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Neuroprotective Effects of Resatorvid Against Traumatic Brain Injury in Rat: Involvement of Neuronal Autophagy and TLR4 Signaling Pathway

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Abstract

Accumulating evidence indicates that autophagy and inflammatory responses contributes to secondary brain injury after traumatic brain injury (TBI), and toll-like receptor 4 (TLR4) is considered to involvement of this cascade and plays an important role. The present study was designed to determine the hypothesis that administration of resatorvid (TAK-242), a TLR4 antagonist, might provide a neuroprotective effect by inhibit TLR4-mediated pathway in a TBI rat model. Rat subjected to controlled cortical impact injury were injected with TAK-242 (0.5 mg/kg, i.v. injected) 10 min prior to injury. The results demonstrated that TAK-242 treatment significantly attenuated TBI-induced neurons loss, brain edema, and neurobehavioral impairment in rats. Immunoblotting analysis showed that TAK-242 treatment reduced TBI-induced TLR4, Beclin 1, and LC3-II levels, and maintained p62 levels at 24 h. Double immunolabeling demonstrated that LC3 dots co-localized with the hippocampus pyramidal neurons, and TLR4 was localized with the hippocampus neurons and astrocytes. In addition, the expression of TLR4 downstream signaling molecules, including MyD88, TRIF, NF-κB, TNF-α, and IL-1β, was significantly downregulated in hippocampus tissue by Western blot analysis. In conclusion, our findings indicate that pre-injury treatment with TAK-242 could inhibit neuronal autophagy and neuroinflammation responses in the hippocampus in a rat model of TBI. The neuroprotective effects of TAK-242 may be related to modulation of the TLR4-MyD88/TRIF-NF-κB signaling pathway. Furthermore, the study also suggests that TAK-242, an attractive potential drug, may be a promising drug candidate for TBI.

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Acknowledgments

The present study was supported by a grant from the Natural Science Foundation of Hebei Province (Grant No. H2014105079).

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Authors and Affiliations

  1. Department of Surgery, Hebei Medical University, No. 361 East Zhongshan Road, Shijiazhuang, 050017, People’s Republic of China

    Yan Feng, Changmeng Cui & Jianzhong Cui

  2. Department of Neurosurgery, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, People’s Republic of China

    Yan Feng

  3. School of Basic Medical Science, North China University of Science and Technology, Tangshan, People’s Republic of China

    Junling Gao, Minghang Li & Ran Li

  4. Department of Neurosurgery, Tangshan Workers’ Hospital, Tangshan, 063000, Hebei, People’s Republic of China

    Ying Cui & Jianzhong Cui

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  1. Yan Feng
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  2. Junling Gao
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  3. Ying Cui
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  4. Minghang Li
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Correspondence to Jianzhong Cui.

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Feng, Y., Gao, J., Cui, Y. et al. Neuroprotective Effects of Resatorvid Against Traumatic Brain Injury in Rat: Involvement of Neuronal Autophagy and TLR4 Signaling Pathway. Cell Mol Neurobiol 37, 155–168 (2017). https://doi.org/10.1007/s10571-016-0356-1

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