Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou 225001, PR China; Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou University, Yangzhou 225001, PR China; Jiangsu Co-Innovation Center for the Prevention and Control of Important Animal Infectious Diseases and Zoonoses, College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, PR China.
Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou 225001, PR China.
Toxicol Lett. 2020 Jun 1;325:1-13. doi: 10.1016/j.toxlet.2020.02.009. Epub 2020 Feb 20.
Olfaction is often affected in parkinsonian patients and its disturbances precede the classical cognitive and locomotor dysfunction. The olfactory bulb might be the region of onset in Parkinson's disease (PD) pathogenesis, evidenced by the presence of disease-related protein aggregates and disturbed olfactory information processing. However, the underlying molecular mechanism that governs the olfactory bulb impairments remains unclear. This study was designed to investigate the relationship between olfactory bulb and inflammatory pathological alterations and the potential mechanisms. Here we found that rotenone led to typical parkinsonian symptoms and decreased tyrosine hydroxylase (TH)-positive neurons in the olfactory bulb. Additionally, increased NF-κB nuclear translocation and NLRP3 inflammasome components expressions caused by rotenone injection were observed accompanied by the activation of microglia and astrocytes in the olfactory bulb. Rotenone also triggered Drp1-mediated mitochondrial fission and this in turn caused mitochondrial damage. Furthermore, Mdivi-1(a selective Drp1 inhibitor) markedly ameliorated the morphologic disruptions of mitochondria and Drp1 translocation, inhibited the nuclear translocation of NF-κB, eventually blocked the downstream pathway of the NLRP3/caspase-1/IL-1β axis and expression of iNOS. Overall, these findings suggest that Drp1-dependent mitochondrial fission induces NF-κB nuclear translocation and NLRP3 inflammasome activation that may further contribute to olfactory bulb disturbances.
嗅觉通常会受到帕金森病患者的影响，其障碍先于经典的认知和运动功能障碍出现。嗅球可能是帕金森病（PD）发病机制的起始区域，这一点可以从疾病相关蛋白聚集体的存在和嗅觉信息处理的紊乱得到证明。然而，支配嗅球损伤的潜在分子机制尚不清楚。本研究旨在探讨嗅球与炎症病理改变之间的关系及其潜在机制。在这里，我们发现鱼藤酮导致典型的帕金森病症状，并减少了嗅球中的酪氨酸羟化酶（TH）阳性神经元。此外，鱼藤酮注射导致 NF-κB 核易位和 NLRP3 炎性小体成分表达增加，同时嗅球中的小胶质细胞和星形胶质细胞被激活。鱼藤酮还触发了 Drp1 介导的线粒体裂变，这反过来又导致线粒体损伤。此外，Mdivi-1（一种选择性 Drp1 抑制剂）显著改善了线粒体形态破坏和 Drp1 易位，抑制了 NF-κB 的核易位，最终阻断了 NLRP3/caspase-1/IL-1β 轴的下游通路和 iNOS 的表达。总的来说，这些发现表明，Drp1 依赖性线粒体裂变诱导 NF-κB 核易位和 NLRP3 炎性小体的激活，这可能进一步导致嗅球障碍。
