State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Yantai University, Yantai, 264005, China.
Acta Pharmacol Sin. 2019 Aug;40(8):991-998. doi: 10.1038/s41401-018-0209-1. Epub 2019 Feb 6.
Olfactory bulb, as one of sensory organs opening to the outside, is susceptible to toxic environment and easy to deteriorate. Recent studies in Parkinson's disease (PD) patients and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys have shown that abnormal α-synuclein is accumulated in the olfactory glomeruli, suggesting that the lesions of PD are not only confined to the substantia nigra (SN) but also located in the olfactory bulb. Thus, olfactory bulb might be the region of onset in PD pathogenesis and a targeted region for diagnosis and treatment of PD. However, the relationship between olfactory bulb and pathogenesis of PD remains unclear. In the present study, we investigated the inflammatory pathological alterations in olfactory bulb and the underlying mechanisms in chronic MPTP mice. Mice were treated with MPTP/P, i.e., MPTP (25 mg/kg, s.c.) plus probenecid (250 mg/kg, i.p.) every 4 days, for ten times. The mice displayed typical parkinsonian syndrome. Then we examined their olfactory function and the pathologic changes in olfactory bulb. The mice showed obvious olfactory dysfunction in a buried pellet test. Immunohistochemical studies revealed that tyrosine hydroxylase (TH) protein levels were significantly decreased, whereas abnormal α-synuclein was significantly increased in the olfactory bulbs. Furthermore, the olfactory bulbs in MPTP/P-treated mice showed significantly increased levels of interleukin-1β (IL-1β), caspase-1, glial fibrillary acidic protein (GFAP), Toll receptor 4 (TLR4), phosphorylation of p65, as well as activated molecules of NOD-like receptor protein 3 (NLRP3) that were associated with neuroinflammation. Our results demonstrate that MPTP/P-caused olfactory bulb damage might be related to NLRP3-mediated inflammation.
嗅球作为与外界相通的感觉器官之一，易受到有毒环境的影响，且容易恶化。最近在帕金森病（PD）患者和 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）处理的猴子中的研究表明，异常的α-突触核蛋白在嗅球的嗅小球中积累，这表明 PD 的病变不仅局限于黑质（SN），还位于嗅球。因此，嗅球可能是 PD 发病机制的起始区域，也是 PD 诊断和治疗的靶向区域。然而，嗅球与 PD 发病机制之间的关系尚不清楚。在本研究中，我们研究了慢性 MPTP 小鼠嗅球的炎症性病理改变及其潜在机制。用 MPTP/P（即 MPTP（25mg/kg，皮下注射）+丙磺舒（250mg/kg，腹腔注射），每 4 天一次，共 10 次）处理小鼠，结果显示其出现典型的帕金森综合征。然后，我们检查了它们的嗅觉功能和嗅球的病理变化。在埋藏丸测试中，这些小鼠表现出明显的嗅觉功能障碍。免疫组织化学研究显示，嗅球中酪氨酸羟化酶（TH）蛋白水平显著降低，而异常的α-突触核蛋白显著增加。此外，MPTP/P 处理的小鼠嗅球中白细胞介素-1β（IL-1β）、半胱天冬酶-1、胶质纤维酸性蛋白（GFAP）、Toll 样受体 4（TLR4）、p65 的磷酸化以及与神经炎症相关的 NOD 样受体蛋白 3（NLRP3）激活分子的水平显著升高。我们的研究结果表明，MPTP/P 引起的嗅球损伤可能与 NLRP3 介导的炎症有关。
