrf2(−/−) mice were divided into eight groups: (1) sham; (2) TBI; (3) TBI + vehicle; (4) TBI + 50 mg/kg UA; (5) TBI + 100 mg/kg UA; (6) TBI + 150 mg/kg UA; (7) TBI + Nrf2(−/−) + vehicle; (8) TBI + Nrf2(−/−) + UA. All mice underwent the TBI with the exception of the sham group. The neurologic outcomes of the mice were evaluated at 24 h after TBI, as well as the expression of Nrf2, NQO1, HO1,SOD, GPx, and MDA. Treatment of UA significantly ameliorated brain edema and the neurological insufficiencies after TBI. In addition, UA treatment markedly strengthened the nuclear translocation of Nrf2 protein and increased the expression of NQO1 and HO1. Moreover, UA significantly increased the expression of AKT, an Nrf2 upstream factor, suggesting that UA play a neuroprotective role through the activation of the Nrf2-ARE signal pathway. On the contrary, UA showed no neuroprotective effect on the Nrf2(−/−) mice. These data indicated that UA increases the activity of antioxidant enzymes and attenuated brain injury via Nrf2 factor.

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References

  1. Maas AI, Stocchetti N, Bullock R (2008) Moderate and severe traumatic brain injury in adults. Lancet Neurol 7:728–741

    Article  PubMed  Google Scholar 

  2. Werner C, Engelhard K (2007) Pathophysiology of traumatic brain injury. Br J Anaesth 99:4–9

    Article  CAS  PubMed  Google Scholar 

  3. Cornelius C, Crupi R, Calabrese V, Graziano A, Milone P, Pennisi G, Radak Z, Calabrese EJ, Cuzzocrea S (2013) Traumatic brain injury: oxidative stress and neuroprotection. Antioxid Redox Signal 19:836–853

    Article  CAS  PubMed  Google Scholar 

  4. Kobayashi MY, Yamamoto M (2006) Nrf2-Keap1 regulation of cellular defense mechanisms against electrophiles and reactive oxygen species. Adv Enzyme Regul 46:113–140

    Article  CAS  PubMed  Google Scholar 

  5. Kandhare AD, Bodhankar SL, Mohan V, Thakurdesai PA (2015) Effect of glycosides based standardized fenugreek seed extract in bleomycin-induced pulmonary fibrosis in rats: decisive role of Bax, Nrf2, NF-kappaB, Muc5ac, TNF-alpha and IL-1beta. Chemi Biol Interact 237:151–165

    Article  CAS  Google Scholar 

  6. Wang B, Zhu X, Kim Y, Li J, Huang S, Saleem S, Li RC, Xu Y, Dore S, Cao W (2012) Histone deacetylase inhibition activates transcription factor Nrf2 and protects against cerebral ischemic damage. Free Radic Biol Med 52:928–936

    Article  CAS  PubMed  Google Scholar 

  7. de Vries HE, Witte M, Hondius D, Rozemuller AJ, Drukarch B, Hoozemans J, van Horssen J (2008) Nrf2-induced antioxidant protection: a promising target to counteract ROS-mediated damage in neurodegenerative disease? Free Radic Biol Med 45:1375–1383

    Article  PubMed  Google Scholar 

  8. Itoh K, Tong KI, Yamamoto M (2004) Molecular mechanism activating Nrf2-Keap1 pathway in regulation of adaptive response to electrophiles. Free Radic Biol Med 36:1208–1213

    Article  CAS  PubMed  Google Scholar 

  9. Zhang M, An C, Gao Y, Leak RK, Chen J, Zhang F (2013) Emerging roles of Nrf2 and phase II antioxidant enzymes in neuroprotection. Prog Neurobiol 100:30–47

    Article  CAS  PubMed  Google Scholar 

  10. Endo H, Nito C, Kamada H, Yu F, Chan PH (2006) Akt/GSK3beta survival signaling is involved in acute brain injury after subarachnoid hemorrhage in rats. Stroke 37:2140–2146

    Article  CAS  PubMed  Google Scholar 

  11. Yap TA, Garrett MD, Walton MI, Raynaud F, de Bono JS, Workman P (2008) Targeting the PI3K-AKT-mTOR pathway: progress, pitfalls, and promises. Curr Opin Pharmacol 8:393–412

    Article  CAS  PubMed  Google Scholar 

  12. Xu Y, Duan C, Kuang Z, Hao Y, Jeffries JL, Lau GW (2013) Pseudomonas aeruginosa pyocyanin activates NRF2-ARE-mediated transcriptional response via the ROS-EGFR-PI3K-AKT/MEK-ERK MAP kinase signaling in pulmonary epithelial cells. PLoS One 8:e72528

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Gong YQ, Huang W, Li KR, Liu YY, Cao GF, Cao C, Jiang Q (2016) SC79 protects retinal pigment epithelium cells from UV radiation via activating Akt-Nrf2 signaling. Oncotarget 7:60123–60132

    PubMed  Google Scholar 

  14. Lee YJ, Jeong HY, Kim YB, Lee YJ, Won SY, Shim JH, Cho MK, Nam HS, Lee SH (2012) Reactive oxygen species and PI3K/Akt signaling play key roles in the induction of Nrf2-driven heme oxygenase-1 expression in sulforaphane-treated human mesothelioma MSTO-211 H cells. Food Chem Toxicol 50:116–123

    Article  CAS  PubMed  Google Scholar 

  15. Baskaran R, Poornima P, Priya LB, Huang CY, Padma VV (2016) Neferine prevents autophagy induced by hypoxia through activation of Akt/mTOR pathway and Nrf2 in muscle cells. Biomed Pharmacother 83:1407–1413

    Article  CAS  PubMed  Google Scholar 

  16. Liu DY, Zhang YL, Wei YZ, Liu GY, Liu YF, Gao QM, Zou LP, Zeng WJ, Zhang N (2016) Activation of AKT pathway by Nrf2/PDGFA feedback loop contributes to HCC progression. Oncotarget. doi:10.18632/oncotarget.11700

    Google Scholar 

  17. Cui T, Li JZ, Kayahara H, Ma L, Wu LX, Nakamura K (2006) Quantification of the polyphenols and triterpene acids in chinese hawthorn fruit by high-performance liquid chromatography. J Agric Food Chem 54:4574–4581

    Article  CAS  PubMed  Google Scholar 

  18. Yang Y, Li C, Xiang X, Dai Z, Chang J, Zhang M, Cai H, Zhang H, Zhang M, Guo Y, Wu Z (2014) Ursolic acid prevents endoplasmic reticulum stress-mediated apoptosis induced by heat stress in mouse cardiac myocytes. J Mol Cell Cardiol 67:103–111

    Article  CAS  PubMed  Google Scholar 

  19. Wang X, Zhang F, Yang L, Mei Y, Long H, Zhang X, Zhang J, Qimuge S, Su X (2011) Ursolic acid inhibits proliferation and induces apoptosis of cancer cells in vitro and in vivo. J Biomed Biotechnol 2011:419343

    PubMed  PubMed Central  Google Scholar 

  20. Lee J, Lee HI, Seo KI, Cho HW, Kim MJ, Park EM, Lee MK (2014) Effects of ursolic acid on glucose metabolism, the polyol pathway and dyslipidemia in non-obese type 2 diabetic mice. Indian J Exp Biol 52:683–691

    PubMed  Google Scholar 

  21. Flierl MA, Stahel PF, Beauchamp KM, Morgan SJ, Smith WR, Shohami E (2009) Mouse closed head injury model induced by a weight-drop device. Nat Protoc 4:1328–1337

    Article  CAS  PubMed  Google Scholar 

  22. Li L, Zhang X, Cui L, Wang L, Liu H, Ji H, Du Y (2013) Ursolic acid promotes the neuroprotection by activating Nrf2 pathway after cerebral ischemia in mice. Brain Res 1497:32–39

    Article  CAS  PubMed  Google Scholar 

  23. Zhang T, Su J, Guo B, Zhu T, Wang K, Li X (2014) Ursolic acid alleviates early brain injury after experimental subarachnoid hemorrhage by suppressing TLR4-mediated inflammatory pathway. Int Immunopharmacol 23:585–591

    Article  PubMed  Google Scholar 

  24. Beni-Adani L, Bassan M, Gibney G, Berenneman DE, Gozes J, Shohami E (2000) Activity-dependent neurotrophic protein is neuroprotective in a mouse model of closed head injury [abstract]. J Pharmacol Exp Ther 296:57–63

  25. Wei W, Wang H, Wu Y, Ding K, Li T, Cong Z, Xu J, Zhou M, Huang L, Ding H, Wu H (2015) Alpha lipoic acid inhibits neural apoptosis via a mitochondrial pathway in rats following traumatic brain injury. Neurochem Int 87:85–91

    Article  CAS  PubMed  Google Scholar 

  26. Xu J, Wang H, Ding K, Zhang L, Wang C, Li T, Wei W, Lu X (2014) Luteolin provides neuroprotection in models of traumatic brain injury via the Nrf2-ARE pathway. Free Radic Biol Med 71:186–195

    Article  CAS  PubMed  Google Scholar 

  27. Ding K, Wang H, Xu J, Li T, Zhang L, Ding Y, Zhu L, He J, Zhou M (2014) Melatonin stimulates antioxidant enzymes and reduces oxidative stress in experimental traumatic brain injury: the Nrf2-ARE signaling pathway as a potential mechanism. Free Radic Biol Med 73:1–11

    Article  CAS  PubMed  Google Scholar 

  28. Rodriguez-Rodriguez A, Egea-Guerrero JJ, Murillo-Cabezas F, Carrillo-Vico A (2014) Oxidative stress in traumatic brain injury. Curr Med Chem 21:1201–1211

    Article  CAS  PubMed  Google Scholar 

  29. Smith JA, Park S, Krause JS, Banik NL (2013) Oxidative stress, DNA damage, and the telomeric complex as therapeutic targets in acute neurodegeneration. Neurochem Int 62:764–775

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Ansari MA, Roberts KN, Scheff SW (2008) A time course of contusion-induced oxidative stress and synaptic proteins in cortex in a rat model of TBI. J Neurotrauma 25:513–526

    Article  PubMed  Google Scholar 

  31. Hou Z, Luo W, Sun X, Hao S, Zhang Y, Xu F, Wang Z, Liu B (2012) Hydrogen-rich saline protects against oxidative damage and cognitive deficits after mild traumatic brain injury. Brain Res Bull 88:560–565

    Article  CAS  PubMed  Google Scholar 

  32. Liu W, Tan X, Shu L, Sun H, Song J, Jin P, Yu S, Sun M, Jia X (2012) Ursolic acid inhibits cigarette smoke extract-induced human bronchial epithelial cell injury and prevents development of lung cancer. Molecules 17:9104–9115

    Article  CAS  PubMed  Google Scholar 

  33. Ma JQ, Ding J, Zhang L, Liu CM (2015) Protective effects of ursolic acid in an experimental model of liver fibrosis through Nrf2/ARE pathway. Clin Res Hepatol Gastroenterol 39:188–197

    Article  CAS  PubMed  Google Scholar 

  34. Yan W, Wang HD, Feng XM, Ding YS, Jin W, Tang K (2009) The expression of NF-E2-related factor 2 in the rat brain after traumatic brain injury. J Trauma 66:1431–1435

    Article  CAS  PubMed  Google Scholar 

  35. Miller DM, Wang JA, Buchanan AK, Hall ED (2014) Temporal and spatial dynamics of nrf2-antioxidant response elements mediated gene targets in cortex and hippocampus after controlled cortical impact traumatic brain injury in mice. J Neurotrauma 31:1194–1201

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This study was grant-supported by the National Natural Science Fund of China (Grant No. 81371357).

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Authors and Affiliations

  1. Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Road, Nanjing, Jiangsu, 210002, People’s Republic of China

    Hui Ding, Handong Wang, Lin Zhu & Wuting Wei

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  1. Hui Ding
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  2. Handong Wang
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Correspondence to Handong Wang.

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Ding, H., Wang, H., Zhu, L. et al. Ursolic Acid Ameliorates Early Brain Injury After Experimental Traumatic Brain Injury in Mice by Activating the Nrf2 Pathway. Neurochem Res 42, 337–346 (2017). https://doi.org/10.1007/s11064-016-2077-8

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  • DOI: https://doi.org/10.1007/s11064-016-2077-8

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