Research Institute for Marine Nutrition and Drugs, College of Food Science and Technology, Guangdong Ocean University, Zhanjiang 524088, China.
Department of Neurology, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Mainz, Germany.
Eur J Pharmacol. 2019 May 5;850:64-74. doi: 10.1016/j.ejphar.2019.01.024. Epub 2019 Jan 24.
While MPP may not directly activate microglia, the initial neuronal damage inflicted by the toxin may trigger microglia, possibly leading to synergistic pro-apoptotic interaction between neuro-inflammation and toxin-induced neurotoxicity, which may further aggravate neurodegeneration. However, what molecular targets are synergistically up or downregulated during this interaction is not well understood. Here, we addressed this by co-culturing fully differentiated human SH-SY5Y cells treated with parkinsonian toxin 1-Methyl-4-phenylpyridinium (MPP), with endotoxin-activated microglial cell line EOC 20 to determine how this interaction affects pro-apoptotic (p38, JNK, and bax:bcl2 ratios) and pro-survival (NF-κB, MEK1) signaling at both mRNA and protein levels. Concurrent MPP and endotoxin-treatment aggravated a decrease in SH-SY5Y cell viability and caused strong synergistic increases in the bax:bcl2 ratio, but also NF-κB and JNK signaling. These effects were attenuated by microglia inhibitor minocycline. Altogether, these data provide further molecular insights into the important role or even conditional requirement of microglia activation in the progressive neurodegenerative nature of PD.
虽然 MPP 可能不会直接激活小胶质细胞，但毒素最初对神经元造成的损伤可能会触发小胶质细胞，从而导致神经炎症和毒素诱导的神经毒性之间可能协同的促凋亡相互作用，这可能进一步加重神经退行性变。然而，在这种相互作用中哪些分子靶标协同上调或下调还不是很清楚。在这里，我们通过共培养用帕金森病毒素 1-甲基-4-苯基吡啶（MPP）处理的完全分化的人 SH-SY5Y 细胞与内毒素激活的小胶质细胞系 EOC 20 来解决这个问题，以确定这种相互作用如何影响促凋亡（p38、JNK 和 bax:bcl2 比值）和促存活（NF-κB、MEK1）信号在 mRNA 和蛋白质水平上的影响。同时用 MPP 和内毒素处理加重了 SH-SY5Y 细胞活力的下降，并导致 bax:bcl2 比值的强烈协同增加，但 NF-κB 和 JNK 信号也增加。这些作用被小胶质细胞抑制剂米诺环素减弱。总的来说，这些数据为小胶质细胞激活在 PD 的进行性神经退行性变中的重要作用甚至条件性要求提供了进一步的分子见解。
