Lipidomic Analysis Reveals Systemic Alterations in Servicemen Exposed to Repeated Occupational Low-Level Blast Waves.

INTRODUCTION: Occupational exposure to blast is a prevalent risk experienced by military personnel. While low-level exposure may not manifest immediate signs of illness, prolonged and repetitive exposure may result in neurophysiological dysfunction. Such repeated exposure to occupational blasts has been linked to structural and functional modifications in the brain, adversely affecting the performance of servicemen in the field. These neurological changes can give rise to symptoms resembling concussion and contribute to the development of post-traumatic stress disorder. MATERIALS AND METHODS: To understand long-term effects of blast exposure, the study was conducted to assess memory function, serum circulatory protein and lipid biomarkers, and associated concussive symptomology in servicemen. Concussion-like symptoms were assessed using the Rivermead Post-Concussion Symptoms Questionnaire (RPSQ) along with memory function using PGI memory scale. The serum protein biomarkers were quantified using a sandwich ELISA assay, and the serum lipid profile was measured using liquid chromatography-mass spectrometer. RESULTS: The findings revealed that repeated low-level blast exposure resulted in impaired memory function, accompanied by elevated levels of serum neurofilament light chain (neuroaxonal injury) and C-reactive protein. Furthermore, alterations in the lipid profile were observed, with an increase in lipid species associated with immune activation. These changes collectively point to systemic inflammation, neuronal injury, and memory dysfunction as pathological characteristics of repeated low-level blast exposure. CONCLUSION: The results of our preliminary investigation offer valuable insights for further large-scale study and provide a guiding principle that necessitates a suitable mitigation approach to safeguard the health of personnel against blast overpressure.

Altered DTI scalars in the hippocampus are associated with morphological and structural changes after traumatic brain injury.

Blunt and diffuse injury is a highly prevalent form of traumatic brain injury (TBI) which can result in microstructural alterations in the brain. The blunt impact on the brain can affect the immediate contact region but can also affect the vulnerable regions like hippocampus, leading to functional impairment and long-lasting cognitive deficits. The hippocampus of the moderate weight drop injured male rats was longitudinally assessed for microstructural changes using in vivo MR imaging from 4 h to Day 30 post-injury (PI). The DTI analysis found a prominent decline in the apparent diffusion coefficient (ADC), radial diffusivity (RD), and axial diffusivity (AD) values after injury. The perturbed DTI scalars accompanied histological changes in the hippocampus, wherein both the microglia and astrocytes showed changes in the morphometric parameters at all timepoints. Along with this, the hippocampus showed presence of Aß positive fibrils and neurite plaques after injury. Therefore, this study concludes that TBI can lead to a complex morphological, cellular, and structural alteration in the hippocampus which can be diagnosed using in vivo MR imaging techniques to prevent long-term functional deficits.

Acute metabolic alterations in the hippocampus are associated with decreased acetylation after blast induced TBI.

INTRODUCTION: Blast induced Traumatic brain injury (BI-TBI) is common among military personnels as well as war affected civilians. In the war zone, people can also encounter repeated exposure of blast wave, which may affect their cognition and metabolic alterations. OBJECTIVE: In this study we assess the metabolic and histological changes in the hippocampus of rats at 24 h post injury. METHOD: Rats were divided into four groups: (i) Sham; (ii) Mild TBI (mi); (iii) Moderate TBI (mo); and (iv) Repetitive mild TBI (rm TBI) and then subjected to different intensities of blast exposure. Hippocampal tissues were collected after 24 h of injury for proton nuclear magnetic resonance spectroscopy (1H NMR spectroscopy) and immunohistochemical (IHC) analysis. RESULTS: The metabolic alterations were found in the hippocampal tissue samples and these alterations showed significant change in glutamate, N-Acetylaspartic acid (NAA), acetate, creatine, phosphoethanolamine (PE), ethanolamine and PC/choline concentrations in rmTBI rats only. IHC studies revealed that AH3 (Acetyl histone) positive cells were decreased in rm TBI tissue samples in comparison to other TBI groups and sham rats. This might reflect an epigenetic alteration due to repeated blast exposure at 24 h post injury. Additionally, astrogliosis was observed in miTBI and moTBI hippocampal tissue while no change was observed in rmTBI tissues. CONCLUSION: The present study reports altered acetylation in the presence of altered metabolism in hippocampal tissue of blast induced rmTBI at 24 h post injury. Mechanistic understanding of these intertwined processes may help in the development of better therapeutic pathways and agents for blast induced TBI in near future.

Temporal profile of serum metabolites and inflammation following closed head injury in rats is associated with HPA axis hyperactivity.

INTRODUCTION: Closed head injury (CHI) causes neurological disability along with systemic alterations that can activate neuro-endocrine response through hypothalamic-pituitary-adrenal (HPA) axis activation. A dysregulated HPA axis function can lead to relocation of energy substrates and alteration in metabolic pathways and inflammation at the systemic level. OBJECTIVES: Assessment of time-dependent changes in serum metabolites and inflammation after both mild and moderate CHI. Along with this, serum corticosterone levels and hypothalamic microglial response were observed. METHODS: Rats underwent mild and moderate weight-drop injury and their serum and hypothalamus were assessed at acute, sub-acute and chronic timepoints. Changes in serum metabolomics were determined using high resolution NMR spectroscopy. Serum inflammatory cytokine, corticosterone levels and hypothalamic microglia were assessed at all timepoints. RESULTS: Metabolites including lactate, choline and branched chain amino acids were found as the classifiers that helped distinguish between control and injured rats during acute, sub-acute and chronic timepoints. While, increased αglucose: ßglucose and TMAO: choline ratios after acute and sub-acute timepoints of mild injury differentiated from moderate injured rats. The injured rats also showed distinct inflammatory profile where IL-1ß and TNF-α levels were upregulated in moderate injured rats while IL-10 levels were downregulated in mild injured rats. Furthermore, injury specific alterations in serum metabolic and immunologic profile were found to be associated with hyperactive HPA axis, with consistent increase in serum corticosterone concentration post injury. The hypothalamic microglia showed a characteristic activated de-ramified cellular morphology in both mild and moderate injured rats. CONCLUSION: The study suggests that HPA axis hyperactivity along with hypothalamic microglial activation led to temporal changes in the systemic metabolism and inflammation. These time dependent changes in the metabolite profile of rats can further strengthen the knowledge of diagnostic markers and help distinguish injury related outcomes after TBI.

Hydrogen Sulfide Reverses LPS-Induced Behavioral Deficits by Suppressing Microglial Activation and Promoting M2 Polarization.

Activation of microglia is a hallmark of neuroinflammation and has been implicated in the development of many psychiatric disorders. Hydrogen sulfide (H2S); a gasotransmitter has recently emerged as a potent antioxidant and anti-inflammatory molecule. However, the protective potential of H2S and its underpin molecular mechanisms in neuroinflammation associated behavioral deficits are still unknown. The present study has been designed to investigate the effect of sodium hydrogen sulfide (NaHS; a source of H2S) on microglial activation and associated behavior phenotype in response to lipopolysaccharide (LPS)-induced neuroinflammation. LPS treatment decreased H2S levels with a concomitant increase in reactive oxygen species (ROS) in the cortex and hippocampus. However, NaHS administration restored the endogenous H2S levels to the normal and decreased ROS levels. NaHS supplementation reduced the number of active microglia in the cortex and hippocampus of LPS treated animals. Morphological analysis of microglia showed significant increase in microglial density, span ratio and soma area in the cortex and hippocampus of LPS treated animals which was decreased by NaHS supplementation. Moreover, NaHS administration reduced the expression of microglial M1 phenotype markers (IL-1ß, TNF-α and nitrite) and concomitantly increased the expression of M2 phenotype markers (IL-4 and TGF-ß) in the brain regions of LPS treated animals. Furthermore, LPS-induced anxiety-like behavior assessed by open field test and elevated plus maze was reversed by NaHS supplementation. Taken together, these findings suggest that H2S supplementation ameliorates LPS-induced behavioral deficits by suppressing pro-inflammatory and promoting anti-inflammatory microglial response. Therefore, H2S releasing drugs may be potential therapeutics to treat neuroinflammation associated psychiatric disorders. Graphical abstract.

Perturbed Biochemical Pathways and Associated Oxidative Stress Lead to Vascular Dysfunctions in Diabetic Retinopathy.

Diabetic retinopathy (DR) is a vascular insult that accompanies the hyperglycemic state. Retinal vasculature holds a pivotal role in maintaining the integrity of the retina, and any alteration to retinal vasculature affects retinal functions. The blood retinal barrier, a prerequisite to vision acuity, is most susceptible to damage during the progression of DR. This is a consequence of impaired biochemical pathways such as the polyol, advanced end glycation products (AGE), hexosamine, protein kinase C (PKC), and tissue renin-angiotensin system (RAS) pathways. Moreover, the role of histone modification and altered miRNA expression is also emerging as a major contributor. Epigenetic changes create a link between altered protein function and redox status of retinal cells, creating a state of metabolic memory. Although various biochemical pathways underlie the etiology of DR, the major insult to the retina is due to oxidative stress, a unifying factor of altered biochemical pathways. This review primarily focuses on the critical biochemical pathways altered in DR leading to vascular dysfunctions and discusses antioxidants as plausible treatment strategies.