Studies on traumatic brain injury induced HPA axis dysfunction with the role of H2S signaling

Abstract

The present study systematically compares the temporal consequences of traumatic brain injury (TBI) induced by blunt impact and blast exposure, highlighting their distinct and overlapping features across neuronal, systemic, and metabolic domains. Blunt impact injury produced motor reflex impairments, heightened anxiety, memory deficits, and persistent hippocampal microstructural alterations. Conversely, blast exposure was characterized by sensory reflex impairments and diffuses white matter hyperintensities. Both models exhibited histological evidence of neuro degeneration, including axotomy and cellular damage. newlineDysregulation of hypothalamic pituitary adrenal (HPA) axis activity was observed in both paradigms: blunt TBI induced acute elevations of ACTH with elevated CORT, whereas blast TBI showed prolonged CORT elevation with suppressed ACTH levels. Metabolic alterations post blunt trauma led to glutamate excitotoxicity and reduced neuronal metabolites, while blast injury showed decreased glutamate and other metabolites. Both injuries showed impaired mitochondrial function, reflected by diminished ATP-linked oxygen consumption, altered activities of complexes I, II, and IV, and heightened oxidative stress. Neuro inflammation was marked by increased activation of microglia and astrocytes. Systemically, serum metabolomics revealed a distinct metabolic profile and sustained inflammatory responses from acute to chronic stages. Gut microbiome analysis indicated dysbiosis, including divergent changes in Firmicutes: Bacteroidetes ratios and reduced microbial diversity. Importantly, treatment with sodium hydrogen sulfide (NaHS), an Hand#8322;S donor, demonstrated therapeutic potential by attenuating oxidative stress and inflammation, restoring mitochondrial respiration, and normalizing gut microbial composition. Collectively, these findings provide an integrated perspective on blunt versus blast TBI pathophysiology and underscore NaHS as a promising candidate. newline newline