This is a free paper and could have a lot of effect on pain management in the future. I just hope that we will soon know if ATH434 will have an effect on Sirtuin 3. If mitochondria work better and produce more NAD, most likely there will be more sirtuin 3.
Sara Ilari et al in Pharmacol Res, May 2020
Antioxidant Modulation of Sirtuin 3 During Acute Inflammatory Pain: The ROS Control
Abstract
Oxidative stress induced post-translational protein modifications are associated with the development of inflammatory hypersensitivities. At least 90% of cellular reactive oxygen species (ROS) are produced in the mitochondria, where the mitochondrial antioxidant, manganese superoxide dismutase (MnSOD), is located. MnSOD's ability to reduce ROS is enhanced by the mitochondrial NAD+-dependent deacetylase sirtuin (SIRT3). SIRT3 can reduce ROS levels by deacetylating MnSOD and enhancing its ability to neutralize ROS or by enhancing the transcription of MnSOD and other oxidative stress-responsive genes. SIRT3 can be post-translationally modified through carbonylation which results in loss of activity. The contribution of post-translational SIRT3 modifications in central sensitization is largely unexplored. Our results reveal that SIRT3 carbonylation contributes to spinal MnSOD inactivation during carrageenan-induced thermal hyperalgesia in rats. Moreover, inhibiting ROS with natural and synthetic antioxidants, prevented SIRT3 carbonylation, restored the enzymatic activity of MnSOD, and blocked the development of thermal hyperalgesia. These results suggest that therapeutic strategies aimed at inhibiting post-translational modifications of SIRT3 may provide beneficial outcomes in pain states where ROS have been documented to play an important role in the development of central sensitization.In conclusion, our data identify mitochondrial dysfunction as crucial player in the pathogenesis of inflammatory pain.
We demonstrate, for the first time, that SIRT3 carbonylation contributes to spinal MnSOD inactivation during carrageenan-induced thermal hyperalgesia in rats. Moreover, inhibiting ROS with antioxidants prevented SIRT3 carbonylation, restored the enzymatic activity of MnSOD and blocked the development of pain. These results suggest that therapeutic strategies aimed at inhibiting post-translational modifications of SIRT3 may provide beneficial outcomes in pain states where ROS have been documented to play an important role in the development of central sensitization. Restoring mitochondrial sirtuins pathway may also represent an innovative approach for therapeutic intervention in specific patient populations in rehabilitation treatment who present with inflammatory pain.
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