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Dynamic Alterations of Brain Injury, Functional Recovery, and Metabolites Profile after Cerebral Ischemia/Reperfusion in Rats Contributes to Potential Biomarkers

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Abstract

Cerebral ischemia-reperfusion (I/R) is characterized by initial transient cerebral ischemia followed by reperfusion. Various pathophysiological processes are involved in brain injury and functional recovery during cerebral I/R. There are few studies on dynamic metabolic process after cerebral I/R. The present study was to observe dynamic alteration of brain injury, functional recovery, and metabolites after cerebral I/R in rats and discover potential metabolic markers. The cerebral I/R model was established by middle cerebral artery occlusion (MCAO) for 90 min, following reperfusion in rats. The results of cerebral infarction area, cerebral edema, and behavior test showed that there were dynamic changes in brain injury and functional recovery at different periods after cerebral I/R. Further analysis showed that the brain injury was severe on the first day of cerebral I/R, and there was a significant functional recovery from the 7th day of cerebral I/R, followed by an aggravation trend of brain injury from the days 7 to 28. Furthermore, Matrix-assisted laser desorption ionization mass spectrometry imaging analysis showed that the expression of ATP, glucose, and citric acid on 7th day was the highest during cerebral I/R, which indicated that energy metabolism and oxidative phosphorylation played important roles during cerebral I/R. In addition, the untargeted metabolomic results showed that the level of isocitric acid, the ratio of oxyglutaric acid/glutamic acid, and the level of pyruvic acid associated with the TCA cycle were also the highest on the 7th day during cerebral I/R, which indicated that the transient spontaneous recovery of ischemic brain on the 7th day after ischemia-reperfusion might be related to oxidative phosphorylation and energy metabolism in the brain in this period. In conclusion, the results suggest that some small molecule metabolites participate in the brain injury and functional recovery during cerebral I/R, which is of great significance to the development of therapeutic drugs and diagnostic markers.

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Funding

This research was supported by the National Key Research & Development Plan (2018YFC0311005), the National Natural Science Foundation of China (81473383), the Drug Innovation Major Projects of China (2018ZX09711001-003-019), the Medical and Health Innovation Project of Chinese Academy of Medical Sciences (2016-I2M-3-007), and Innovation Fund for Graduate of Beijing Union Medical College (2018-1007-04).

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Authors and Affiliations

  1. Beijing Key Laboratory of Drug Target Identification and New Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China

    Xiao Cheng, Ying-Lin Yang, Wei-Han Li, Man Liu, Shan-Shan Zhang, Yue-Hua Wang & Guan-Hua Du

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  1. Xiao Cheng
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  2. Ying-Lin Yang
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  3. Wei-Han Li
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  4. Man Liu
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  5. Shan-Shan Zhang
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  6. Yue-Hua Wang
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  7. Guan-Hua Du
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Correspondence to Yue-Hua Wang or Guan-Hua Du.

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All animal care and experimental procedures regarding the animals were approved by the ethic committees of Institute of Materia Medica, Chinese Academy of Medical Sciences, and Peking Union Medical College.

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Cheng, X., Yang, YL., Li, WH. et al. Dynamic Alterations of Brain Injury, Functional Recovery, and Metabolites Profile after Cerebral Ischemia/Reperfusion in Rats Contributes to Potential Biomarkers. J Mol Neurosci 70, 667–676 (2020). https://doi.org/10.1007/s12031-019-01474-x

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