Melatonin alleviates brain injury in copper-laden rats: Underlying benefits for Wilson’s disease

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY Biochemical pharmacology Pub Date : 2024-08-13 DOI:10.1016/j.bcp.2024.116490

Xiaodan Zhang , Lihong Zhou , Yulong Peng , Shiyu He , Zhen Mao , Jin Cai , Aobo Geng , Hong Yang , Peili Huang

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Abstract

Copper serves as an indispensable cofactor for all living organisms, and its excessive accumulation has been associated with a variety of diseases. Wilson’s disease (WD) serves as an illustrative example of copper toxicity in humans, frequently presenting with liver and/or neuropsychiatric symptoms. The current therapeutic drugs, penicillamine (PA) and zinc gluconate (ZnG), have constraints, and research on their combination efficacy remains insufficient. It has been reported that melatonin (MLT) plays a vital role in binding to transition metals and exhibits strong antioxidant capacity. To investigate the therapeutic efficacy of MLT and combined treatment, rats were randomly divided into the following seven groups: the control (Con) group, copper-laden model rat (Mod) group, PA-treated group, ZnG-treated group, MLT- treated group, PA-ZnG-treated group, and PA-MLT-treated group. Then potential mechanisms and targets were investigated using a combination of metabolomics and network pharmacology and verified by molecular docking and qPCR. The findings revealed that MLT and the combination significantly improved behavior, pathology and copper levels in copper-laden rats. The results of the metabolomics study showed that profoundly altered metabolites were identified, and alanine, aspartate and glutamate metabolism, pyruvate metabolism, citrate cycle (TCA cycle), and glycolysis/gluconeogenesis were explored. In addition, molecular docking showed that MLT had high binding affinity with key targets, and qPCR results revealed that MLT could reverse the mRNA expression of targets GOT2 and PKM2. It was concluded that MLT effectively improves brain injury in copper-laden rats, and this effect was linked with the altered features of the metabolite profiles.

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褪黑素可减轻铜负荷大鼠的脑损伤：对威尔逊氏病的潜在益处

铜是所有生物体不可或缺的辅助因子，铜的过度积累与多种疾病有关。威尔逊氏病（WD）是铜毒性在人类中的一个典型例子，经常出现肝脏和/或神经精神症状。目前的治疗药物青霉胺（PA）和葡萄糖酸锌（ZnG）有其局限性，对它们的综合疗效研究仍然不足。据报道，褪黑素（MLT）在与过渡金属结合方面发挥着重要作用，并具有很强的抗氧化能力。为了研究 MLT 和联合治疗的疗效，研究人员将大鼠随机分为以下七组：对照（Con）组、铜负荷模型大鼠（Mod）组、PA 治疗组、ZnG 治疗组、MLT 治疗组、PA-ZnG 治疗组和 PA-MLT 治疗组。然后结合代谢组学和网络药理学研究了潜在的机制和靶点，并通过分子对接和 qPCR 进行了验证。研究结果表明，MLT及其组合能明显改善铜负荷大鼠的行为、病理和铜水平。代谢组学研究结果表明，大鼠体内的代谢物发生了深刻的变化，丙氨酸、天冬氨酸和谷氨酸代谢、丙酮酸代谢、柠檬酸循环（TCA 循环）和糖酵解/葡萄糖生成都得到了探索。此外，分子对接显示 MLT 与关键靶点具有高结合亲和力，qPCR 结果显示 MLT 可逆转靶点 GOT2 和 PKM2 的 mRNA 表达。研究认为，MLT能有效改善铜负荷大鼠的脑损伤，而这一效果与代谢物谱特征的改变有关。

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来源期刊

Biochemical pharmacology 医学-药学

CiteScore

10.30

自引率

1.70%

发文量

420

审稿时长

17 days

期刊介绍： Biochemical Pharmacology publishes original research findings, Commentaries and review articles related to the elucidation of cellular and tissue function(s) at the biochemical and molecular levels, the modification of cellular phenotype(s) by genetic, transcriptional/translational or drug/compound-induced modifications, as well as the pharmacodynamics and pharmacokinetics of xenobiotics and drugs, the latter including both small molecules and biologics. The journal''s target audience includes scientists engaged in the identification and study of the mechanisms of action of xenobiotics, biologics and drugs and in the drug discovery and development process. All areas of cellular biology and cellular, tissue/organ and whole animal pharmacology fall within the scope of the journal. Drug classes covered include anti-infectives, anti-inflammatory agents, chemotherapeutics, cardiovascular, endocrinological, immunological, metabolic, neurological and psychiatric drugs, as well as research on drug metabolism and kinetics. While medicinal chemistry is a topic of complimentary interest, manuscripts in this area must contain sufficient biological data to characterize pharmacologically the compounds reported. Submissions describing work focused predominately on chemical synthesis and molecular modeling will not be considered for review. While particular emphasis is placed on reporting the results of molecular and biochemical studies, research involving the use of tissue and animal models of human pathophysiology and toxicology is of interest to the extent that it helps define drug mechanisms of action, safety and efficacy.