Microglia-induced neuroinflammation plays a vital role in the etiology and progression of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and multiple sclerosis. The neuroprotective role of androgens, including testosterone and its metabolite dihydrotestosterone (DHT), has been increasingly demonstrated in these diseases, but few studies investigated the effects of androgen on neuroinflammation. This study investigated the role of DHT in lipopolysaccharide (LPS)-induced neuroinflammation, neuronal damage and behavioral dysfunction, as well as underlying mechanisms. We showed that DHT inhibited LPS-induced release of proinflammatory factors, including TNF-α, IL-1β, IL-6; iNOS, COX-2, NO, and PGE2 in BV2 cells and primary microglia by suppressing the TLR4-mediated NF-κB and MAPK p38 signaling pathways, thus protecting SH-SY5Y neurons from inflammatory damage induced by activated microglia. In an LPS-induced neuroinflammation mouse model, endogenous DHT depletion by castration exacerbated inflammatory responses by upregulating the levels of TNF-α, IL-1β, IL-6, iNOS, and COX-2 in the serum and brain by increasing the LR4-mediated NF-κB and MAPK pathway activation, but these effects were restored by exogenous DHT supplementation. Moreover, DHT also regulated the mRNA levels of the anti-inflammatory cytokines IL-10 and IL-13 in the brain. In addition, DHT modulated the expression of Aβ, the apoptotic proteins caspase-3, Bcl-2, and Bax, and synaptophysin, as well as neuronal damage in LPS-treated mouse brains. Further behavioral tests revealed that DHT ameliorated LPS-induced spatial and learning impairment and motor incoordination, and partly improved the locomotor activity in LPS-injected mice. Therefore, this study suggests that DHT exerts anti-neuroinflammatory and neuroprotective effects; thus, androgen replacement therapy is a potential therapeutic strategy for improving cognitive and behavioral function in neuroinflammation-related diseases.

中文翻译：

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二氢睾丸激素在LPS诱导的神经炎症中的神经保护作用。

小胶质细胞引起的神经炎症在神经退行性疾病（包括阿尔茨海默氏病，帕金森氏病和多发性硬化症）的病因和进展中起着至关重要的作用。在这些疾病中越来越多地证明了雄激素的神经保护作用，包括睾丸激素及其代谢产物二氢睾丸激素（DHT），但很少有研究研究雄激素对神经炎症的影响。这项研究调查了DHT在脂多糖（LPS）诱导的神经炎症，神经元损伤和行为障碍以及潜在机制中的作用。我们发现DHT抑制LPS诱导的促炎因子（包括TNF-α，IL-1β，IL-6）的释放。通过抑制TLR4介导的NF-κB和MAPK p38信号通路，BV2细胞和原发性小胶质细胞中的iNOS，COX-2，NO和PGE2，从而保护SH-SY5Y神经元免受激活的小胶质细胞引起的炎症损害。在LPS诱发的神经炎症小鼠模型中，去势ration割引起的内源性DHT耗竭通过增加LR4上调血清和脑中TNF-α，IL-1β，IL-6，iNOS和COX-2的水平而加剧了炎症反应。介导的NF-κB和MAPK途径激活，但这些作用通过外源DHT补充得以恢复。此外，DHT还调节脑中抗炎细胞因子IL-10和IL-13的mRNA水平。此外，DHT调节了LPS处理的小鼠大脑中Aβ，凋亡蛋白caspase-3，Bcl-2和Bax的表达以及突触素的表达，以及神经元的损伤。进一步的行为测试表明，DHT改善了LPS引起的空间和学习障碍以及运动不协调，并部分改善了注射LPS的小鼠的运动活性。因此，这项研究表明DHT具有抗神经炎症和神经保护作用。因此，雄激素替代疗法是改善神经炎症相关疾病的认知和行为功能的潜在治疗策略。