SIRT1: A likely key for future therapeutic strategies for pain management
Sara Ilari, Saverio Nucera, Lucia Carmela Passacatini, Rosamaria Caminiti, Valeria Mazza, Roberta Macrì, Maria Serra, Federica Scarano, Valentina Malafoglia, Ernesto Palma, Francesca Oppedisano, Jessica Maiuolo, Carlo Tomino, Vincenzo Mollace, Carolina Muscoli
Abstract
Sirtuin 1 (SIRT1), a NAD+ -dependent histone deacetylase, plays a crucial role in mitigating oxidative stress, regulating inflammation, and maintaining mitochondrial function. Reduced SIRT1 activity has been linked to elevated pro-inflammatory cytokines, mitochondrial dysfunction, and chronic pain, all of which are observed in long COVID pathology. Emerging evidence identifies mitochondrial dysfunction and oxidative stress as central contributors to these symptoms. Increases reactive oxygen species (ROS) such as superoxide, nitric oxide, and peroxynitrite, leading to oxidative damage, chronic inflammation, and central/peripheral sensitization. Nutraceuticals, particularly the polyphenolic fraction of bergamot (BPF), have demonstrated potent antioxidant, anti-inflammatory, and antiviral properties. This study highlights BPF's ability to modulate SIRT1 activity in a rat model of inflammation and hyperalgesia. It provides novel evidence of SIRT1 nitration within the nucleus as a key event in inflammatory pain pathogenesis. BPF administration preserved SIRT1 activity, reduced oxidative stress markers such as malondialdehyde (MDA) and 8-hydroxydeoxyguanosine (8-OHdG), and minimized post-translational modifications of nuclear proteins, including nitration, acetylation, and carbonylation. Additionally, it alleviated hyperalgesia and allodynia. These findings underscore the therapeutic potential of polyphenols like BPF in reducing oxidative stress and inflammation-driven pain. By activating SIRT1, BPF may provide relief for pain conditions. Further research on SIRT1-targeted therapies is essential to combat inflammation and oxidative stress, preventing chronic conditions and enhancing treatment options.