Neuroprotective Effects of Resatorvid Against Traumatic Brain Injury in Rat: Involvement of Neuronal Autophagy and TLR4 Signaling Pathway
| Autor: | Changmeng Cui, Ran Li, Ying Cui, Ming-Hang Li, Yan Feng, Junling Gao, Jianzhong Cui |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine Traumatic brain injury Hippocampus Neuroprotection Rats Sprague-Dawley Random Allocation 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Brain Injuries Traumatic Autophagy medicine Animals Neuroinflammation Neurons Sulfonamides business.industry Cell Biology General Medicine medicine.disease Rats Toll-Like Receptor 4 Neuroprotective Agents Treatment Outcome 030104 developmental biology nervous system TRIF TLR4 Signal transduction business Neuroscience 030217 neurology & neurosurgery Signal Transduction |
| Zdroj: | Cellular and Molecular Neurobiology. 37:155-168 |
| ISSN: | 1573-6830 0272-4340 |
| DOI: | 10.1007/s10571-016-0356-1 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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