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

ABSTRACT

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.