Division of Neuroscience, Department of Pharmacology, ISF College of Pharmacy, Moga (Affiliated to IK Gujral Punjab Technical University, Jalandhar), Moga, Punjab 144603, India.
Division of Neuroscience, Department of Pharmacology, ISF College of Pharmacy, Moga (Affiliated to IK Gujral Punjab Technical University, Jalandhar), Moga, Punjab 144603, India.
Behav Brain Res. 2025 Jan 5;476:115280. doi: 10.1016/j.bbr.2024.115280. Epub 2024 Oct 4.
SIRT1 (Sirtuin 1) is a NAD+-dependent deacetylase that functions through nucleoplasmic transfer and is present in nearly all mammalian tissues. SIRT1 is believed to deacetylate its protein substrates, resulting in neuroprotective actions, including reduced oxidative stress and inflammation, increased autophagy, increased nerve growth factors, and preserved neuronal integrity in aging or neurological disease. Nrf2 is a transcription factor that regulates the genes responsible for oxidative stress response and substance detoxification. The activation of Nrf2 guards cells against oxidative damage, inflammation, and carcinogenic stimuli. Several neurological abnormalities and inflammatory disorders have been associated with variations in Nrf2 activation caused by either pharmacological or genetic factors. Recent evidence indicates that Nrf2 is at the center of a complex cellular regulatory network, establishing it as a transcription factor with genuine pleiotropy. HO-1 is most likely a component of a defense mechanism in cells under stress, as it provides negative feedback for cell activation and mediator synthesis. This mediator is upregulated by Nrf2, nitric oxide (NO), and other factors in various inflammatory states. HO-1 or its metabolites, such as CO, may mitigate inflammation by modulating signal transduction pathways. Neurological diseases may be effectively treated by modulating the activity of HO-1. Multiple studies have demonstrated that SIRT1 and Nrf2 share an important connection. SIRT1 enhances Nrf2, activates HO-1, protects against oxidative injury, and decreases neuronal death. This has been associated with numerous neurodegenerative and neuropsychiatric disorders. Therefore, activating the SIRT1/Nrf2/HO-1 pathway may help treat various neurological disorders. This review focuses on the current understanding of the SIRT1 and Nrf2/HO-1 neuroprotective processes and the potential therapeutic applications of their target activators in neurodegenerative and neuropsychiatric disorders.
SIRT1（Sirtuin 1）是一种 NAD+-依赖性去乙酰化酶，通过核质转移发挥作用，存在于几乎所有哺乳动物组织中。SIRT1 被认为可以去乙酰化其蛋白质底物，从而产生神经保护作用，包括减少氧化应激和炎症、增加自噬、增加神经生长因子以及在衰老或神经疾病中保持神经元完整性。Nrf2 是一种转录因子，可调节负责氧化应激反应和物质解毒的基因。Nrf2 的激活可保护细胞免受氧化损伤、炎症和致癌刺激。几种神经异常和炎症性疾病与 Nrf2 激活的变化有关，这些变化是由药理学或遗传因素引起的。最近的证据表明，Nrf2 是一个复杂的细胞调节网络的中心，使其成为具有真正多效性的转录因子。HO-1 很可能是细胞应激下防御机制的一个组成部分，因为它为细胞激活和介质合成提供负反馈。这种介质被 Nrf2、一氧化氮（NO）和其他因素在各种炎症状态下上调。HO-1 或其代谢物，如 CO，可能通过调节信号转导途径来减轻炎症。通过调节 HO-1 的活性，可能有效地治疗神经疾病。多项研究表明，SIRT1 和 Nrf2 之间存在重要联系。SIRT1 增强 Nrf2、激活 HO-1、保护免受氧化损伤并减少神经元死亡。这与许多神经退行性和神经精神疾病有关。因此，激活 SIRT1/Nrf2/HO-1 通路可能有助于治疗各种神经退行性疾病。本综述重点介绍了 SIRT1 和 Nrf2/HO-1 神经保护过程的最新理解，以及它们的靶激活剂在神经退行性和神经精神疾病中的潜在治疗应用。
