Temporal metabolomic alteration in rat brains of experimental intracerebral hemorrhage

Abstract

Background: Intracerebral hemorrhage (ICH) is the top lethal and disabling form of stroke. The pathophysiology of ICH is not fully understood yet. Metabolites are indicators and regulators of cellular processes. However, the overall brain metabolic pattern and the temporal alterations after ICH remain unknown.

Methods: A total of 40 male rats were randomly assigned to sham group and ICH group. ICH was induced by collagenase Ⅶ. Body weight was assessed. Neurological deficits were evaluated by modified neurological severity score. Then, the perihematomal brain tissues were collected for metabolites detection using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS). The metabolic profiles were displayed by principal component analysis (PCA), partial least-squares-discriminant analysis (PLS-DA) and cluster analysis. The significant differential metabolites were screened by fold change > 2.0, the false discovery rate (FDR) < 0.05 and Variable Importance of Projection (VIP) > 1. Next, the relevant metabolic pathways were discerned by MetaboAnalyst website. A metabolite-protein interaction network was subsequentially constructed to further annotate the function of differential metabolites.

Results: Rats suffered from compromised body weight increasement and impaired neurological function. The metabolomics profiles of brain tissues in the post-ICH rats were markedly different from those in the sham group on days 3 and 14. Thirty-four metabolites (bilirubin, uric acid, 6-Methylnicotinamide et al.) were abnormally upregulated in the acute stage, while 27 metabolites were disturbed in the recovery stage, including bilirubin, uric acid, and histamine et al. Seven and three metabolic pathways altered in the acute and recovery stage, respectively. Metabolite-protein interaction analysis revealed that the disturbed metabolites may participate in ICH pathophysiology by altering amino acid metabolism, peroxisome proliferators-activated receptor signaling pathway, fatty acid metabolism and urea cycle in the acute stage, while influencing amino acid metabolism, urea cycle and peroxisome in the recovery stage.

Conclusions: Our study mapped the pathological metabolomics profiles of the post-ICH rat brains in the acute and recovery phases. This work will assist in discovering novel therapeutic targets and treatments for ICH.

Keywords: Acute phase; Intracerebral hemorrhage; Metabolite-protein interaction; Metabolomics; Recovery phase.