Zhao Zhe, Li Fangyuan, Ning Jingwen, Peng Ran, Shang Junmei, Liu Hui, Shang Meiyu, Bao Xiu-Qi, Zhang Dan
State Key Laboratory of Bioactive Substrate and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Acta Pharm Sin B. 2021 Sep;11(9):2859-2879. doi: 10.1016/j.apsb.2021.03.020. Epub 2021 Mar 13.
Parkinson's disease (PD) is the second most common neurodegenerative disease, but none of the current treatments for PD can halt the progress of the disease due to the limited understanding of the pathogenesis. In PD development, the communication between the brain and the gastrointestinal system influenced by gut microbiota is known as microbiota-gut-brain axis. However, the explicit mechanisms of microbiota dysbiosis in PD development have not been well elucidated yet. FLZ, a novel squamosamide derivative, has been proved to be effective in many PD models and is undergoing the phase I clinical trial to treat PD in China. Moreover, our previous pharmacokinetic study revealed that gut microbiota could regulate the absorption of FLZ . The aims of our study were to assess the protective effects of FLZ treatment on PD and to further explore the underlying microbiota-related mechanisms of PD by using FLZ as a tool. In the current study, chronic oral administration of rotenone was utilized to induce a mouse model to mimic the pathological process of PD. Here we revealed that FLZ treatment alleviated gastrointestinal dysfunctions, motor symptoms, and dopaminergic neuron death in rotenone-challenged mice. 16S rRNA sequencing found that PD-related microbiota alterations induced by rotenone were reversed by FLZ treatment. Remarkably, FLZ administration attenuated intestinal inflammation and gut barrier destruction, which subsequently inhibited systemic inflammation. Eventually, FLZ treatment restored blood-brain barrier structure and suppressed neuroinflammation by inhibiting the activation of astrocytes and microglia in the substantia nigra (SN). Further mechanistic research demonstrated that FLZ treatment suppressed the TLR4/MyD88/NF-B pathway both in the SN and colon. Collectively, FLZ treatment ameliorates microbiota dysbiosis to protect the PD model inhibiting TLR4 pathway, which contributes to one of the underlying mechanisms beneath its neuroprotective effects. Our research also supports the importance of microbiota-gut-brain axis in PD pathogenesis, suggesting its potential role as a novel therapeutic target for PD treatment.
帕金森病（PD）是第二常见的神经退行性疾病，但由于对其发病机制了解有限，目前针对PD的治疗方法均无法阻止疾病进展。在PD发展过程中，受肠道微生物群影响的大脑与胃肠道系统之间的交流被称为微生物群-肠道-脑轴。然而，PD发展过程中微生物群失调的具体机制尚未完全阐明。FLZ是一种新型的鳞状酰胺衍生物，已在许多PD模型中被证明有效，目前正在中国进行治疗PD的I期临床试验。此外，我们之前的药代动力学研究表明，肠道微生物群可以调节FLZ的吸收。我们研究的目的是评估FLZ治疗对PD的保护作用，并以FLZ为工具进一步探索PD潜在的微生物群相关机制。在本研究中，通过慢性口服鱼藤酮诱导小鼠模型以模拟PD的病理过程。在此我们发现，FLZ治疗可减轻鱼藤酮诱导的小鼠的胃肠功能障碍、运动症状和多巴胺能神经元死亡。16S rRNA测序发现，FLZ治疗可逆转鱼藤酮诱导的与PD相关的微生物群改变。值得注意的是，给予FLZ可减轻肠道炎症和肠道屏障破坏，并随后抑制全身炎症。最终，FLZ治疗通过抑制黑质（SN）中星形胶质细胞和小胶质细胞的激活，恢复了血脑屏障结构并抑制了神经炎症。进一步的机制研究表明，FLZ治疗在SN和结肠中均抑制了TLR4/MyD88/NF-κB通路。总体而言，FLZ治疗通过抑制TLR4通路改善微生物群失调，从而保护PD模型，这是其神经保护作用的潜在机制之一。我们的研究还支持了微生物群-肠道-脑轴在PD发病机制中的重要性，表明其作为PD治疗新靶点的潜在作用。
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