Department of Pharmacology and Pharmacotherapy, Semmelweis University, Nagyvarad ter 4, 1089 Budapest, Hungary.
Int J Mol Sci. 2023 Aug 28;24(17):13334. doi: 10.3390/ijms241713334.
Selegiline and rasagiline are two selective monoamine oxidase B (MAO-B) inhibitors used in the treatment of Parkinson's disease. In their clinical application, however, differences in L-dopa-sparing potencies have been observed. The aim of this study was to find neurochemical and behavioral explanations for the antiparkinsonian effects of these drugs. We found that selegiline possesses a dopaminergic enhancer effect: it stimulated the electrically induced [H]dopamine release without influencing the resting [H]dopamine release from rat striatal slices in 10-10 mol/L concentrations. Rasagiline added in 10 to 10 mol/L concentrations did not alter the resting or electrically stimulated [H]dopamine release. Rasagiline (10 mol/L), however, suspended the stimulatory effect of selegiline on the electrically induced [H]dopamine release. The trace amine-associated receptor 1 (TAAR1) antagonist EPPTB (10-10 mol/L) also inhibited the stimulatory effect of selegiline on [H]dopamine release. The effect of selegiline in its enhancer dose (5.33 nmol/kg) against tetrabenazine-induced learning deficit measured in a shuttle box apparatus was abolished by a 5.84 nmol/kg dose of rasagiline. The selegiline metabolite (-)methamphetamine (10 mol/L) also exhibited enhancer activity on [H]dopamine release. We have concluded that selegiline acts as an MAO-B inhibitor and a dopaminergic enhancer drug, and the latter relates to an agonist effect on TAAR1. In contrast, rasagiline is devoid of enhancer activity but may act as an antagonist on TAAR1.
司来吉兰和雷沙吉兰是两种用于治疗帕金森病的选择性单胺氧化酶 B（MAO-B）抑制剂。然而，在它们的临床应用中，已经观察到 L-多巴节省效力的差异。本研究的目的是为这些药物的抗帕金森作用找到神经化学和行为学的解释。我们发现司来吉兰具有多巴胺能增强作用：它在 10-10 mol/L 浓度下刺激电诱导的 [H]多巴胺释放，而不影响大鼠纹状体切片中静息的 [H]多巴胺释放。以 10 至 10 mol/L 浓度添加的雷沙吉兰不会改变静息或电刺激的 [H]多巴胺释放。然而，雷沙吉兰（10 mol/L）中止了司来吉兰对电诱导的 [H]多巴胺释放的刺激作用。微量胺相关受体 1（TAAR1）拮抗剂 EPPTB（10-10 mol/L）也抑制了司来吉兰对 [H]多巴胺释放的刺激作用。在穿梭箱装置中测量的噻苯哒嗪诱导的学习缺陷中，司来吉兰在增强剂量（5.33 nmol/kg）下的作用被 5.84 nmol/kg 剂量的雷沙吉兰所消除。司来吉兰代谢物（-）甲基苯丙胺（10 mol/L）也表现出对 [H]多巴胺释放的增强活性。我们得出结论，司来吉兰作为 MAO-B 抑制剂和多巴胺能增强药物起作用，后者与 TAAR1 的激动剂作用有关。相比之下，雷沙吉兰没有增强活性，但可能作为 TAAR1 的拮抗剂起作用。
