RESUMO
Traumatic brain injury (TBI) results in complex pathological reactions, where the initial lesion is followed by secondary inflammation and edema. Our laboratory and others have reported that angiotensin receptor blockers (ARBs) have efficacy in improving recovery from traumatic brain injury in mice. Treatment of mice with a subhypotensive dose of the ARB candesartan results in improved functional recovery, and reduced pathology (lesion volume, inflammation and gliosis). In order to gain a better understanding of the molecular mechanisms through which candesartan improves recovery after controlled cortical impact injury (CCI), we performed transcriptomic profiling on brain regions after injury and drug treatment. We examined RNA expression in the ipsilateral hippocampus, thalamus and hypothalamus at 3 or 29 days post injury (dpi) treated with either candesartan (0.1 mg/kg) or vehicle. RNA was isolated and analyzed by bulk mRNA-seq. Gene expression in injured and/or candesartan treated brain region was compared to that in sham vehicle treated mice in the same brain region to identify genes that were differentially expressed (DEGs) between groups. The most DEGs were expressed in the hippocampus at 3 dpi, and the number of DEGs reduced with distance and time from the lesion. Among pathways that were differentially expressed at 3 dpi after CCI, candesartan treatment altered genes involved in angiogenesis, interferon signaling, extracellular matrix regulation including integrins and chromosome maintenance and DNA replication. At 29 dpi, candesartan treatment reduced the expression of genes involved in the inflammatory response. Some changes in gene expression were confirmed in a separate cohort of animals by qPCR. Fewer DEGs were found in the thalamus, and only one in the hypothalamus at 3 dpi. Additionally, in the hippocampi of sham injured mice, 3 days of candesartan treatment led to the differential expression of 384 genes showing that candesartan in the absence of injury had a powerful impact on gene expression specifically in the hippocampus. Our results suggest that candesartan has broad actions in the brain after injury and affects different processes at acute and chronic times after injury. These data should assist in elucidating the beneficial effect of candesartan on recovery from TBI.
RESUMO
Oxidative stress and calcium excitotoxicity are hallmarks of traumatic brain injury (TBI). While these early disruptions may be corrected over a relatively short period of time, long-lasting consequences of TBI including impaired cognition and mood imbalances can persist for years, even in the absence of any evidence of overt injury based on neuroimaging. This investigation examined the possibility that disordered protein deimination occurs as a result of TBI and may thus contribute to the long-term pathologies of TBI. Protein deimination is a calcium-activated, posttranslational modification implicated in the autoimmune diseases rheumatoid arthritis and multiple sclerosis, where aberrant deimination creates antigenic epitopes that elicit an autoimmune attack. The present study utilized proteomic analyses to show that blast TBI alters the deimination status of proteins in the porcine cerebral cortex. The affected proteins represent a small subset of the entire brain proteome and include glial fibrillary acidic protein and vimentin, proteins reported to be involved in autoimmune-based pathologies. The data also indicate that blast injury is associated with an increase in immunoglobulins in the brain, possibly representing autoantibodies directed against novel protein epitopes. These findings indicate that aberrant protein deimination is a biomarker for blast TBI and may therefore underlie chronic neuropathologies of head injury.
