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Early Reciprocal Effects in a Murine Model of Traumatic Brain Injury and Femoral Fracture.

ABSTRACT: Traumatic brain injury (TBI) represents a major cause of death and disability in early adulthood. Concomitant extracranial injury such as long bone fracture was reported to exacerbate TBI pathology. However, early reciprocal effects and mechanisms have been barely investigated. To address this issue, C57BL/6N mice were subjected to either the controlled cortical impact (CCI) model of TBI, fracture of the left femur (FF), combined injury (CCI+FF), or sham procedure. Behavioral alterations were monitored until 5 days post injury (dpi), followed by (immuno-)histology, gene and protein expression analyses using quantitative PCR, western blot, and ELISA. We found that CCI+FF mice exhibited increased neurological impairments, reduced recovery, and altered anxiety-related behavior compared to single injury groups. At 5?dpi, cerebral lesion size was not affected by combined injury but exaggerated hippocampal substance loss and increased perilesional astrogliosis were observed in CCI+FF mice compared to isolated CCI. Bone gene expression of the osteogenic markers Runx2, osteocalcin, alkaline phosphatase, and bone sialoprotein was induced by fracture injury but attenuated by concomitant TBI. Plasma concentrations of the biomarkers osteopontin and progranulin were elevated in CCI+FF mice compared to other experimental groups. Taken together, using a murine model of TBI and femoral fracture, we report early reciprocal impairments of brain tissue maintenance, behavioral recovery, and bone repair gene expression. Increased circulating levels of the biomarkers osteopontin and progranulin indicate ongoing tissue inflammation and repair. Our results may have implications for future therapeutic approaches to interfere with the pathological crosstalk between TBI and concomitant bone fracture.

SUBMITTER: Ritter K

PROVIDER: S-EPMC7834824 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Early Reciprocal Effects in a Murine Model of Traumatic Brain Injury and Femoral Fracture.

Ritter Katharina K Jung Kirsten K Dolderer Christopher C Appel Dominik D Oswald Christine C CC Ritz Ulrike U Schäfer Michael K E MKE

Mediators of inflammation 20210118

Traumatic brain injury (TBI) represents a major cause of death and disability in early adulthood. Concomitant extracranial injury such as long bone fracture was reported to exacerbate TBI pathology. However, early reciprocal effects and mechanisms have been barely investigated. To address this issue, C57BL/6N mice were subjected to either the controlled cortical impact (CCI) model of TBI, fracture of the left femur (FF), combined injury (CCI+FF), or sham procedure. Behavioral alterations were mo ...[more]

PMID: 33531878

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Project description:Traumatic brain injury (TBI) is a commonly occurring injury in sports, victims of motor vehicle accidents, and falls. TBI has become a pressing public health concern with no specific therapeutic treatment. Mild TBI (mTBI), which accounts for approximately 90% of all TBI cases, may frequently lead to long-lasting cognitive, behavioral, and emotional impairments. The incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are gastrointestinal hormones that induce glucose-dependent insulin secretion, promote β-cell proliferation, and enhance resistance to apoptosis. GLP-1 mimetics are marketed as treatments for type 2 diabetes mellitus (T2DM) and are well tolerated. Both GLP-1 and GIP mimetics have shown neuroprotective properties in animal models of Parkinson's and Alzheimer's disease. The aim of this study is to evaluate the potential neuroprotective effects of liraglutide, a GLP-1 analog, and twincretin, a dual GLP-1R/GIPR agonist, in a murine mTBI model. First, we subjected mice to mTBI using a weight-drop device and, thereafter, administered liraglutide or twincretin as a 7-day regimen of subcutaneous (s.c.) injections. We then investigated the effects of these drugs on mTBI-induced cognitive impairments, neurodegeneration, and neuroinflammation. Finally, we assessed their effects on neuroprotective proteins expression that are downstream to GLP-1R/GIPR activation; specifically, PI3K and PKA phosphorylation. Both drugs ameliorated mTBI-induced cognitive impairments evaluated by the novel object recognition (NOR) and the Y-maze paradigms in which neither anxiety nor locomotor activity were confounds, as the latter were unaffected by either mTBI or drugs. Additionally, both drugs significantly mitigated mTBI-induced neurodegeneration and neuroinflammation, as quantified by immunohistochemical staining with Fluoro-Jade/anti-NeuN and anti-Iba-1 antibodies, respectively. mTBI challenge significantly decreased PKA phosphorylation levels in ipsilateral cortex, which was mitigated by both drugs. However, PI3K phosphorylation was not affected by mTBI. These findings offer a new potential therapeutic approach to treat mTBI, and support further investigation of the neuroprotective effects and mechanism of action of incretin-based therapies for neurological disorders.

Project description:It is commonly observed that patients with bone fracture concomitated with traumatic brain injury (TBI) had significantly increased fracture healing while the underlying mechanisms were not fully revealed. Long non-coding RNAs (lncRNAs) were known for paly complicated roles in bone homeostasis while its role in TBI accelerated fracture were rarely reported. The present study was designed to determine the role of lncRNAs in TBI accelerated fracture via transcriptome sequencing and further bioinformatical analysis. Blood samples from 3 fracture only patients, 3 fracture concomitated with TIB patients and 3 healthy controls were harvested and were subsequently subjected to transcriptome lncRNAs sequencing. Differentially expression genes were identified, and pathway enrichment were performed by Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyze. High high-dimensional data portraying by self-organizing map (SOM) machine learning was applied to further interpret the data. A xCell method were then used to predict cellular behavior in all samples based on gene expression profiles and a lncRNA-cell interaction network were generated. A total of 874 differentially expressed genes were identified, of which about 26% were lncRNAs. Those identified lncRNAs were mainly enriched on traumatic brain injury related- and damage repair related-pathways. SOM analyzes revealed that those differentially expressed lncRNAs could be divided into three major module implications and were mainly enriched on transcriptional regulation and immune related signal pathways, which promote us to further explore cellular behaviors based on differentially expressed lncRNAs. We have predicted that basophils, CD8+ T effector memory cells, B cells, and naïve B cells were significantly down-regulated while microvascular endothelia cells were predicated significantly up-regulated with TBI/Fr group was the lowest or highest, respectively. ENSG00000278905, ENSG00000240980, ENSG00000255670, and ENSG00000196634 were the most differentially expression lcnRNA that related to all changes of cellular behavior. The present study has revealed for the first time that several critical lncRNAs may participate in TBI accelerated fracture potentially via regulating cellular behaviors of basophils, cytotoxic T cells, B cells and endothelia cells.

Project description:It is commonly observed that patients with bone fracture concomitant with traumatic brain injury (TBI) had significantly increased fracture healing, but the underlying mechanisms were not fully revealed. Long non-coding RNAs (lncRNAs) are known to play complicated roles in bone homeostasis, but their role in TBI accelerated fracture was rarely reported. The present study was designed to determine the role of lncRNAs in TBI accelerated fracture via transcriptome sequencing and further bioinformatics analyses. Blood samples from three fracture-only patients, three fracture concomitant with TBI patients, and three healthy controls were harvested and were subsequently subjected to transcriptome lncRNA sequencing. Differentially expressed genes were identified, and pathway enrichment was performed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. High-dimensional data visualization by self-organizing map (SOM) machine learning was applied to further interpret the data. An xCell method was then used to predict cellular behavior in all samples based on gene expression profiles, and an lncRNA-cell interaction network was generated. A total of 874 differentially expressed genes were identified, of which about 26% were lncRNAs. Those identified lncRNAs were mainly enriched on TBI-related and damage repair-related pathways. SOM analyses revealed that those differentially expressed lncRNAs could be divided into three major module implications and were mainly enriched on transcriptional regulation and immune-related signal pathways, which promote us to further explore cellular behaviors based on differentially expressed lncRNAs. We have predicted that basophils, CD8+ T effector memory cells, B cells, and naïve B cells were significantly downregulated, while microvascular endothelial cells were predicted to be significantly upregulated in the Fr/TBI group, was the lowest and highest, respectively. ENSG00000278905, ENSG00000240980, ENSG00000255670, and ENSG00000196634 were the most differentially expressed lncRNAs related to all changes of cellular behavior. The present study has revealed for the first time that several critical lncRNAs may participate in TBI accelerated fracture potentially via regulating cellular behaviors of basophils, cytotoxic T cells, B cells, and endothelial cells.

Dataset Information

Early Reciprocal Effects in a Murine Model of Traumatic Brain Injury and Femoral Fracture.

Publications

Early Reciprocal Effects in a Murine Model of Traumatic Brain Injury and Femoral Fracture.

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