Abstract
Neuropathic pain is a chronic painful disease. Data have shown that reactive oxygen species (ROS) are implicated in chronic pain. Particularly, the enhanced ROS production alters the mitochondrial genome and proteome through the accumulation of lipid peroxidation products, such as 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA). Sirtuin 3 (SIRT3) is a mitochondrial protein and its activity can reduce ROS levels by modulating key antioxidant enzymes, such as manganese superoxide dismutase (MnSOD). Here, we evaluated the role of SIRT3 in the maintenance of basal levels of ROS in a model of chronic constriction injury (CCI) of the sciatic nerve and the protective effects of a natural antioxidant, the bergamot polyphenolic fraction (BPF). Rats were exposed to CCI of the sciatic nerve in the presence or absence of BPF (25–75 mg/kg). Level of acetylation, post-translational modulation on cysteine residues of proteins by HNE and SIRT3 activation, were detected in the spinal cord through western blotting, WES methodology and enzymatic assays. Our results reported that SIRT3 carbonylation and therefore its inactivation contributes to mitochondrial MnSOD hyperacetylation during CCI induced neuropathic pain in rats. In particular, we have demonstrated a close relation between oxidative stress, hyperalgesia, allodynia and sirtuins inactivation reverted by BPF administration.
Highlights
Neuropathic pain is the most common clinical manifestation of peripheral neuropathy, resulting from diabetes, infections, nerve-related diseases and drugs; the prevalence of neuropathic pain is almost 19% of adult Europeans [1,2,3,4].Peripheral nerve injuries are often the cause of the onset of persistent pain indicating a disease progression process, which can result in chronic pain [2]
It is well known that neuropathic pain produces thermal hyperalgesia and allodynia contributing to the development of reactive oxygen and nitrogen species (ROS; RNS) and cytokines, able to carry out oxidative, nitrosative and nitrative activities implicated in persistent pain states [9,10,11,12,13]
The Chronic Constriction Injury (CCI) model of peripheral nerve provides a model system to investigate the effectiveness of potential therapeutic agents to modify chronic neuropathic pain
Summary
Neuropathic pain is the most common clinical manifestation of peripheral neuropathy, resulting from diabetes, infections, nerve-related diseases and drugs; the prevalence of neuropathic pain is almost 19% of adult Europeans [1,2,3,4]. Removal of free radicals by natural or synthetic antioxidants blocks protein post-translational modification, attenuating the observed biochemical changes and preventing the development of pain [32,47,48,49] In this regard, it has been observed that polyphenols, such as resveratrol, bergamot, hydroxytyrosol and oleuropein, have strong antioxidant and anti-inflammatory properties [19,21,32,50,51]. The co-administration of morphine and BPF can be a good therapeutic approach for the treatment of chronic pain thanks to its ability to inhibit, in a dose-dependent manner, the development of tolerance preserving analgesic-morphine property [32] Based on these data, here, we propose that, in the chronic constriction injury (CCI) model of neuropathic pain, SIRT3 modifications can alter mitochondrial homeostasis contributing to the insurgence and maintenance of pain
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