Nikita Golovachev, Lorraine Siebold, Richard L Sutton, Sima Ghavim, Neil G Harris, Brenda Bartnik-Olson
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引用次数: 0
Abstract
Background: Research on traumatic brain injury (TBI) highlights the significance of counteracting its metabolic impact via exogenous fuels to support metabolism and diminish cellular damage. While ethyl pyruvate (EP) treatment shows promise in normalizing cellular metabolism and providing neuroprotection, there is a gap in understanding the precise metabolic pathways involved. Metabolomic analysis of the acute post-injury metabolic effects, with and without EP treatment, aims to deepen our knowledge by identifying and comparing the metabolite profiles, thereby illuminating the injury's effects and EP's therapeutic potential.
Methods: In the current study, an untargeted metabolomics approach was used to reveal brain metabolism changes in rats 24 h after a controlled cortical impact (CCI) injury, with or without EP treatment. Using principal component analysis (PCA), volcano plots, Random Forest and pathway analysis we differentiated the brain metabolomes of CCI and sham injured animals treated with saline (Veh) or EP, identifying key metabolites and pathways affected by injury. Additionally, the effect of EP on the non-injured brain was also explored.
Results: PCA showed a clear separation of the four study groups (sham-Veh, CCI-Veh, sham-EP, CCI-EP) based on injury. Following CCI injury (CCI-Veh), 109 metabolites belonging to the amino acid, carbohydrate, lipid, nucleotide, and xenobiotic families exhibited a twofold change at 24 h compared to the sham-Veh group, with 93 of these significantly increasing and 16 significantly decreasing (p < 0.05). CCI animals were treated with EP (CCI-EP) showed only 5 metabolites in the carbohydrate, amino acids, peptides, nucleotides, lipids, and xenobiotics super families that exhibited a twofold change, compared to the CCI-Veh group (p < 0.05). In the non-injured brain, EP treatment (sham-EP) resulted in a twofold change in 6 metabolites within the amino acid, peptide, nucleotide, and lipid super families compared to saline treated sham animals (sham-Veh, p < 0.05).
Conclusions: This study delineates the unique metabolic signatures resulting from a CCI injury and those related to EP treatment in both the injured and non-injured brain, underscoring the metabolic adaptations to brain injury and the effects of EP. Our analysis uncovers significant shifts in metabolites associated with inflammation, energy metabolism, and neuroprotection after injury, and demonstrates how EP intervention after injury alters metabolites associated with mitigating inflammation and oxidative damage.
背景：有关创伤性脑损伤（TBI）的研究表明，通过外源性燃料来支持新陈代谢和减轻细胞损伤，从而抵消其对新陈代谢的影响具有重要意义。虽然丙酮酸乙酯（EP）治疗有望使细胞代谢正常化并提供神经保护，但对其中涉及的精确代谢途径的了解还存在差距。对接受和未接受丙酮酸乙酯（EP）治疗的急性损伤后代谢影响进行代谢组学分析，旨在通过识别和比较代谢物谱加深我们的认识，从而阐明损伤的影响和丙酮酸乙酯的治疗潜力：在本研究中，采用非靶向代谢组学方法揭示了大鼠大脑皮层受控撞击（CCI）损伤24小时后大脑代谢的变化，无论是否进行了EP治疗。利用主成分分析（PCA）、火山图、随机森林和通路分析，我们区分了接受生理盐水（Veh）或EP治疗的CCI动物和假性损伤动物的脑代谢组，确定了受损伤影响的关键代谢物和通路。此外，我们还探讨了 EP 对非损伤大脑的影响：结果：PCA 显示，四个研究组（sham-Veh、CCI-Veh、sham-EP、CCI-EP）根据损伤情况明显分开。CCI损伤后（CCI-Veh），与假Veh组相比，109种氨基酸、碳水化合物、脂质、核苷酸和异生物家族的代谢物在24小时内出现了两倍的变化，其中93种显著增加，16种显著减少（P 结论：该研究描述了大脑中独特的代谢物，包括氨基酸、碳水化合物、脂质、核苷酸和异生物家族的代谢物：本研究描述了CCI损伤导致的独特代谢特征，以及损伤和非损伤大脑中与EP治疗相关的代谢特征，强调了脑损伤的代谢适应性和EP的影响。我们的分析揭示了损伤后与炎症、能量代谢和神经保护相关的代谢物的重大变化，并展示了损伤后的 EP 干预如何改变与减轻炎症和氧化损伤相关的代谢物。
期刊介绍：
The Journal of Neuroinflammation is a peer-reviewed, open access publication that emphasizes the interaction between the immune system, particularly the innate immune system, and the nervous system. It covers various aspects, including the involvement of CNS immune mediators like microglia and astrocytes, the cytokines and chemokines they produce, and the influence of peripheral neuro-immune interactions, T cells, monocytes, complement proteins, acute phase proteins, oxidative injury, and related molecular processes.
Neuroinflammation is a rapidly expanding field that has significantly enhanced our knowledge of chronic neurological diseases. It attracts researchers from diverse disciplines such as pathology, biochemistry, molecular biology, genetics, clinical medicine, and epidemiology. Substantial contributions to this field have been made through studies involving populations, patients, postmortem tissues, animal models, and in vitro systems.
The Journal of Neuroinflammation consolidates research that centers around common pathogenic processes. It serves as a platform for integrative reviews and commentaries in this field.
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