Abstract
Traumatic brain injury (TBI) is a major cause of disability and mortality worldwide, in part resulting from secondary apoptosis of neurons in peri-contusion areas. Serpina3k, a serine protease inhibitor, has been shown to inhibit apoptosis in injury models. In this study, we investigated the anti-apoptotic function of serpina3k in vivo using a mouse model of TBI, as well as the underlying neuroprotective mechanism in vitro using the SH-SY5Y human neuroblastoma cell line. TBI was induced in adult male C57BL/6 mice using controlled cortical impact. Serpina3k protein was intravenously administered at a concentration of 0.5 mg/kg twice daily for up to 14 days. SH-SY5Y cells were subjected to biaxial stretch injury and then treated with different concentrations of serpina3k. We found that endogenous serpina3k protein levels were elevated in peri-contusion areas of the mouse brain following TBI. Serpina3k-treated mice had fewer apoptotic neurons, lower levels of oxidative stress, and showed greater recovery of neurological deficits relative to vehicle-treated mice. Meanwhile, in the SH-SY5Y cell injury model, serpina3k at an optimal concentration (150 nM) inhibited the generation of intracellular reactive oxygen species, abrogated changes of the mitochondrial membrane potential, and reduced the phospho-extracellular regulated protein kinases (p-ERK)/ERK, phospho-P38 (p-P38)/P38, B cell lymphoma (Bcl)-2-associated X protein/Bcl-2, and cleaved caspase-3/caspase-3 ratios, thereby reducing the apoptosis rate. These results demonstrate that serpina3k exerts a neuroprotective function following TBI and thus has therapeutic potential.
Highlights
Traumatic brain injury (TBI) is a major cause of disability and mortality worldwide [1, 2]
Serpina3k treatment reduced the loss of normal neurons (P < 0.01; Figures 2A,B) and the number of apoptotic neurons (P < 0.05; Figures 2A,C) relative to vehicle-treated mice at 7 days post-TBI
We found that the pERK/extracellular regulated protein kinases (ERK), p-P38/P38, Bcl-2-associated X protein (Bax)/B cell lymphoma (Bcl)-2, and cleaved caspase-3/caspase3 ratios were increased at 2 h after stretch injury (SI), while these increases were attenuated by serpina3k treatment (P < 0.01, < 0.05, < 0.01, and < 0.05, respectively; Figures 8A–H)
Summary
Traumatic brain injury (TBI) is a major cause of disability and mortality worldwide [1, 2]. In the United States, ∼5.3 million people are living with TBI-induced disabilities [3]. In China, the population-based mortality of TBI is estimated to be ∼13 cases per 100,000 people [4]. Irrespective of the outcome of these cases, the economic consequences of TBI are enormous [5, 6]. Primary injury following TBI leads to the death of numerous nerve cells in the damaged core regions. This is accompanied by apoptosis, programmed cell death, caused by secondary damage such as oxidative stress and inflammation around the core areas [7]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
