Recently, depression has been identified as a prevalent and severe mental disorder. However, the mechanisms underlying the depression risk remain elusive. The neuroinflammation and NLRP3 inflammasome activation are known to be involved in the pathology of depression. Dihydrolipoic acid (DHLA) has been reported as a strong antioxidant and exhibits anti-inflammatory properties in various diseases, albeit the direct relevance between DHLA and depression is yet unknown. The present study aimed to investigate the preventive effect and potential mechanism of DHLA in the lipopolysaccharide (LPS)-induced sickness behavior in rats. Adult male Sprague–Dawley rats were utilized. LPS and DHLA were injected intraperitoneally every 2 days and daily, respectively. Fluoxetine (Flu) was injected intraperitoneally daily. PD98059, an inhibitor of ERK, was injected intraperitoneally 1 h before DHLA injection daily. Small interfering ribonucleic acid (siRNA) for nuclear factor erythroid 2-like (Nrf2) was injected into the bilateral hippocampus 14 days before the DHLA injection. Depression-like behavior tests were performed. Western blot and immunofluorescence staining detected the ERK/Nrf2/HO-1/ROS/NLRP3 pathway-related proteins. The DHLA and fluoxetine treatment exerted preventive effects in LPS-induced sickness behavior rats. The DHLA treatment increased the expression of ERK, Nrf2, and HO-1 but decreased the ROS generation levels and reduced the expression of NLRP3, caspase-1, and IL-1β in LPS-induced sickness behavior rats. PD98059 abolished the effects of DHLA on preventive effect as well as the levels of Nrf2 and HO-1 proteins. Similarly, Nrf2 siRNA reversed the preventive effect of DHLA administration via the decreased expression of HO-1. These findings suggested that DHLA exerted a preventive effect via ERK/Nrf2/HO-1/ROS/NLRP3 pathway in LPS-induced sickness behavior rats. Thus, DHLA may serve as a potential therapeutic strategy for depression.

中文翻译：

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二氢硫辛酸可通过调节大鼠Nrf2 / HO-1 / NLRP3信号传导来预防脂多糖诱导的行为缺陷和神经炎症。

最近，抑郁症已被确定为一种普遍的严重精神障碍。但是，抑郁风险的潜在机制仍然难以捉摸。已知神经发炎和NLRP3炎症小体激活与抑郁症的病理过程有关。二氢硫辛酸（DHLA）被认为是一种强抗氧化剂，在多种疾病中均表现出抗炎特性，尽管DHLA与抑郁症之间的直接相关性尚不清楚。本研究旨在探讨DHLA在脂多糖（LPS）诱导的大鼠疾病行为中的预防作用和潜在机制。使用成年雄性Sprague–Dawley大鼠。LPS和DHLA分别每2天和每天腹膜内注射一次。每天腹膜内注射氟西汀（Flu）。PD98059，ERK抑制剂，每天DHLA注射前1小时腹膜内注射。在DHLA注射前14天，将双核海马2样核因子（Nrf2）的小干扰核糖核酸（siRNA）注射到双侧海马中。进行了类似抑郁症的行为测试。免疫印迹和免疫荧光染色检测到ERK / Nrf2 / HO-1 / ROS / NLRP3途径相关蛋白。DHLA和氟西汀治疗对LPS诱发的疾病行为大鼠具有预防作用。DHLA处理在LPS诱发的疾病行为大鼠中增加ERK，Nrf2和HO-1的表达，但降低ROS生成水平并降低NLRP3，caspase-1和IL-1β的表达。PD98059取消了DHLA的预防作用以及Nrf2和HO-1蛋白的水平。同样，Nrf2 siRNA通过减少HO-1的表达逆转了DHLA的预防作用。这些发现表明，DHLA在LPS诱导的疾病行为大鼠中通过ERK / Nrf2 / HO-1 / ROS / NLRP3途径发挥了预防作用。因此，DHLA可作为抑郁症的潜在治疗策略。