Neuroprotection by dihydrotestosterone in LPS-induced neuroinflammation
Neuroprotection by dihydrotestosterone in LPS-induced neuroinflammation
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DOI：
10.1016/j.nbd.2020.104814
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发表时间：
2020-07-01
影响因子：
6.1
通讯作者：
Liu, Xiaoqiang
中科院分区：
文献类型：
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作者：
Yang, Lei;Zhou, Renyuan;Liu, Xiaoqiang
小胶质细胞诱导的神经炎症在神经退行性疾病的病因和进展中起着至关重要的作用，包括阿尔茨海默病、帕金森病和多发性硬化症。雄激素，包括睾酮及其代谢物双氢睾酮（DHT）的神经保护作用在这些疾病中得到越来越多的证明，但很少有研究调查雄激素对神经炎症的影响。本研究探讨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机制。我们发现DHT抑制lps诱导的促炎因子的释放，包括tnf - α、IL-1 β、IL-6；iNOS, COX-2， NO和PGE2通过抑制tlr4介导的NF-kappa B和MAPK p38信号通路，从而保护SH-SY5Y神经元免受活化小胶质细胞诱导的炎症损伤。在lps诱导的神经炎症小鼠模型中，去势引起的内源性DHT消耗通过增加lr4介导的NF-kappa B和MAPK通路的激活，通过上调血清和脑中tnf - α、IL-1 β、IL-6、iNOS和COX-2的水平，加剧了炎症反应，但这些作用通过补充外源性DHT恢复。此外，DHT还调节脑内抗炎细胞因子IL-10和IL-13的mRNA水平。此外，DHT可调节A β、凋亡蛋白caspase-3、Bcl-2、Bax和synaptophysin的表达以及lps处理小鼠脑内的神经元损伤。进一步的行为测试显示DHT改善了lps诱导的空间和学习障碍以及运动不协调，并部分改善了lps注射小鼠的运动活动。因此，本研究提示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。
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-alpha, IL-1 beta, IL-6; iNOS, COX-2, NO, and PGE2 in BV2 cells and primary microglia by suppressing the TLR4-mediated NF-kappa B 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-alpha, IL-1 beta, IL-6, iNOS, and COX-2 in the serum and brain by increasing the LR4-mediated NF-kappa B 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 A beta, 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.