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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acute-Phase Proteins / metabolism
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Animals
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Brain Injuries, Traumatic / complications
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Brain Injuries, Traumatic / immunology
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Brain Injuries, Traumatic / metabolism*
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Complement System Proteins / metabolism
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Computational Biology
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Gene Expression Profiling
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Gene Expression Regulation*
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Male
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NF-kappa B / metabolism
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NFATC Transcription Factors / metabolism
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Neurodegenerative Diseases / etiology
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Neurodegenerative Diseases / metabolism
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Principal Component Analysis
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Proteostasis
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Rats, Sprague-Dawley
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Real-Time Polymerase Chain Reaction
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Signal Transduction
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Toll-Like Receptors / metabolism
Substances
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Acute-Phase Proteins
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NF-kappa B
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NFATC Transcription Factors
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Toll-Like Receptors
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Complement System Proteins
Grants and funding
This work was funded through a private grant from the Moody Project for Translational Traumatic Brain Injury Research. Recipients are DRB, HAW, HEW, MS, HS, IJB, KMJ, MAP, DSD, DSP, HLH. The funder did not play any role in the study design, data collection and analysis, or in the preparation or decision to publish manuscript. GenUs Biosystems provided support in the form of salaries for authors [MTF, KEOT], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section. Paradise genomics provided support in the form of salaries for [MTF], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of MTF is articulated in the ‘author contributions’ section.