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.

中文翻译：

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吡咯并喹啉醌及其酯衍生物对原代皮层神经元的神经毒性和细胞凋亡。

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疾病的潜力。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，在原代小鼠皮层神经元中检查了PQQ和PQQE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诱导的细胞凋亡涉及Bax的增加，Bcl-2的减少，线粒体细胞色素C释放到细胞质中，caspase-3的活化和PARP的裂解。一次小鼠脑内注射PQQ或PQQE表现出相似的结果。基于这些发现，高浓度的PQQ或PQQE治疗可以诱导广泛的神经毒性和细胞凋亡。在小鼠皮层神经元中，PQQ和PQQE的最低观察到的不良反应水平（LOAELs）分别为10μM和2μM，未观察到的不良反应水平（NOAELs）分别为5μM和1μM。