Neuroprotective Effects of Serpina3k in Traumatic Brain Injury

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.

Tanshinone IIA Promotes M2 Microglia by ERβ/IL-10 Pathway and Attenuates Neuronal Loss in Mouse TBI Model

“…34 In order to explore the underlying pathogenesis and evaluate potential therapies several TBI models, including CCI, weight-drop injury, fluid percussion injury, blast brain injury, and penetrating brain injury, have been used in mice. [35][36][37][38] In our study, CCI brain injury model was used due to its ease of operation and high accuracy compared with that of other models. We confirmed our CCI model was success with mNSS, loss of neurons and activated microglia.…”

Ischemic Stroke Increased Gadolinium Deposition in the Brain and Aggravated Astrocyte Injury After Gadolinium‐Based Contrast Agent Administration: Linear Versus Macrocyclic Agents

“…The mitochondrial membrane potential was measured using a JC‐1 dye kit (Beyotime Biotechnology, Shanghai, China) following the manufacturer's protocol 29 . JC‐1 exhibits bright red fluorescence at a high membrane potential but exhibits green fluorescence at a low potential.…”

A model of traumatic brain injury using human iPSC-derived cortical brain organoids

“…22,23 Previous efforts to study TBI in vitro have used stretch and shear forces to either rodent organotypic slices 24 or rudimentary single-or two-cell type cultures. 25,26 While these models are useful for studying axonal injury, they have limited translational relevance with regards to the extracellular matrix, stiffness and cell-cell interactions that substantially influence the biophysical properties of mechanical injury in vivo. [27][28][29] To address these concerns, we adapted a 3-dimensional induced pluripotent stem cell (iPSC)-cortical organoid model 30 coupled with mechanical injury via highintensity focused ultrasound (HIFU) with which we can precisely deliver mild/moderate (e.g.…”