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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

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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.

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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).

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).

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Author notes

  1. Yu-Long Lan, Xun Wang and Yu-Jie Zou contributed equally to this work.

Authors and Affiliations

  1. Department of Neurosurgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, China

    Yu-Long Lan, Xun Wang, Jin-Shan Xing, Jia-Cheng Lou, Bin-Bin Ma & Bo Zhang

  2. Department of Neurosurgery, Shenzhen People’s Hospital, Shenzhen, China

    Yu-Long Lan, Xun Wang, Jin-Shan Xing, Jia-Cheng Lou, Bin-Bin Ma & Bo Zhang

  3. Department of Pharmacy, Dalian Medical University, Dalian, 116044, China

    Yu-Long Lan

  4. Department of Physiology, Dalian Medical University, Dalian, 116044, China

    Yu-Long Lan & Shuang Zou

  5. Department of Nursing, The First Affiliated Hospital of Dalian Medical University, Dalian, 116023, China

    Yu-Jie Zou

  6. Department of Pediatrics, Children’s Hospital of Boston, Harvard Medical School, Boston, MA, 02115, USA

    Yan Ding

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  1. Yu-Long Lan
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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.

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Correspondence to Bo Zhang.

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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.

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Lan, YL., Wang, X., Zou, YJ. et al. 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. Inflamm. Res. 68, 311–323 (2019). https://doi.org/10.1007/s00011-019-01217-z

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