褪黑素对神经病理性疼痛诱发的情绪障碍的影响及抗炎和 抗凋亡机制
文献类型：学位论文
| 作者 | Mokhtari Tahmineh
|
| 答辩日期 | 2023-01 |
| 文献子类 | 博士 |
| 授予单位 | 中国科学院大学 |
| 授予地点 | 中国科学院心理研究所 |
| 其他责任者 | 胡理 |
| 关键词 | 慢性疼痛 抑郁 焦虑 神经炎症 NLRP3 炎症小体 细胞凋 亡 褪黑激素 |
| 学位名称 | 理学博士 |
| 学位专业 | 神经科学 |
| 其他题名 | Effects of melatonin on neuropathic pain-induced mood disorders and its anti-inflammatory and anti-apoptotic mechanisms |
| 中文摘要 | 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. |
| 英文摘要 | 背景：神经病理痛（NP）作为一种疼痛综合征，具有多种不同的临床表现，如异常性疼痛、痛觉过敏、自发性疼痛和多种感觉的异常。其中，高达 80% 的慢性疼痛患者还并发有有精神疾病，例如抑郁症和焦虑症。 NP被认为是一种慢性疾病，通常伴有情绪变化。含有核因子-B (NF-B)/NLR 家族 pyrin 结构域 3 (NLRP3) 轴在将应激反应转化为免疫系统反应方面发挥重要作用。相关研究发现，神经病理痛模型下，情绪调节的相关脑区中出现了神经炎症和细胞凋亡。最近的研究表明，具有抗氧化和抗炎特性的褪黑激素（MLT）可用于预防和治疗神经系统疾病。在本研究中，我们评估了褪黑激素对大鼠神经病理痛模型诱导的情感障碍（即焦虑和抑郁）的调节作用，以及其对相应脑区内细胞的抗凋亡和抗炎作用。 方法：成年雄性大鼠分为四组(n=13)，包括假手术组、褪黑素组（MLT）：即腹腔注射MLT（10mg/kg）， 慢性坐骨神经结扎组（CCI）：坐骨神经结扎术后+腹腔注射溶剂对照，以及CCI+MLT组：CCI术后两周给与褪黑激素。接下来，我们使用行为测试来评估疼痛感觉，焦虑和抑郁的严重程度。最后，对大鼠进行分子和组织病理学研究。 其中从以下方面探究了MLT所起的作用：1) 在第 0 天（手术前）、3、7、14 和 21 天通过热板试验 (HPT) 和丙酮滴试验 (ADT) 评估疼痛严重程度，2) 在第 22 至 26 天通过高架十字迷宫试验 (EPMT)，强迫游泳试验 (FST)、悬尾试验 (TST) 和旷场试验 (OFT) 评估焦虑和抑郁，3) 评估 NF-κB/NLRP3 轴成分，包括 NF-κB、NLRP3、以及凋亡相关蛋白，如 CARD (ASC) 和 Caspase-1 的激活程度，4) 细胞因子，包括白细胞介素 1 β (IL-1β) 和 IL-18，以及 5) 细胞凋亡和凋亡调节介质（Bax 和 Bcl2）在 前额叶皮层（PFC）和海马体（HC）的表达含量。 结果：行为测试显示，NP模型大鼠出现了情绪异常。 NP 通过上调 NF-ᴋB、NLRP3、ASC 和活性 Caspase-1 并提高前额叶皮层 (PFC) 和海马 (HC) 中细胞因子（IL1β 和 IL-18）的浓度来激活 NF-κB/NLRP3 炎性体通路。慢性疼痛条件下， Bax（促凋亡蛋白）被显著上调， Bcl2（抗凋亡蛋白）被显著下调，从而加速HC 和 PFC 中的细胞凋亡。 MLT 治疗显著消除了 NP 的影响，表现为疼痛严重程度降低、情感障碍改善、NF-κB-NLRP3 炎性体通路正常化以及调节了HC 和 PFC 中细胞凋亡相关的细胞因子水平，即MLT 可通过逆转 Bax和 Bcl2的表达水平的异常，抑制细胞凋亡。 结论：我们的研究结果表明，动物暴露于慢性 NP 通过激活 NF-κB/NLRP3 轴和 HC 和 PFC 中凋亡调节介质的失调来诱导情绪改变。 MLT 对NP 诱导的焦虑和抑郁样行为中的挽救作用可能是由其抗凋亡和抗炎特性介导的。 |
| 语种 | 中文 |
| 源URL | [http://ir.psych.ac.cn/handle/311026/44832]  |
| 专题 | 心理研究所_认知与发展心理学研究室 |
| 推荐引用方式 GB/T 7714 | Mokhtari Tahmineh. 褪黑素对神经病理性疼痛诱发的情绪障碍的影响及抗炎和 抗凋亡机制[D]. 中国科学院心理研究所. 中国科学院大学. 2023. |
入库方式： OAI收割
来源：心理研究所
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