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Visual Outcomes in Experimental Rodent Models of Blast-Mediated Traumatic Brain Injury.

ABSTRACT: Blast-mediated traumatic brain injuries (bTBI) cause long-lasting physical, cognitive, and psychological disorders, including persistent visual impairment. No known therapies are currently utilized in humans to lessen the lingering and often serious symptoms. With TBI mortality decreasing due to advancements in medical and protective technologies, there is growing interest in understanding the pathology of visual dysfunction after bTBI. However, this is complicated by numerous variables, e.g., injury location, severity, and head and body shielding. This review summarizes the visual outcomes observed by various, current experimental rodent models of bTBI, and identifies data showing that bTBI activates inflammatory and apoptotic signaling leading to visual dysfunction. Pharmacologic treatments blocking inflammation and cell death pathways reported to alleviate visual deficits in post-bTBI animal models are discussed. Notably, techniques for assessing bTBI outcomes across exposure paradigms differed widely, so we urge future studies to compare multiple models of blast injury, to allow data to be directly compared.

SUBMITTER: Evans LP

PROVIDER: S-EPMC8081965 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Visual Outcomes in Experimental Rodent Models of Blast-Mediated Traumatic Brain Injury.

Evans Lucy P LP Roghair Ariel M AM Gilkes Noah J NJ Bassuk Alexander G AG

Frontiers in molecular neuroscience 20210415

Blast-mediated traumatic brain injuries (bTBI) cause long-lasting physical, cognitive, and psychological disorders, including persistent visual impairment. No known therapies are currently utilized in humans to lessen the lingering and often serious symptoms. With TBI mortality decreasing due to advancements in medical and protective technologies, there is growing interest in understanding the pathology of visual dysfunction after bTBI. However, this is complicated by numerous variables, e.g., i ...[more]

PMID: 33935648

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Project description:Abstract Explosive blast-induced traumatic brain injury (TBI) is the signature insult in modern combat casualty care and has been linked to post-traumatic stress disorder, memory loss, and chronic traumatic encephalopathy. In this article we report on blast-induced mild TBI (mTBI) characterized by fiber-tract degeneration and axonal injury revealed by cupric silver staining in adult male rats after head-only exposure to 35 psi in a helium-driven shock tube with head restraint. We now explore pathways of secondary injury and repair using biochemical/molecular strategies. Injury produced ?25% mortality from apnea. Shams received identical anesthesia exposure. Rats were sacrificed at 2 or 24 h, and brain was sampled in the hippocampus and prefrontal cortex. Hippocampal samples were used to assess gene array (RatRef-12 Expression BeadChip; Illumina, Inc., San Diego, CA) and oxidative stress (OS; ascorbate, glutathione, low-molecular-weight thiols [LMWT], protein thiols, and 4-hydroxynonenal [HNE]). Cortical samples were used to assess neuroinflammation (cytokines, chemokines, and growth factors; Luminex Corporation, Austin, TX) and purines (adenosine triphosphate [ATP], adenosine diphosphate, adenosine, inosine, 2'-AMP [adenosine monophosphate], and 5'-AMP). Gene array revealed marked increases in astrocyte and neuroinflammatory markers at 24 h (glial fibrillary acidic protein, vimentin, and complement component 1) with expression patterns bioinformatically consistent with those noted in Alzheimer's disease and long-term potentiation. Ascorbate, LMWT, and protein thiols were reduced at 2 and 24 h; by 24 h, HNE was increased. At 2 h, multiple cytokines and chemokines (interleukin [IL]-1?, IL-6, IL-10, and macrophage inflammatory protein 1 alpha [MIP-1?]) were increased; by 24 h, only MIP-1? remained elevated. ATP was not depleted, and adenosine correlated with 2'-cyclic AMP (cAMP), and not 5'-cAMP. Our data reveal (1) gene-array alterations similar to disorders of memory processing and a marked astrocyte response, (2) OS, (3) neuroinflammation with a sustained chemokine response, and (4) adenosine production despite lack of energy failure-possibly resulting from metabolism of 2'-3'-cAMP. A robust biochemical/molecular response occurs after blast-induced mTBI, with the body protected from blast and the head constrained to limit motion.

Project description:BackgroundInjuries to the brain promote upregulation of prostaglandins, notably the proinflammatory PGF2?, and overactivation of their cognate G-protein-coupled FP receptor, which could exacerbate neuronal damage. Our study is focused on investigation of the FP receptor as a target for novel neuroprotective drugs in a preclinical animal traumatic brain injury (TBI) model.MethodsAccordingly, the effects of acute intraperitoneal post-treatment with selective FP antagonist AL-8810 were studied in wildtype (WT) and FP receptor knockout (FP-/-) mice after controlled cortical impact (CCI). Neurological impairments were evaluated using neurological deficit scores (NDS) and the grip strength test. Cortical lesions and overall brain pathology were assessed using immunohistochemistry.ResultsMorphological analyses of cerebral vasculature and anastomoses revealed no differences between WT and FP-/- mice. CCI produced cortical lesions characterized by cavitation, neuronal loss, and hematoma with a volume of 20.0 ± 1.0 mm(3) and significant hippocampal swelling (146.5 ± 7.4% of contralateral) compared with sham (P < 0.05). Post-treatment with AL-8810 (1 to 10 mg/kg) had no significant effect on cortical lesions, which suggests the irreversible effect of primary CCI injury, but significantly reduced hippocampal swelling to a size not significantly different from the sham group. Post-treatment with AL-8810 at a dose of 10 mg/kg significantly improved NDS at 24 and 48 hours after CCI (P < 0.001 and P < 0.01, respectively). In the AL-8810 group, CCI-induced decrease in grip strength was three-fold (2.93 ± 1.71) less and significantly different than in the saline-treated group. The FP-/- mice had significantly less hippocampal swelling, but not NDS, compared with WT mice. In addition, immunohistochemistry showed that pharmacologic blockade and genetic deletion of FP receptor led to attenuation of CCI-induced gliosis and microglial activation in selected brain regions.ConclusionThis study provides, for the first time, demonstration of the unique role of the FP receptor as a potential target for disease-modifying CNS drugs for treatment of acute traumatic injury.

Project description:Long-term molecular changes in the brain resulting from blast exposure may be mediated by epigenetic changes, such as deoxyribonucleic acid (DNA) methylation, that regulate gene expression. Aberrant regulation of gene expression is associated with behavioral abnormalities, where DNA methylation bridges environmental signals to sustained changes in gene expression. We assessed DNA methylation changes in the brains of rats exposed to three 74.5 kPa blast overpressure events, conditions that have been associated with long-term anxiogenic manifestations weeks or months following the initial exposures. Rat frontal cortex eight months post-exposure was used for cell sorting of whole brain tissue into neurons and glia. We interrogated DNA methylation profiles in these cells using Expanded Reduced Representation Bisulfite Sequencing. We obtained data for millions of cytosines, showing distinct methylation profiles for neurons and glia and an increase in global methylation in neuronal versus glial cells (p<10(-7)). We detected DNA methylation perturbations in blast overpressure-exposed animals, compared with sham blast controls, within 458 and 379 genes in neurons and glia, respectively. Differentially methylated neuronal genes showed enrichment in cell death and survival and nervous system development and function, including genes involved in transforming growth factor β and nitric oxide signaling. Functional validation via gene expression analysis of 30 differentially methylated neuronal and glial genes showed a 1.2 fold change in gene expression of the serotonin N-acetyltransferase gene (Aanat) in blast animals (p<0.05). These data provide the first genome-based evidence for changes in DNA methylation induced in response to multiple blast overpressure exposures. In particular, increased methylation and decreased gene expression were observed in the Aanat gene, which is involved in converting serotonin to the circadian hormone melatonin and is implicated in sleep disturbance and depression associated with traumatic brain injury.

Dataset Information

Visual Outcomes in Experimental Rodent Models of Blast-Mediated Traumatic Brain Injury.

Publications

Visual Outcomes in Experimental Rodent Models of Blast-Mediated Traumatic Brain Injury.

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