• Qianqian Li, Xiao Wu, Yanyan Yang, Yue Zhang, Fang He, Xiang Xu, Ziwei Zhang, Luyang Tao, and Chengliang Luo.
• School of Forensic Medicine, Wannan Medical College, Wuhu, 241002, Anhui, China.
• Int. J. Biochem. Cell Biol. 2019 Feb 1; 107: 154-165.

AbstractSubstance P (SP) is believed to play a role in traumatic brain injury (TBI), and the inhibition of binding of SP to the tachykinin neurokinin-1 receptor (NK1R) using NK1R antagonists had made favorable effects on TBI. Our current study addresses the functional roles and underlying mechanisms of SP and NK1R antagonist L-733,060 following TBI. Adult male wild type C57BL/6 J and SP knock out (SPKO) mice received a controlled cortical impact and outcome parameters were assessed. The results showed that TBI-induced motor and spatial memory deficits, lesion volume, brain water content and blood-brain barrier disruption were alleviated both in L-733,060-treated C57BL/6 J mice and vehicle-treated SPKO mice. L-733,060 treatment and SP deletion inhibited TBI-induced the release of cytochrome c from mitochondria to cytoplasm, activation of caspase-3, oxidative stress and neuroinflammation. Higher SP levels in serum and cortex were observed in wild type mice undergoing TBI relative to wild type sham group, but very little expression of cortical SP was detected in the SP-/- mice either TBI or not. Upregulation of NK1R expression after TBI was observed, and there was no significant difference between wild type and SPKO groups. in vitro, L-733,060 and SP deletion inhibited scratch injury-induced cell death, loss of mitochondrial membrane potential and reactive oxygen species (ROS) production following TBI. Together, the results of this study implicate a functional role for NK1-R antagonist L-733,060 and deletion of SP in TBI-induced neurological outcome, oxidative damage, neuroinflammation and cell death. Upregulation of NK1R maybe a consequence of TBI, independent of the levels of substance P. This study raises the possibility that targeting SP through its receptor NK1R or genetic deletion may have therapeutic efficacy in TBI.Copyright © 2018 Elsevier Ltd. All rights reserved.

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