实验性脑出血大鼠脑内代谢组学的时变特征。
Temporal metabolomic alteration in rat brains of experimental intracerebral hemorrhage.
机构信息
Institute of Integrative Medicine, Department of Integrated Traditional Chinese and Western Medicine, Xiangya Hospital, Central South University, Changsha 410008, PR China.
Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital, Zhengzhou University, Zhengzhou 450052, PR China.
出版信息
Brain Res Bull. 2021 May;170:234-245. doi: 10.1016/j.brainresbull.2021.02.021. Epub 2021 Feb 22.
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.
背景
脑出血（ICH）是最致命和致残的中风形式。ICH 的病理生理学尚未完全了解。代谢物是细胞过程的指标和调节剂。然而，ICH 后的整体大脑代谢模式和时间变化仍不清楚。
方法
将 40 只雄性大鼠随机分为假手术组和 ICH 组。胶原酶 VII 诱导 ICH。评估体重。改良神经功能缺损评分评估神经功能缺损。然后，使用高效液相色谱-串联质谱法（HPLC-MS）检测血肿周围脑组织中的代谢产物。通过主成分分析（PCA）、偏最小二乘判别分析（PLS-DA）和聚类分析显示代谢谱。通过倍数变化>2.0、错误发现率（FDR）<0.05 和投影变量重要性（VIP）>1 筛选显著差异代谢物。然后，通过 MetaboAnalyst 网站识别相关代谢途径。随后构建代谢物-蛋白质相互作用网络，以进一步注释差异代谢物的功能。
结果
大鼠体重增加受损，神经功能受损。ICH 后大鼠脑组织的代谢组学图谱在第 3 天和第 14 天与假手术组明显不同。34 种代谢物（胆红素、尿酸、6-甲基烟酰胺等）在急性期异常上调，而 27 种代谢物在恢复期紊乱，包括胆红素、尿酸和组氨酸等。急性期和恢复期分别有 7 个和 3 个代谢途径改变。代谢物-蛋白质相互作用分析表明，紊乱的代谢物可能通过改变急性期的氨基酸代谢、过氧化物酶体增殖物激活受体信号通路、脂肪酸代谢和尿素循环，以及影响恢复期的氨基酸代谢、尿素循环和过氧化物酶体，参与 ICH 病理生理学。
结论
本研究描绘了 ICH 后大鼠大脑在急性期和恢复期的病理代谢组学图谱。这项工作将有助于发现治疗 ICH 的新的治疗靶点和治疗方法。
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