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首页> 外文期刊>Neurochemistry International: The International Journal for the Rapid Publication of Critical Reviews, Preliminary and Original Research Communications in Neurochemistry >GluN2B-containing NMDA receptors as possible targets for the neuroprotective and antidepressant effects of fluoxetine
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GluN2B-containing NMDA receptors as possible targets for the neuroprotective and antidepressant effects of fluoxetine

机译：含GluN2B的NMDA受体可能是氟西汀的神经保护和抗抑郁作用的靶标

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摘要

Accumulating evidence has indicated the involvement of glutamatergic neurotransmission in the pathophysiology of excitotoxicity and in the mechanism of action of antidepressants. We have previously shown that tricyclic desipramine and the selective serotonin reuptake inhibitor fluoxetine inhibit NMDA receptors (NMDARs) in the clinically relevant, low micromolar concentration range. As the different subtypes of NMDARs are markedly different in their physiological and pathological functions, our aim was to investigate whether the effect of antidepressants is subtype-specific. Using whole-cell patch-clamp recordings in rat cortical cell cultures, we studied the age-dependence of inhibition of NMDA-induced currents after treatment with desipramine and fluoxetine, as the expression profile of the NMDAR subtypes changes as a function of days in vitro. We also investigated the inhibitory effect of these antidepressants on NMDA-induced currents in HEK 293 cell lines that stably expressed rat recombinant NMDARs with GluN1a/GluN2A or GluN1a/GluN2B subunit compositions. The inhibitory effect of desipramine was not age-dependent, whereas fluoxetine displayed a continuously decreasing inhibitory profile, which was similar to the GluN1/GluN2B subtype-selective antagonist ifenprodil. In HEK 293 cells, desipramine equally inhibited NMDA currents in both cell lines, whereas fluoxetine showed an inhibitory effect only in cells that expressed the GluN1/GluN2B subtype. Our data show that fluoxetine is a selective inhibitor of GluN2B-containing NMDARs, whereas desipramine inhibits both GluN1/GluN2A and GluN1/GluN2B subtypes. As the clinical efficacy of these drugs is very similar, the putative NMDAR-associated therapeutic effect of antidepressants may be mediated only via inhibition of the GluN2B-containing subtype. The manifestation of the GluN1/GluN2B-selectivity of fluoxetine suggests the neuroprotective potential for this drug in both acute and chronic neurodegenerative disorders.
机译：越来越多的证据表明，谷氨酸能神经传递与兴奋性毒性的病理生理以及抗抑郁药的作用机制有关。先前我们已经表明，三环地昔帕明和选择性5-羟色胺再摄取抑制剂氟西汀在临床相关的低微摩尔浓度范围内抑制NMDA受体（NMDARs）。由于不同类型的NMDAR的生理和病理功能明显不同，因此我们的目的是研究抗抑郁药的作用是否为亚型特异性。使用大鼠皮质细胞培养物中的全细胞膜片钳记录，我们研究了地昔帕明和氟西汀治疗后NMDA诱导的电流抑制的年龄依赖性，因为NMDAR亚型的表达谱随体外天数变化。我们还研究了这些抗抑郁药对稳定表达具有GluN1a / GluN2A或GluN1a / GluN2B亚基组成的大鼠重组NMDAR的HEK 293细胞系中NMDA诱导的电流的抑制作用。地昔帕明的抑制作用不是年龄依赖性的，而氟西汀显示出持续降低的抑制作用，类似于GluN1 / GluN2B亚型选择性拮抗剂艾芬地尔。在HEK 293细胞中，地昔帕明在两种细胞系中均均抑制NMDA电流，而氟西汀仅在表达GluN1 / GluN2B亚型的细胞中显示抑制作用。我们的数据表明，氟西汀是含GluN2B的NMDAR的选择性抑制剂，而地昔帕明同时抑制GluN1 / GluN2A和GluN1 / GluN2B亚型。由于这些药物的临床疗效非常相似，因此可能仅通过抑制含GluN2B的亚型来介导与NMDAR相关的抗抑郁药的治疗作用。氟西汀的GluN1 / GluN2B-选择性表现出该药物在急性和慢性神经退行性疾病中的神经保护潜力。

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