The SIRT-1/Nrf2/HO-1 axis: Guardians of neuronal health in neurological disorders

Abstract

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.