Traumatic brain injury induces long-lasting changes in immune and regenerative signaling

Abstract

There are no existing treatments for the long-term degenerative effects of traumatic brain injury (TBI). This is due, in part, to our limited understanding of chronic TBI and uncertainty about which proposed mechanisms for long-term neurodegeneration are amenable to treatment with existing or novel drugs. Here, we used microarray and pathway analyses to interrogate TBI-induced gene expression in the rat hippocampus and cortex at several acute, subchronic and chronic intervals (24 hours, 2 weeks, 1, 2, 3, 6 and 12 months) after parasagittal fluid percussion injury. We used Ingenuity pathway analysis (IPA) and Gene Ontology enrichment analysis to identify significantly expressed genes and prominent cell signaling pathways that are dysregulated weeks to months after TBI and potentially amenable to therapeutic modulation. We noted long-term, coordinated changes in expression of genes belonging to canonical pathways associated with the innate immune response (i.e., NF-κB signaling, NFAT signaling, Complement System, Acute Phase Response, Toll-like receptor signaling, and Neuroinflammatory signaling). Bioinformatic analysis suggested that dysregulation of these immune mediators—many are key hub genes—would compromise multiple cell signaling pathways essential for homeostatic brain function, particularly those involved in cell survival and neuroplasticity. Importantly, the temporal profile of beneficial and maladaptive immunoregulatory genes in the weeks to months after the initial TBI suggests wider therapeutic windows than previously indicated.

MicroRNA sequencing of rat hippocampus and human biofluids identifies acute, chronic, focal and diffuse traumatic brain injuries

“…S1C). These observations are concordant with our previous observations of chronic dysregulation of immune response genes in the TBI rat brain 9 .…”

Initiators of Classical and Lectin Complement Pathways Are Differently Engaged after Traumatic Brain Injury—Time-Dependent Changes in the Cortex, Striatum, Thalamus and Hippocampus in a Mouse Model

“…Moreover, these changes are not only observed in the cortex but are also observed in other brain regions, such as the striatum, hippocampus, and thalamus, and may contribute to the progression of neurodegeneration. Our results are in line with those obtained in FPI model in injured cortex and hippocampus [88]. In addition, our study provides the first evidence that strong changes appear in striatum, a structure involved in movement planning, as well as in cognition and reward processes and in the thalamus, an area important for consciousness, arousal, cognition, behavior, working memory, executive function, motor control, sustained, and vigilant attention [89].…”

The Gene Coexpression Analysis Identifies Functional Modules Dynamically Changed After Traumatic Brain Injury

“…A previous study has provided temporal profiles of 12 biomarkers in body fluids of TBI patients, demonstrated an association between the severity of TBI and the peak heights of each molecules, and suggested that release mechanisms may vary among different types of molecules, which further hints that successive measurements are essential for TBI diagnosis [ 7 ]. Utilizing microarray analysis, a recent study has described abnormal expression of immune mediators and brain injury-induced factors, along with regenerative immunoregulatory genes, in animal models of TBI, and remarked that such dysregulation of gene expression can be long-lasting after the initial injuries [ 8 ]. Also in experimental TBI, high levels of expression of Serpina3n, an astroglial activation marker, are found in neurons in the early stage of the injury [ 9 ].…”