Department of Urology, Jing'an District Central Hospital, Fudan University, Shanghai 200040, China.
Department of Urology, Tianjin Medical University General Hospital, Tianjin Medical University 300070 Tianjin, China; Department of Urology, Jing'an District Central Hospital, Fudan University, Shanghai 200040, China.
Neurobiol Dis. 2020 Jul;140:104814. doi: 10.1016/j.nbd.2020.104814. Epub 2020 Feb 19.
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.
小胶质细胞诱导的神经炎症在神经退行性疾病（包括阿尔茨海默病、帕金森病和多发性硬化症）的发病机制和进展中起着至关重要的作用。雄激素（包括睾酮及其代谢物二氢睾酮（DHT））的神经保护作用在这些疾病中得到了越来越多的证实，但很少有研究调查雄激素对神经炎症的影响。本研究探讨了 DHT 在脂多糖（LPS）诱导的神经炎症、神经元损伤和行为功能障碍中的作用及其潜在机制。我们发现，DHT 通过抑制 TLR4 介导的 NF-κB 和 MAPK p38 信号通路，抑制 LPS 诱导的促炎因子（包括 TNF-α、IL-1β、IL-6；iNOS、COX-2、NO 和 PGE2）的释放，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伤。在 LPS 诱导的神经炎症小鼠模型中，通过去势导致内源性 DHT 耗竭，通过增加 TLR4 介导的 NF-κB 和 MAPK 通路的激活，上调血清和大脑中 TNF-α、IL-1β、IL-6、iNOS 和 COX-2 的水平，加剧炎症反应，但这些作用可被外源性 DHT 补充所恢复。此外，DHT 还调节大脑中抗炎细胞因子 IL-10 和 IL-13 的 mRNA 水平。此外，DHT 调节 LPS 处理的小鼠大脑中 Aβ、凋亡蛋白 caspase-3、Bcl-2 和 Bax 以及突触素的表达，以及神经元损伤。进一步的行为测试表明，DHT 改善 LPS 诱导的空间和学习障碍以及运动协调障碍，并部分改善 LPS 注射小鼠的运动活动。因此，本研究表明 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认知和行为功能的潜在治疗策略。
