Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, SP 05508-900, Brazil.
Chem Res Toxicol. 2024 Aug 19;37(8):1306-1314. doi: 10.1021/acs.chemrestox.4c00052. Epub 2024 Jul 27.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the dysfunction and death of motor neurons through multifactorial mechanisms that remain unclear. ALS has been recognized as a multisystemic disease, and the potential role of skeletal muscle in disease progression has been investigated. Reactive aldehydes formed as secondary lipid peroxidation products in the redox processes react with biomolecules, such as DNA, proteins, and amino acids, resulting in cytotoxic effects. 4-Hydroxy-2-nonenal (HNE) levels are elevated in the spinal cord motor neurons of ALS patients, and HNE-modified proteins have been identified in the spinal cord tissue of an ALS transgenic mice model, suggesting that reactive aldehydes can contribute to motor neuron degeneration in ALS. One biological pathway of aldehyde detoxification involves conjugation with glutathione (GSH) or carnosine (Car). Here, the detection and quantification of Car, GSH, GSSG (glutathione disulfide), and the corresponding adducts with HNE, Car-HNE, and GS-HNE, were performed in muscle and liver tissues of a hSOD1 ALS rat model by reverse-phase high-performance liquid chromatography coupled to electrospray ion trap tandem mass spectrometry in the selected reaction monitoring mode. A significant increase in the levels of GS-HNE and Car-HNE was observed in the muscle tissue of the end-stage ALS animals. Therefore, analyzing variations in the levels of these adducts in ALS animal tissue is crucial from a toxicological perspective and can contribute to the development of new therapeutic strategies.
肌萎缩侧索硬化症（ALS）是一种致命的神经退行性疾病，其特征是运动神经元通过多种机制发生功能障碍和死亡，这些机制尚不清楚。ALS 已被认为是一种多系统疾病，并且已经研究了骨骼肌在疾病进展中的潜在作用。在氧化还原过程中形成的作为次级脂质过氧化产物的反应性醛与生物分子（如 DNA、蛋白质和氨基酸）反应，导致细胞毒性作用。ALS 患者脊髓运动神经元中的 4-羟基-2-壬烯醛（HNE）水平升高，并且在 ALS 转基因小鼠模型的脊髓组织中已鉴定出 HNE 修饰的蛋白质，表明反应性醛可以有助于 ALS 中的运动神经元退化。醛解毒的一种生物途径涉及与谷胱甘肽（GSH）或肌肽（Car）缀合。在这里，通过反相高效液相色谱-电喷雾串联质谱在选择反应监测模式下，在 hSOD1 ALS 大鼠模型的肌肉和肝脏组织中检测和定量了 Car、GSH、GSSG（谷胱甘肽二硫化物）以及与 HNE、Car-HNE 和 GS-HNE 的相应加合物。在终末期 ALS 动物的肌肉组织中观察到 GS-HNE 和 Car-HNE 的水平显着增加。因此，从毒理学角度来看，分析 ALS 动物组织中这些加合物水平的变化至关重要，并且可以为新的治疗策略的发展做出贡献。
