Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy.
IRCCS MultiMedica, Milan, Italy.
Theranostics. 2023 Sep 4;13(14):4872-4884. doi: 10.7150/thno.86831. eCollection 2023.
Reactive oxygen species (ROS) have emerged as essential signaling molecules regulating cell survival, death, inflammation, differentiation, growth, and immune response. Environmental factors, genetic factors, or many pathological condition such as diabetes increase the level of ROS generation by elevating the production of advanced glycation end products, reducing free radical scavengers, increasing mitochondrial oxidative stress, and by interfering with DAG-PKC-NADPH oxidase and xanthine oxidase pathways. Oxidative stress, and therefore the accumulation of intracellular ROS, determines the deregulation of several proteins and caspases, damages DNA and RNA, and interferes with normal neuronal function. Furthermore, ROS play an essential role in the polymerization, phosphorylation, and aggregation of tau and amyloid-beta, key mediators of cognitive function decline. At the neuronal level, ROS interfere with the DNA methylation pattern and various apoptotic factors related to cell death, promoting neurodegeneration. Only few drugs are able to quench ROS production in neurons. The cross-linking pathways between diabetes and dementia suggest that antidiabetic medications can potentially treat dementia. Among antidiabetic drugs, glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been found to reduce ROS generation and ameliorate mitochondrial function, protein aggregation, neuroinflammation, synaptic plasticity, learning, and memory. The incretin hormone glucagon-like peptide-1 (GLP-1) is produced by the enteroendocrine L cells in the distal intestine after food ingestion. Upon interacting with its receptor (GLP-1R), it regulates blood glucose levels by inducing insulin secretion, inhibiting glucagon production, and slowing gastric emptying. No study has evidenced a specific GLP-1RA pathway that quenches ROS production. Here we summarize the effects of GLP-1RAs against ROS overproduction and discuss the putative efficacy of Exendin-4, Lixisenatide, and Liraglutide in treating dementia by decreasing ROS.
活性氧（ROS）已成为调节细胞存活、死亡、炎症、分化、生长和免疫反应的重要信号分子。环境因素、遗传因素或许多病理状况，如糖尿病，通过提高晚期糖基化终产物的生成、减少自由基清除剂、增加线粒体氧化应激以及干扰 DAG-PKC-NADPH 氧化酶和黄嘌呤氧化酶途径，增加 ROS 的生成水平。氧化应激，因此细胞内 ROS 的积累，决定了几种蛋白质和半胱天冬酶的失调，损害 DNA 和 RNA，并干扰正常的神经元功能。此外，ROS 在 tau 和淀粉样β的聚合、磷酸化和聚集中起重要作用，是认知功能下降的关键介质。在神经元水平上，ROS 干扰与细胞死亡相关的 DNA 甲基化模式和各种凋亡因子，促进神经退行性变。只有少数药物能够抑制神经元中的 ROS 生成。糖尿病和痴呆之间的交联途径表明，抗糖尿病药物可能潜在地治疗痴呆。在抗糖尿病药物中，胰高血糖素样肽-1 受体激动剂（GLP-1RAs）已被发现可减少 ROS 生成并改善线粒体功能、蛋白质聚集、神经炎症、突触可塑性、学习和记忆。肠内分泌 L 细胞在进食后产生促胰岛素激素胰高血糖素样肽-1（GLP-1）。与受体（GLP-1R）相互作用后，它通过诱导胰岛素分泌、抑制胰高血糖素生成和减缓胃排空来调节血糖水平。没有研究证明存在特定的 GLP-1RA 途径可以抑制 ROS 的产生。在这里，我们总结了 GLP-1RAs 对 ROS 过度产生的影响，并讨论了 Exendin-4、Lixisenatide 和 Liraglutide 通过减少 ROS 治疗痴呆的潜在疗效。
