Jones Emily J, Skinner Benjamin M, Parker Aimee, Baldwin Lydia R, Greenman John, Carding Simon R, Funnell Simon G P
Food, Microbiome and Health Research Programme, Quadram Institute, Norwich, United Kingdom.
School of Life Sciences, University of Essex, Colchester, United Kingdom.
Biomicrofluidics. 2024 Sep 13;18(5):054105. doi: 10.1063/5.0200459. eCollection 2024 Sep.
The death of dopamine-producing neurons in the substantia nigra in the base of the brain is a defining pathological feature in the development of Parkinson's disease (PD). PD is, however, a multi-systemic disease, also affecting the peripheral nervous system and gastrointestinal tract (GIT) that interact via the gut-brain axis (GBA). Our dual-flow GIT-brain microphysiological system (MPS) was modified to investigate the gut-to-brain translocation of the neurotoxin trigger of PD, 1-methyl-4-phenylpyridinium (MPP), and its impact on key GIT and brain cells that contribute to the GBA. The modular GIT-brain MPS in combination with quantitative and morphometric image analysis methods reproduces cell specific neurotoxin-induced dopaminergic cytotoxicity and mitochondria-toxicity with the drug having no detrimental impact on the viability or integrity of cellular membranes of GIT-derived colonic epithelial cells. Our findings demonstrate the utility and capability of the GIT-brain MPS for measuring neuronal responses and its suitability for identifying compounds or molecules produced in the GIT that can exacerbate or protect against neuronal inflammation and cell death.
大脑基部黑质中产生多巴胺的神经元死亡是帕金森病（PD）发展过程中的一个决定性病理特征。然而，PD是一种多系统疾病，也会影响通过肠-脑轴（GBA）相互作用的外周神经系统和胃肠道（GIT）。我们对双流动GIT-脑微生理系统（MPS）进行了改进，以研究PD的神经毒素触发物1-甲基-4-苯基吡啶鎓（MPP）从肠道到大脑的转运，及其对有助于GBA的关键GIT和脑细胞的影响。模块化GIT-脑MPS与定量和形态计量图像分析方法相结合，再现了细胞特异性神经毒素诱导的多巴胺能细胞毒性和线粒体毒性，而该药物对源自GIT的结肠上皮细胞的细胞膜活力或完整性没有不利影响。我们的研究结果证明了GIT-脑MPS在测量神经元反应方面的实用性和能力，以及它在识别GIT中产生的可加剧或预防神经元炎症和细胞死亡的化合物或分子方面的适用性。
