Advertisement

Bazedoxifene protects cerebral autoregulation after traumatic brain injury and attenuates impairments in blood–brain barrier damage: involvement of anti-inflammatory pathways by blocking MAPK signaling

  • Yu-Long Lan
  • Xun Wang
  • Yu-Jie Zou
  • Jin-Shan Xing
  • Jia-Cheng Lou
  • Shuang Zou
  • Bin-Bin Ma
  • Yan Ding
  • Bo ZhangEmail author
Original Research Paper
  • 26 Downloads

Abstract

Objective

Traumatic brain injury (TBI) is a significant cause of death and long-term deficits in motor and cognitive functions for which there are currently no effective chemotherapeutic drugs. Bazedoxifene (BZA) is a third-generation selective estrogen receptor modulator (SERM) and has been investigated as a treatment for postmenopausal osteoporosis. It is generally safe and well tolerated, with favorable endometrial and breast safety profiles. Recent findings have shown that SERMs may have therapeutic benefits; however, the role of BZA in the treatment of TBI and its molecular and cellular mechanisms remain poorly understood. The aim of the present study was to examine the neuroprotective effects of BZA on early TBI in rats and to explore the underlying mechanisms of these effects.

Materials and methods

TBI was induced using a modified weight-drop method. Neurological deficits were evaluated according to the neurological severity score (NSS). Morris water maze and open-field behavioral tests were used to test cognitive functions. Brain edema was measured by brain water content, and impairments in the blood–brain barrier (BBB) were evaluated by expression analysis of tight junction-associated proteins, such as occludin and zonula occludens-1 (ZO-1). Neuronal injury was assessed by hematoxylin and eosin (H&E) staining. LC–MS/MS analysis was performed to determine the ability of BZA to cross the BBB.

Results

Our results indicated that BZA attenuated the impaired cognitive functions and the increased BBB permeability of rats subjected to TBI through activation of inflammatory cascades. In vivo experiments further revealed that BZA provided this neuroprotection by suppressing TBI-induced activation of the MAPK/NF-κB signaling pathway. Thus, mechanically, the anti-inflammatory effects of BZA in TBI may be partially mediated by blocking the MAPK signaling pathway.

Conclusions

These findings suggest that BZA might attenuate neurological deficits and BBB damage to protect against TBI by blocking the MAPK/NF-κB signaling pathway.

Keywords

Bazedoxifene Traumatic brain injury Inflammation Neuroprotection 

Notes

Acknowledgements

This work is supported by grants from National Natural Science Foundation of China (nos. 81372714, 81672480), Liaoning Provincial Natural Science Foundation of China (no. 201602244), Distinguished Professor Project of Liaoning Province, Special Grant for Translational Medicine, Dalian Medical University (no. 2015002), Basic research projects in colleges and universities of Liaoning Province (no. LQ2017033).

Author contributions

Conceptualization, YLL; Funding acquisition, BZ; Investigation, YLL, XW, YJZ, JSX, JCL, and SZ; Methodology, YLL and XW; Writing-original draft, YLL; Writing-review and editing, YLL, XW, JCLL, JSX, SZ, BBM, YD, and BZ.

Funding

This work is supported by grants from National Natural Science Foundation of China (nos. 81372714, 81672480), Liaoning Provincial Natural Science Foundation of China (no. 201602244), Distinguished Professor Project of Liaoning Province, Special Grant for Translational Medicine, Dalian Medical University (no. 2015002), Basic research projects in colleges and universities of Liaoning Province (no. LQ2017033).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

Supplementary material

11_2019_1217_MOESM1_ESM.doc (2.1 mb)
Supplementary material 1 (DOC 2183 KB)
11_2019_1217_MOESM2_ESM.doc (640 kb)
Supplementary material 2 (DOC 639 KB)
11_2019_1217_MOESM3_ESM.doc (35 kb)
Supplementary material 3 (DOC 35 KB)
11_2019_1217_MOESM4_ESM.doc (36 kb)
Supplementary material 4 (DOC 36 KB)

References

  1. 1.
    Shlosberg D, Benifla M, Kaufer D, Friedman A. Blood–brain barrier break down as a therapeutic target in traumatic brain injury. Nat Rev Neurol. 2010;6:393–403.CrossRefGoogle Scholar
  2. 2.
    Li S, Zaninotto AL, Neville IS, Paiva WS, Nunn D, Fregni F. Clinical utility of brain stimulation modalities following traumatic brain injury: current evidence. Neuropsychiatr Dis Treat. 2015;11:1573–86.Google Scholar
  3. 3.
    Mustafa AG, Alshboul OA. Pathophysiology of traumatic brain injury. Neurosciences (Riyadh). 2013;18:222–34.Google Scholar
  4. 4.
    Moretti R, Pansiot J, Bettati D, Strazielle N, Ghersi-Egea JF, Damante G, Fleiss B, Titomanlio L, Gressens P. Blood–brain barrier dysfunction in disorders of the developing brain. Front Neurosci. 2015;9:40.CrossRefGoogle Scholar
  5. 5.
    Schwarzmaier SM, Plesnila N. Contributions of the immunesystem to the pathophysiology of traumatic brain injury-evidence by intravital microscopy. Front Cell Neurosci. 2014;8:358.CrossRefGoogle Scholar
  6. 6.
    Li H, Sun J, Wang F, Ding G, Chen W, Fang R, Yao Y, Pang M, Lu ZQ, Liu J. Sodium butyrate exerts neuroprotective effects by restoring the blood–brain barrier in traumatic brain injury mice. Brain Res. 2016;1642:70–8.CrossRefGoogle Scholar
  7. 7.
    Blixt J, Svensson M, Gunnarson E, Wanecek M. Aquaporins and blood–brain barrier permeability in early edema development after traumatic brain injury. Brain Res. 2015;1611:18–28.CrossRefGoogle Scholar
  8. 8.
    Shi H, Wang HL, Pu HJ, Shi YJ, Zhang J, Zhang WT, Wang GH, Hu XM, Leak RK, Chen J, Gao YQ. Ethyl pyruvate protects against blood–brain barrier damage and improves long-term neurological outcomes in a rat model of traumatic brain injury. CNS Neurosci Ther. 2015;21:374–84.CrossRefGoogle Scholar
  9. 9.
    Wen J, Qian S, Yang Q, Deng L, Mo Y, Yu Y. Overexpression of netrin-1 increases the expression of tight junction-associated proteins, claudin-5, occludin, and ZO-1, following traumatic brain injury in rats. Exp Ther Med. 2014;8:881–6.CrossRefGoogle Scholar
  10. 10.
    Alves JL. Blood–brain barrier and traumatic brain injury. J Neurosci Res. 2014;92:141–7.CrossRefGoogle Scholar
  11. 11.
    Alvarez JI, Dodelet-Devillers A, Kebir H, Ifergan I, Fabre PJ, Terouz S, Sabbagh M, Wosik K, Bourbonnière L, Bernard M, van Horssen J, de Vries HE, Charron F, Prat A. The Hedgehog pathway promotes blood–brain barrier integrity and CNS immune quiescence. Science. 2011;334:1727–31.CrossRefGoogle Scholar
  12. 12.
    Brown GC, Neher JJ. Inflammatory neurodegeneration and mechanisms of microglial killing of neurons. Mol Neurobiol. 2010;41:242–7.CrossRefGoogle Scholar
  13. 13.
    Ye L, Huang Y, Zhao L, Li Y, Sun L, Zhou Y, Qian G, Zheng JC. IL-1β and TNF-α induce neurotoxicity through glutamate production: a potential role for neuronal glutaminase. J Neurochem. 2013;125:897–908.CrossRefGoogle Scholar
  14. 14.
    Bolton SJ, Anthony DC, Perry VH. Loss of the tight junction proteins occludin and zonula occludens-1 from cerebral vascular endothelium during neutrophil-induced blood–brain barrier breakdown in vivo. Neuroscience. 1998;86:1245–57.CrossRefGoogle Scholar
  15. 15.
    Rosenberg GA. Matrix metalloproteinases and their multiple roles in neurodegenerative diseases. Lancet Neurol. 2009;8:205–16.CrossRefGoogle Scholar
  16. 16.
    Rahman A, Fazal F. Blocking NF-κB: an inflammatory issue. Proc Am Thorac Soc. 2011;8:497–503.CrossRefGoogle Scholar
  17. 17.
    Karin M, Yamamoto Y, Wang QM. The IKK NF-kappa B system: a treasure trove for drug development. Nat Rev Drug Discov. 2004;3:17–26.CrossRefGoogle Scholar
  18. 18.
    Nadler Y, Alexandrovich A, Grigoriadis N, Hartmann T, Rao KS, Shohami E, Stein R. Increased expression of the gamma-secretase components presenilin-1 and nicastrin in activated astrocytes and microglia following traumatic brain injury. Glia. 2008;56:552–67.CrossRefGoogle Scholar
  19. 19.
    Zhang ZY, Zhang Z, Fauser U, Schluesener HJ. Global hypomethylation defines a sub-population of reactive microglia/macrophages in experimental traumatic brain injury. Neurosci Lett. 2007;429:1–6.CrossRefGoogle Scholar
  20. 20.
    Ralay Ranaivo H, Wainwright MS. Albumin activates astrocytes and microglia through mitogen-activated protein kinase pathways. Brain Res. 2010;1313:222–31.CrossRefGoogle Scholar
  21. 21.
    Xie N, Wang C, Lin Y, Li H, Chen L, Zhang T, Sun Y, Zhang Y, Yin D, Chi Z. The role of p38 MAPK in valproic acid induced microglia apoptosis. Neurosci Lett. 2010;482:51–6.CrossRefGoogle Scholar
  22. 22.
    Chung TW, Moon SK, Chang YC, Ko JH, Lee YC, Cho G, Kim SH, Kim JG, Kim CH. Novel and therapeutic effect of caffeic acid and caffeic acid phenyl ester on hepatocarcinoma cells: complete regression of hepatoma growth and metastasis by dual mechanism. FASEB J. 2004;18:1670–81.CrossRefGoogle Scholar
  23. 23.
    Shelly W, Draper MW, Krishnan V, Wong M, Jaffe RB. Selective estrogen receptor modulators: an update on recent clinical findings. Obstet Gynecol Surv. 2008;63:163–81.Google Scholar
  24. 24.
    Gatti D, Rossini M, Sblendorio I, Lello S. Pharmacokinetic evaluation of bazedoxifene for the treatment of osteoporosis. Expert Opin Drug Metab Toxicol. 2013;9:883–92.CrossRefGoogle Scholar
  25. 25.
    Palacios S. Third generation SERMs: anything new? Maturitas. 2010;67:101–2.CrossRefGoogle Scholar
  26. 26.
    Komm BS, Kharode YP, Bodine PV, Harris HA, Miller CP, Lyttle CR. Bazedoxifene acetate: a selective estrogen receptor modulator with improved selectivity. Endocrinology. 2005;146:3999–4008.CrossRefGoogle Scholar
  27. 27.
    Komm BS, Lyttle CR. Developing a SERM: stringent preclinical selection criteria leading to an acceptable candidate (WAY-140424) for clinical evaluation. Ann N Y Acad Sci. 2001;949:317–26.CrossRefGoogle Scholar
  28. 28.
    Roof RL, Duvdevani R, Heyburn JW, Stein DG. Progesterone rapidly decreases brain edema: treatment delayed up to 24 hours is still effective. Exp Neurol. 1996;138:246–51.CrossRefGoogle Scholar
  29. 29.
    Baskin YK1, Dietrich WD, Green EJ. Two effective behavioral tasks for evaluating sensorimotor dysfunction following traumatic brain injury in mice. J Neurosci Methods. 2003;129:87–93.CrossRefGoogle Scholar
  30. 30.
    García-Rivera D, Delgado R, Bougarne N, Haegeman G, Berghe WV. Gallic acid indanone and mangiferin xanthone are strong determinants of immunosuppressive anti-tumour effects of Mangifera indica L. bark in MDA-MB231 breast cancer cells. Cancer Lett. 2011;305:21–31.CrossRefGoogle Scholar
  31. 31.
    Kim HN, Kim DH, Kim EH, Lee MH, Kundu JK, Na HK, Cha YN, Surh YJ. Sulforaphane inhibits phorbol ester-stimulated IKK-NF-κB signaling and COX-2 expression inhuman mammary epithelial cells by targeting NF-κB activating kinase and ERK. Cancer Lett. 2014;351:41–9.CrossRefGoogle Scholar
  32. 32.
    Abbott NJ. Blood–brain barrier structure and function and the challenges for CNS drug delivery. J Inherit Metab Dis. 2013;36:437–49.CrossRefGoogle Scholar
  33. 33.
    Diaz-Arrastia R, Kochanek PM, Bergold P, Kenney K, Marx CE, Grimes CJ, Loh LT, Adam LT, Oskvig D, Curley KC, Salzer W. Pharmacotherapy of traumatic brain injury: state of the science and the road forward: report of the Department of Defense Neurotrauma Pharmacology Workgroup. J Neurotrauma. 2014;31:135–58.CrossRefGoogle Scholar
  34. 34.
    Kokiko ON, Murashov AK, Hoane MR. Administration of raloxifene reduces sensorimotor and working memory deficits following traumatic brain injury. Behav Brain Res. 2006;170:233–40.CrossRefGoogle Scholar
  35. 35.
    Raghava N, Das BC, Ray SK. Neuroprotective effects of estrogen in CNS injuries: insights from animal models. Neurosci Neuroecon. 2017;6:15–29.CrossRefGoogle Scholar
  36. 36.
    Chakrabarti M, Haque A, Banik NL, Nagarkatti P, Nagarkatti M, Ray SK. Estrogen receptor agonists for attenuation of neuroinflammation and neurodegeneration. Brain Res Bull. 2014;109:22–31.CrossRefGoogle Scholar
  37. 37.
    Ray SK, Samntaray S, Banik NL. Future directions for using estrogen receptor agonists in the treatment of acute and chronic spinal cord injury. Neural Regen Res. 2016;11:1418–9.Google Scholar
  38. 38.
    Soustiel JF, Palzur E, Nevo O, Thaler I, Vlodavsky E. Neuroprotective anti-apoptosis effect of estrogens in traumatic brain injury. J Neurotrauma. 2005;22:345–52.CrossRefGoogle Scholar
  39. 39.
    Lim SW, Nyam Tt E, Hu CY, Chio CC, Wang CC, Kuo JR. Estrogen receptor-α is involved in tamoxifen neuroprotective effects in a traumatic brain injury male rat model. World Neurosurg. 2018;112:e278–87.CrossRefGoogle Scholar
  40. 40.
    Tsai YT, Wang CC, Leung PO, Lin KC, Chio CC, Hu CY, Kuo JR. Extracellular signal-regulated kinase 1/2 is involved in a tamoxifen neuroprotective effect in a lateral fluid percussion injury rat model. J Surg Res. 2014;189:106–16.CrossRefGoogle Scholar
  41. 41.
    Archer DF, Pinkerton JV, Utian WH, Menegoci JC, de Villiers TJ, Yuen CK, Levine AB, Chines AA, Constantine GD. Constantine, Bazedoxifene, a selective estrogen receptor modulator: effects on the endometrium, ovaries, and breast from a randomized controlled trial in osteoporotic postmenopausal women. Menopause. 2009;16:1109–15.CrossRefGoogle Scholar
  42. 42.
    Kanis JA, Johansson H, Oden A, McCloskey EV. Bazedoxifene reduces vertebral and clinical fractures in postmenopausal women at high risk assessed with FRAX. Bone. 2009;44:1049–54.CrossRefGoogle Scholar
  43. 43.
    Chodobski A, Zink BJ, Szmydynger-Chodobska J. Blood–brain barrier pathophysiology in traumatic brain injury. Transl Stroke Res. 2011;2:492–516.CrossRefGoogle Scholar
  44. 44.
    Higashida T, Kreipke CW, Rafols JA, Peng C, Schafer S, Schafer P, Ding JY, Dornbos D 3rd, Li X, Guthikonda M, Rossi NF, Ding Y. The role of hypoxia-inducible factor-1alpha, aquaporin-4, and matrix metalloproteinase-9 in blood–brain barrier disruption and braine dema aftertraumatic brain injury. J Neurosurg. 2011;114:92–101.CrossRefGoogle Scholar
  45. 45.
    Zhao YZ, Zhang M, Liu HF1. Wang JP1. Progesterone is neuroprotective by inhibiting cerebral edema after ischemia. Neural Regen Res. 2015;10:1076–81.CrossRefGoogle Scholar
  46. 46.
    Kim EK, Choi EJ. Pathological roles of MAPK signaling pathways in human diseases. Biochim Biophys Acta. 2010;1802:396–405.CrossRefGoogle Scholar
  47. 47.
    Chen T, Liu W, Chao X, Qu Y, Zhang L, Luo P, Xie K, Huo J, Fei Z. Neuroprotective effect of osthole against oxygen and glucose deprivation in rat cortical neurons: involvement of mitogen-activated protein kinase pathway. Neuroscience. 2011;183:203–11.CrossRefGoogle Scholar
  48. 48.
    Chen T, Cao L, Dong W, Luo P, Liu W, Qu Y, Fei Z. Protective effects of mGluR5 positive modulators against traumatic neuronal injury through PKC-dependent activation of MEK/ERK pathway. Neurochem Res. 2012;37:983–90.CrossRefGoogle Scholar
  49. 49.
    Drean A, Goldwirt L, Verreault M. Blood–brain barrier, cytotoxic chemotherapies and glioblastoma. Expert Rev Neurother. 2016;16:1285–300.CrossRefGoogle Scholar
  50. 50.
    Lin JH. CSF as a surrogate for assessing CNS exposure: an industrial perspective. Curr Drug Metab. 2008;9:46–59.CrossRefGoogle Scholar
  51. 51.
    Corrigan JD, Hammond FM. Traumatic brain injury as a chronic health condition. Arch Phys Med Rehabil. 2013;94:1199–201.CrossRefGoogle Scholar
  52. 52.
    Colantonio A. Sex. Gender, and traumatic brain injury: a commentary. Arch Phys Med Rehabil. 2016;97:1–4.CrossRefGoogle Scholar
  53. 53.
    Saverino C, Swaine B, Jaglal S, Lewko J, Vernich L, Voth J, Calzavara A, Colantonio A. Rehospitalization after traumatic brain injury: a population-based study. Arch Phys Med Rehabil. 2016;97:19–25.CrossRefGoogle Scholar
  54. 54.
    Suzuki T, Bramlett HM, Dietrich WD. The importance of gender on the beneficial effects of posttraumatic hypothermia. Exp Neurol. 2003;184:1017–26.CrossRefGoogle Scholar
  55. 55.
    Wagner AK, Kline AE, Ren D, Willard LA, Wenger MK, Zafonte RD, Dixon CE. Gender associations with chronic methylphenidate treatment and behavioral performance following experimental traumatic brain injury. Behav Brain Res. 2007;181:200–9.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of NeurosurgeryThe Second Affiliated Hospital of Dalian Medical UniversityDalianChina
  2. 2.Department of NeurosurgeryShenzhen People’s HospitalShenzhenChina
  3. 3.Department of PharmacyDalian Medical UniversityDalianChina
  4. 4.Department of PhysiologyDalian Medical UniversityDalianChina
  5. 5.Department of NursingThe First Affiliated Hospital of Dalian Medical UniversityDalianChina
  6. 6.Department of Pediatrics, Children’s Hospital of BostonHarvard Medical SchoolBostonUSA

Personalised recommendations