Abstract：
This determination of the mitochondrial effect of pharmacologically different antidepressants (agomelatine, ketamine and vortioxetine) was evaluated and quantified in vitro in pig brain-isolated mitochondria. We measured the activity of mitochondrial complexes, citrate synthase, malate dehydrogenase and monoamine oxidase, and the mitochondrial respiratory rate. Total hydrogen peroxide production and ATP production were assayed. The most potent inhibitor of all mitochondrial complexes and complex I-linked respiration was vortioxetine. Agomelatine and ketamine inhibited only complex IV activity. None of the drugs affected complex II-linked respiration, citrate synthase or malate dehydrogenase activity. Hydrogen peroxide production was mildly increased by agomelatine, which might contribute to increased oxidative damage and adverse effects at high drug concentrations. Vortioxetine significantly reduced hydrogen peroxide concentrations, which might suggest antioxidant mechanism activation. All tested antidepressants were partial MAO-A inhibitors, which might contribute to their antidepressant effect. We observed vortioxetine-induced MAO-B inhibition, which might be linked to decreased hydrogen peroxide formation and contribute to its procognitive and neuroprotective effects. Mitochondrial dysfunction could be linked to the adverse effects of vortioxetine, as vortioxetine is the most potent inhibitor of mitochondrial complexes and complex I-linked respiration. Clarifying the molecular interaction between drugs and mitochondria is important to fully understand their mechanism of action and the connection between their mechanisms and their therapeutic and/or adverse effects.
摘要：
药理学上不同的抗抑郁药（阿戈美拉汀，氯胺酮和沃替西汀）在猪脑分离的线粒体中进行了体外评估和定量。我们测量了线粒体复合物的活性，柠檬酸合成酶，苹果酸脱氢酶和单胺氧化酶，和线粒体呼吸频率。测定总过氧化氢产量和ATP产量。所有线粒体复合物和复合物I相关呼吸中最有效的抑制剂是沃替西汀。阿戈美拉汀和氯胺酮仅抑制复合物IV活性。这些药物都没有影响复杂的II相关呼吸，柠檬酸合酶或苹果酸脱氢酶活性。阿戈美拉汀轻度增加了过氧化氢的产量，这可能有助于在高药物浓度下增加氧化损伤和不良反应。沃替西汀显著降低过氧化氢浓度，这可能表明抗氧化机制活化。所有测试的抗抑郁药都是部分MAO-A抑制剂，这可能有助于他们的抗抑郁作用。我们观察到沃替西汀诱导的MAO-B抑制，这可能与减少过氧化氢的形成有关，并有助于其促认知和神经保护作用。线粒体功能障碍可能与沃替西汀的不良反应有关，因为沃替西汀是线粒体复合物和复杂的I相关呼吸的最有效抑制剂。阐明药物与线粒体之间的分子相互作用对于充分了解它们的作用机制以及它们的机制与它们的治疗和/或不良反应之间的联系非常重要。
