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: βglucose 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-1β 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.
Graphical abstract
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Abbreviations
- ACTH:
-
Adrenocorticotropic hormone
- BCAAs:
-
Branched-chain amino acids
- CHI:
-
Closed head injury
- CORT:
-
Corticosterone
- CRF:
-
Corticotropin-releasing factor
- HPA:
-
Hypothalamic–pituitary–adrenal axis
- PCA:
-
Principal component analysis
- PLS-DA:
-
Partial least squares-discriminant analysis
- TBI:
-
Traumatic brain injury
- TMAO:
-
Trimethylamine N-oxide
- TSP:
-
Trimethylsilylpropanoic acid
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Funding
This work was supported by the Defence Research & Development Organisation (DRDO), Ministry of Defence, India (INM-324). Palkin Arora is supported by DRDO fellowship (EST/3009/JRF/2020). Megha Kumari is supported by University Grants Commission (UGC) fellowship (344728).
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PA and RT: Conceptualization, Methodology and Analysis. PA: Data curation and original draft preparation, KS: Data acquisition and revised the manuscript for intellectual information. MK: Sample preparation and data acquisition. All authors have read and approved the final version of the manuscript.
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11306_2022_1886_MOESM2_ESM.tif
Supplementary file2 (TIF 205 KB)—Metabolic pathways affected post injury included a Hypotaurine and taurine metabolism, and b Glycine, serine and threonine metabolism and pyruvate metabolism; blue boxes indicate pathways affected and red boxes indicate metabolites altered
11306_2022_1886_MOESM3_ESM.xlsx
Supplementary file3 (XLSX 23 KB)—Metabolite relative integral data at all timepoints used in the study post mild and moderate injury
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Arora, P., Singh, K., Kumari, M. et al. Temporal profile of serum metabolites and inflammation following closed head injury in rats is associated with HPA axis hyperactivity. Metabolomics 18, 28 (2022). https://doi.org/10.1007/s11306-022-01886-8
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DOI: https://doi.org/10.1007/s11306-022-01886-8