NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, Jiangsu, 214063, China; Department of Radiopharmaceuticals, School of Pharmacy, Nanjing Medical University, Nanjing, Jiangsu, 211166, China.
NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, Jiangsu, 214063, China.
Neurotoxicology. 2020 May;78:47-56. doi: 10.1016/j.neuro.2020.02.005. Epub 2020 Feb 14.
Pyrroloquinoline quinone (PQQ) and its esterified derivative, PQQ ester (PQQE), have potential to treat or diagnose neurological and psychological disorders. However, their neurotoxicity remains unclear. To provide reference data for the brain targeting drug delivery techniques, the cytotoxic effects of PQQ and PQQE were examined in primary mouse cortical neurons. The results indicated that both PQQ and PQQE decreased neuron viability, reduced intracellular ATP level and disrupted the mitochondrial membrane potential in a concentration- and time-dependent manner, while PQQ was less potent than PQQE. PQQ and PQQE induced apoptosis involving increase of Bax, decrease of Bcl-2, release of mitochondrial cytochrome C into the cytosol, activation of caspase-3 and cleavage of PARP. A single mouse intracephalic injection of PQQ or PQQE showed similar results. Based on these findings, high-concentration PQQ or PQQE treatment could induce a wide range of neurotoxicity and apoptosis. The lowest observed adverse effect levels (LOAELs) of PQQ and PQQE were 10 μM and 2 μM respectively and the no observed adverse effect levels (NOAELs) were 5 μM and 1 μM respectively in mice cortical neurons.
吡咯并喹啉醌（PQQ）及其酯化衍生物 PQQ 酯（PQQE）具有治疗或诊断神经和心理障碍的潜力。然而，它们的神经毒性仍不清楚。为了为脑靶向药物递送技术提供参考数据，研究了 PQQ 和 PQQE 对原代小鼠皮质神经元的细胞毒性作用。结果表明，PQQ 和 PQQE 均以浓度和时间依赖性方式降低神经元活力，降低细胞内 ATP 水平并破坏线粒体膜电位，而 PQQ 的效力低于 PQQE。PQQ 和 PQQE 诱导涉及 Bax 增加、Bcl-2 减少、线粒体细胞色素 C 释放到细胞质、caspase-3 激活和 PARP 切割的细胞凋亡。单次向小鼠脑内注射 PQQ 或 PQQE 显示出类似的结果。基于这些发现，高浓度的 PQQ 或 PQQE 处理可能会引起广泛的神经毒性和细胞凋亡。在小鼠皮质神经元中，PQQ 和 PQQE 的最低观察到不良效应水平（LOAEL）分别为 10 μM 和 2 μM，未观察到不良效应水平（NOAEL）分别为 5 μM 和 1 μM。
