The aim of the present study was to examine the neuroprotective potential of pioglitazone via activation of Nrf2/ARE-dependent HO-1 signaling pathway in chronic neuroinflammation and progressive neurodegeneration mouse model induced by lipopolysaccharide (LPS). After assessing spatial memory, anxiety and motor-coordination, TH+ neurons in substantia nigra (SN) were counted. The oxidative stress marker carbonyl protein levels and HO-1 enzyme activity were also evaluated. RT-qPCR was conducted to detect HO-1, Nrf2 and NF-κp65 mRNA expression levels and Nrf2 transcriptional activation of antioxidant response element (ARE) of HO-1 was investigated. Pioglitazone ameliorated LPS-induced dopaminergic neuronal loss, as well as mitigated neurobehavioral impairments. It enhanced Nrf2 mRNA expression, and augmented Nrf2/ARE-dependent HO-1 pathway activation by amplifying HO-1 mRNA expression. Moreover, it induced a significant decrease in NF-κB p65 mRNA expression, while reducing carbonyl protein levels and restoring the HO-1 enzyme activity. Interestingly, LPS induced Nrf2/antioxidant response element (ARE) of HO-1 activation, ultimately resulting in slight enhanced HO-1 mRNA expression. However, LPS elicited decrease in HO-1 enzyme activity. Zinc protoporphyrin-IX (ZnPPIX) administrated with pioglitazone abolished its effects in the LPS mouse model. The study results demonstrate that coordinated activation of Nrf2/ARE-dependent HO-1 pathway defense mechanism by the PPARγ agonist pioglitazone mediated its neuroprotective effects.

本研究的目的是在脂多糖（LPS）诱导的慢性神经炎症和进行性神经变性小鼠模型中检查吡格列酮通过激活 Nrf2/ARE 依赖性 HO-1 信号通路的神经保护潜力。在评估空间记忆、焦虑和运动协调性后，对黑质 (SN) 中的 TH+ 神经元进行了计数。还评估了氧化应激标记物羰基蛋白水平和 HO-1 酶活性。 RT-qPCR检测HO-1、Nrf2和NF-κp65 mRNA表达水平，并研究Nrf2对HO-1抗氧化反应元件（ARE）的转录激活。吡格列酮可改善 LPS 诱导的多巴胺能神经元损失，并减轻神经行为损伤。它增强 Nrf2 mRNA 表达，并通过放大 HO-1 mRNA 表达增强 Nrf2/ARE 依赖性 HO-1 通路激活。此外，它还诱导 NF-κB p65 mRNA 表达显着降低，同时降低羰基蛋白水平并恢复 HO-1 酶活性。有趣的是，LPS 诱导 HO-1 激活的 Nrf2/抗氧化反应元件 (ARE)，最终导致 HO-1 mRNA 表达轻微增强。然而，LPS 导致 HO-1 酶活性降低。锌原卟啉-IX (ZnPPIX) 与吡格列酮联合给药在 LPS 小鼠模型中消除了其作用。研究结果表明，PPARγ 激动剂吡格列酮协调激活 Nrf2/ARE 依赖性 HO-1 通路防御机制介导其神经保护作用。