其他摘要 | Background: Neuropathic pain (NP) as a pain syndrome is characterized by different features such as allodynia, hyperalgesia, spontaneous pain and sensory abnormalities. Up to 80% of patients with chronic pain suffer from mental health disorders, e.g., depression and anxiety. NP is considered a chronic disease often accompanied by mood alterations. Nuclear factor-kappa B (NF-κB)/ NLR family pyrin domain containing 3 (NLRP3) axis plays an import role in converting stress responses into immune system responses. The roles of neuroinflammation and subsequent cell death in the critical regions of mood regulation have been investigated in NP models. Recent researches have revealed that melatonin (MLT) with antioxidant and anti-inflammatory features can be used to prevent and treat neurological disorders. In a preclinical study, we evaluated the anti-apoptotic and anti-inflammatory impacts of MLT on NP-induced affective disorders (i.e., anxiety & depression) in rats.
Methods: Adult male rats were separated into four groups (n=13) of sham, MLT: received MLT i.p. (10 mg/kg), chronic constrictive injury (CCI): nerve ligation received the vehicle, and CCI + MLT. MLT was administered for two weeks postoperatively. Next, we used behavioral tests to evaluate pain severity, anxiety, and depression. Finally, rats were scarified for molecular and histopathological studies. The effects of MLT on the following factors were examined: 1) pain severity through hot plate test (HPT) and an acetone drop test (ADT) on days 0 (before surgery), 3, 7, 14, and 21, 2) anxiety and depression through elevated plus maze test (EPMT), forced swimming test (FST), tail suspension test (TST), and open field test (OFT) on days 22 to 26, 3) activation of NF-κB/NLRP3 axis components, including NF-κB, NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC), and Caspase-1, 4) secretion of cytokines, including interleukin 1 beta (IL-1β) and IL-18, and 5) apoptosis and apoptotic regulatory mediators (Bax and Bcl2) in the prefrontal cortex (PFC) and hippocampus (HC).
Results: Behavioral tests revealed that the rats exposed to chronic NP developed emotional abnormalities. NP activated NF-ᴋB/NLRP3 inflammasome pathways by upregulating NF-κB, NLRP3, ASC, and active Caspase-1 and enhancing the concentrations of cytokines (IL1β and IL- 18) in the prefrontal cortex (PFC) and hippocampus (HC). Chronic pain significantly upregulated Bax (pro-apoptotic protein), downregulated Bcl2 (anti-apoptotic protein), and accelerated cell death via apoptosis in the HC and PFC. The treatment with MLT significantly eliminated the effects of NP, indicated by the reduced pain severity, improved affective disorders, normalized NF-κB-NLRP3 inflammasome pathways, and modulated levels of cytokines in the HC and PFC. MLT could promote cell survival from apoptosis by modulating Bax and Bcl2.
Conclusion: Our findings indicated that the exposure of animals to chronic NP induced the mood alterations via activation of NF-κB/NLRP3 axis and dysregulation of apoptotic regulatory mediators in the HC and PFC. The beneficial effects of MLT in NP-induced anxiety and depressive-like behaviors might be mediated by its anti-apoptotic and anti-inflammatory properties. |
修改评论