Melatonin improves brain function in a model of chronic Gulf War Illness with modulation of oxidative stress, NLRP3 inflammasomes, and BDNF-ERK-CREB pathway in the hippocampus.
Melatonin improves brain function in a model of chronic Gulf War Illness with modulation of oxidative stress, NLRP3 inflammasomes, and BDNF-ERK-CREB pathway in the hippocampus.
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DOI：
10.1016/j.redox.2021.101973
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发表时间：
2021-07
期刊：
影响因子：
11.4
通讯作者：
Shetty AK
中科院分区：
文献类型：
--
作者：
Madhu LN;Kodali M;Attaluri S;Shuai B;Melissari L;Rao X;Shetty AK
持续的认知和情绪功能障碍是海湾战争疾病（GWI）退伍军人的主要CNS症状。本研究探讨了褪黑激素（MEL）在慢性GWI大鼠模型中改善认知和情绪功能的抗氧化、抗衰老和促认知作用的疗效。在暴露于GWI相关化学物质和应激后6个月，大鼠用溶剂或MEL（5、10、20、40和80 mg/kg）处理8周。行为测试显示接受载体的GWI大鼠的认知和情绪功能障碍，其与氧化应激升高、NRF 2、过氧化氢酶和线粒体复合物蛋白减少、星形胶质细胞肥大、具有NLRP 3炎性体的活化小胶质细胞、促炎细胞因子升高、神经发生减弱和海马中的突触丢失相关。10 mg/kg MEL缓解了简单和联想识别记忆功能障碍和快感缺失，同时沿着氧化应激降低、谷胱甘肽和复合物III增强以及NLRP 3炎性体、IL-18、TNF-α和IFN-γ减少。MEL在20 mg/kg下也使NRF 2和过氧化氢酶正常化，并增加小胶质细胞分支。此外，40 mg/kg MEL可减少星形胶质细胞肥大、活化小胶质细胞、NF-kB-NLRP 3-caspase-1信号传导、IL-1β、MCP-1和MIP-1α。此外，80 mg/kg的MEL激活了BDNF-ERK-CREB信号通路，增强了海马中的神经发生并减少了突触丢失，并改善了更复杂的海马依赖性认知功能。因此，MEL治疗对于改善慢性GWI大鼠模型中的认知和情绪功能是有效的，并且MEL的作用是剂量依赖性的。这项研究提供了MEL有望减轻慢性GWI退伍军人神经炎症、认知和情绪障碍的第一个证据。低剂量褪黑素可改善慢性GWI模型的认知记忆功能障碍和快感缺失。在慢性GWI模型中，中等剂量的褪黑激素改善了更复杂的认知功能。褪黑激素治疗减少了氧化应激，增强了GWI脑中的线粒体复合物蛋白。褪黑激素抑制GWI脑中的NLRP 3炎性体和促炎细胞因子。褪黑激素激活BDNF-ERK-CREB信号通路，增强GWI脑中的神经发生。
Persistent cognitive and mood dysfunction is the primary CNS symptom in veterans afflicted with Gulf War Illness (GWI). This study investigated the efficacy of melatonin (MEL) for improving cognitive and mood function with antioxidant, antiinflammatory, and pro-cognitive effects in a rat model of chronic GWI. Six months after exposure to GWI-related chemicals and stress, rats were treated with vehicle or MEL (5, 10, 20, 40, and 80 mg/kg) for eight weeks. Behavioral tests revealed cognitive and mood dysfunction in GWI rats receiving vehicle, which were associated with elevated oxidative stress, reduced NRF2, catalase and mitochondrial complex proteins, astrocyte hypertrophy, activated microglia with NLRP3 inflammasomes, elevated proinflammatory cytokines, waned neurogenesis, and synapse loss in the hippocampus. MEL at 10 mg/kg alleviated simple and associative recognition memory dysfunction and anhedonia, along with reduced oxidative stress, enhanced glutathione and complex III, and reduced NLRP3 inflammasomes, IL-18, TNF-α, and IFN-γ. MEL at 20 mg/kg also normalized NRF2 and catalase and increased microglial ramification. MEL at 40 mg/kg, in addition, reduced astrocyte hypertrophy, activated microglia, NF-kB-NLRP3-caspase-1 signaling, IL-1β, MCP-1, and MIP-1α. Moreover, MEL at 80 mg/kg activated the BDNF-ERK-CREB signaling pathway, enhanced neurogenesis and diminished synapse loss in the hippocampus, and improved a more complex hippocampus-dependent cognitive function. Thus, MEL therapy is efficacious for improving cognitive and mood function in a rat model of chronic GWI, and MEL's effect was dose-dependent. The study provides the first evidence of MEL's promise for alleviating neuroinflammation and cognitive and mood impairments in veterans with chronic GWI. A low dose of Melatonin alleviated recognition memory dysfunction and anhedonia in a model of chronic GWI. A moderate dose of Melatonin improved more complex cognitive function in a model of chronic GWI. Melatonin treatment reduced oxidative stress and enhanced mitochondrial complex proteins in the GWI brain. Melatonin inhibited NLRP3 inflammasomes and proinflammatory cytokines in the GWI brain. Melatonin activated the BDNF-ERK-CREB signaling pathway and enhanced neurogenesis in the GWI brain.
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影响因子：
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