Dataset Information

Quantitative Proteomics Reveals the Dynamic Pathophysiology across Different Stages in a Rat Model of Severe Traumatic Brain Injury

ABSTRACT: Background: Severe Traumatic Brain Injury (TBI) has become a growing health problem, causing a vast society burden worldwide. However, characteristic mechanisms between acute and subacute stages have not been systemically revealed. Methods: Sixty rats were randomly divided into sham surgery and model groups. Severe TBI model was induced by controlled cortical impact (CCI). Neurological deficits were evaluated by modified neurological severity score (mNSS). H&E staining and immunofluorescence were performed to assess the injured brain tissues. The protein expressions of hippocampus were analyzed by the tandem mass tag-based (TMT) quantitative proteomics on the third and fourteenth days. The shared and stage-specific differentially expressed proteins (DEPs) were screened, and then analyzed by the gene ontology (GO), Kyoto encyclopedia of genes and genomes (KEGG) and protein-protein interaction (PPI). Eventually, target proteins were further verified by Western blotting (WB). Results: The neurological deficits always exist from the acute stage to the subacute stage of severe TBI and showed a downward trend. The brain parenchyma of TBI models was dramatically impaired. A total of 375 and 139 DEPs were identified at day 3 and 14, respectively. Sixty-three DEPs were co-existed between the two stages. Both stages were mainly related to the complement and coagulation cascades pathway. Three pathways associated with gastric acid secretion, insulin secretion and thyroid hormone synthesis were only enriched in the acute phase. Comparatively, amyotrophic lateral sclerosis (ALS) was significantly enriched in the subacute stage. WB confirmed the reliability of the TMT quantitative proteomics results. Conclusion: Our findings highlight the same and different pathological processes in the acute and subacute phases of severe TBI and provide potential protein biomarkers.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Rattus Norvegicus (rat)

TISSUE(S): Brain

SUBMITTER: Weikang Luo

LAB HEAD: Yang Wang

PROVIDER: PXD029312 | Pride | 2023-06-07

REPOSITORIES: Pride

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Quantitative Proteomics Reveals the Dynamic Pathophysiology Across Different Stages in a Rat Model of Severe Traumatic Brain Injury.

Luo Weikang W Yang Zhaoyu Z Zhang Wei W Zhou Dan D Guo Xiaohang X Wang Shunshun S He Feng F Wang Yang Y

Frontiers in molecular neuroscience 20220125

<h4>Background</h4>Severe traumatic brain injury (TBI) has become a global health problem and causes a vast worldwide societal burden. However, distinct mechanisms between acute and subacute stages have not been systemically revealed. The present study aimed to identify differentially expressed proteins in severe TBI from the acute to subacute phase.<h4>Methods</h4>Sixty Sprague Dawley (SD) rats were randomly divided into sham surgery and model groups. The severe TBI models were induced by the c ...[more]

PMID: 35145378

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Project description:Cerebral ischemia/reperfusion injury (CI/RI), including neurological behavior deficits, cerebral infarction, blood-brain barrier (BBB) dysfunction, and neuroinflammation, et al. is a severe challenge in treatment of ischemic stroke. Traditional Chinese medicine (TCM) with the characteristics of multi-components and multi-functions for multiple targets/pathways has been historically used in the treatment of stroke and post stroke recovery in China. QiShenYiQi (QSYQ), a representative component-based Chinese medicine, is capable of reducing organ injury caused by ischemia/reperfusion via multiple mechanisms. Recently, we have previously reported that the positive action of QSYQ against the acute phase of CI/RI is partly via modulation of neuroinflammatory response. However, the effects and underlying mechanisms of QSYQ on subacute phase of CI/RI remain unknown, which are aimed to investigate in present study. The pharmacological action of QSYQ treatment on brain damage was estimated in the experimental stroke rats underwent 90 min ischemia and 8 days reperfusion by assessing the neurological and locomotor deficits, cerebral infarction, brain edema, and BBB integrity. Furthermore, we used TMT-based quantitative proteomics technology to identify significantly differentially expressed proteins following QSYQ treatment, which could give important clues for revealing the possible mechanism underlying the positive role of QSYQ in CI/RI. Besides, immunohistochemistry, western blot analysis, RT-qPCR, and rat ELISA kits were executed to further verify the accuracy of proteomics analysis results. As a consequence, we found that treatment with QSYQ (600mg/kg) for 7 days obviously improved neurological and behavioral impairment, attenuated infarct volume and brain edema, and alleviated BBB breakdown in stroke rats. Bioinformatics analysis suggested that differentially expressed protein galectin-3 mediated inflammatory response was closely related to the beneficial effect of QSYQ. Results of immunohistochemistry, western blot analysis and RT-qPCR showed that the model rats treated with QSYQ (600mg/kg) markedly downregulated the mRNA and protein expression level of galectin-3 in brain tissues compared to the untreated stroke rats. In addition, the decrease of mRNA level in brain tissues and contents in serum of TNF-α and IL-6 following QSYQ treatment were also observed. These interesting finding manifested that the effective action of QSYQ against subacute phase of CI/RI was partly via regulating galectin-3 mediated inflammatory reaction.

Project description:Warfare has long been associated with traumatic brain injury (TBI) in militarized zones. Common forms of TBI can be caused by a physical insult to the head-brain or by the effects of a high velocity blast shock wave generated by the detonation of an explosive device. While both forms of trauma are distinctly different regarding the mechanism of trauma induction, there are striking similarities in the cognitive and emotional status of survivors. Presently, proven effective therapeutics for the treatment of either form of TBI are unavailable. To be able to develop efficacious therapies, studies involving animal models of physical- and blast-TBI are required to identify possible novel or existing medicines that may be of value in the management of clinical events. We examined indices of cognition and anxiety-like behavior and the hippocampal gene transcriptome of mice subjected to both forms of TBI. We identified common behavioral deficits and gene expression regulations, in addition to unique injury-specific forms of gene regulation. Molecular pathways presented a pattern similar to that seen in gene expression. Interestingly, pathways connected to AlzheimerM-bM-^@M-^Ys disease displayed a markedly different form of regulation depending on the type of TBI. While these data highlight similarities in behavioral outcomes after trauma, the divergence in hippocampal transcriptome observed between models suggests that, at the molecular level, the TBIs are quite different. These models may provide tools to help define therapeutic approaches for the treatment of physical- and blast-TBIs. Based upon observations of increasing numbers of personnel displaying TBI related emotional and behavioral changes in militarized zones, the development of efficacious therapies will become a national if not a global priority. Keywords: Physical-traumatic brain injury; Blast-traumatic brain injury; Cognitive dysfunction; Gene expression; Molecular pathway(s); Neurodegeneration; Stem cells; AlzheimerM-bM-^@M-^Ys disease A mild physical-TBI was induced using a concussive head trauma device described previously (Milman et al., 2005; Zohar et al., 2003). Briefly, mice were lightly anesthetized (Isoflurane) and placed under the weight-drop concussive head trauma instrument. The device consisted of a metal tube (inner diameter 13 mm), placed vertically over the mouse head. A metal weight (30 g) was dropped from the top of the tube (80 cm) and struck the skull at the right side temporal area between the corner of the eye and the ear. A sponge supported the head, allowing some antero-posterior motion without any rotational head movement at the moment of the impact. Experimental conditions used to create a mild low-level blast-TBI and the subsequent model characterization, have been described in detail elsewhere (Rubovitch et al., 2011). In brief, mice were anaesthetized with a combination of ketamine (100 mg/kg) and xylazine (10 mg/kg). Once the animals were fully anaesthetized they were placed at a defined distance from a detonation source, in this case 7 meters. Pressure sensors were used to measure the explosion shock wave pressure (PSI) generated by the detonation (Free-Field ICPM-BM-. Blast Pressure Sensor; PCB Piezoelectronics, Depew, NY, USA, Model 137). At 7 meters from the source of the detonation, the animals were exposed to a maximum of a 2.5 PSI (17.2 kPa) pressure shock wave. Immediately after the induction of the injury, mice were placed back in their cages. Once the animals had recovered from the anesthesia, basic neurological assessments were undertaken to identify any acute neurological dysfunction. Only animals exhibiting no evidence of acute neurological damage post injury were subsequently used in further experiments. Sham treated mouse groups were treated identically; however, they were not exposed to physical- or blast-TBI. Mouse hippocampus tissues were randomly selected from the larger library of samples generated from the behavioral experiments and the numbers utilized in the gene expression study were as follows: sham, n = 5: physical-TBI, n = 4; blast-TBI, n = 7.

Dataset Information

Quantitative Proteomics Reveals the Dynamic Pathophysiology across Different Stages in a Rat Model of Severe Traumatic Brain Injury

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Quantitative Proteomics Reveals the Dynamic Pathophysiology Across Different Stages in a Rat Model of Severe Traumatic Brain Injury.

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