Mild traumatic brain injury-induced hippocampal gene expressions: The identification of target cellular processes for drug development

Abstract

Background Neurological dysfunction after traumatic brain injury (TBI) poses short-term or long-lasting health issues for family members and health care providers. Presently there are no approved medicines to treat TBI. Epidemiological evidence suggests that TBI may cause neurodegenerative disease later in life. In an effort to illuminate target cellular processes for drug development, we examined the effects of a mild TBI on hippocampal gene expression in mouse. Methods mTBI was induced in a closed head, weight drop-system in mice (ICR). Animals were anesthetized and subjected to mTBI (30 g). Fourteen days after injury the ipsilateral hippocampus was utilized for cDNA gene array studies. mTBI animals were compared with sham-operated animals. Genes regulated by TBI were identified to define TBI-induced physiological/pathological processes. mTBI regulated genes were divided into functional groupings to provide gene ontologies. Genes were further divided to identify molecular/cellular pathways regulated by mTBI. Results Numerous genes were regulated after a single mTBI event that mapped to many ontologies and molecular pathways related to inflammation and neurological physiology/pathology, including neurodegenerative disease. Conclusions These data illustrate diverse transcriptional changes in hippocampal tissues triggered by a single mild injury. The systematic analysis of individual genes that lead to the identification of functional categories, such as gene ontologies and then molecular pathways, illustrate target processes of relevance to TBI pathology. These processes may be further dissected to identify key factors that can be evaluated at the protein level to highlight possible treatments for TBI in human disease and potential biomarkers of neurodegenerative processes.

Neuroprotective Effects and Treatment Potential of Incretin Mimetics in a Murine Model of Mild Traumatic Brain Injury

“…We previously reported that our mTBI model, in line with other studies, induces key neuroinflammatory changes, including elevations in astrocyte and microglial expression, proinflammatory cytokine TNF-α levels, and expression of genes involved in inflammatory processes in several regions of the brain (Baratz et al, 2015;Tweedie et al, 2016a;Bader et al, 2019). In the current study, treatment with either liraglutide or twincretin reduced elevated microglial reactivity but failed to mitigate astrocyte changes, which is interesting in the light of recent studies suggesting that neurodegenerative processes triggered by neuroinflammation and the activation of microglia are mediated via A1 activated astrocytes (Liddelow et al, 2017;Yun et al, 2018).…”

Neuroprotective effects of (Val8)GLP-1-Glu-PAL in the MPTP Parkinson’s disease mouse model

“…GLP--1 analogues have shown neuroprotective effects in various diseases, such as Alzheimer's disease, Parkinson's disease, head trauma or stroke (Darsalia et al, 2012;Holscher, 2013;P. L. McClean & Holscher, 2014;Perry & Greig, 2004;Sato et al, 2013;Tweedie et al, 2013). Furthermore, two previous studies showed good protection of MPTP treated mice using the GLP--1 agonist exendin--4 (Kim et al, 2009;Li et al, 2009).…”

Older Age Results in Differential Gene Expression after Mild Traumatic Brain Injury and Is Linked to Imaging Differences at Acute Follow-up

“…Moreover, in preclinical models of ischemic injury, B cell deficiency was found to exacerbate histological damage and functional outcomes, while adoptive transfer of B cells was shown to decrease infarct size and improve neurological deficits ( Li et al, 2013 ). Gene expression is also related to inflammatory regulation shown in a preclinical model of a mild single TBIs within the hippocampus ( Tweedie et al, 2016 ). If indeed the gene expression profile we detected promotes a suppression of B lymphocyte function, then this could be a mechanism for inhibiting the neuroprotective effects of the humoral immune response through T cell regulation and secretion of interleukin 10, thereby contributing to worse outcomes reported in older adults with a TBI.…”