Frizzo Marcos Emilio
Department of Morphological Sciences, Universidade Federal do Rio Grande do Sul, Rua Sarmento Leite, 500. CEP 90050-170, Porto Alegre, Brazil.
Curr Ther Res Clin Exp. 2017 Jul 8;87:9-12. doi: 10.1016/j.curtheres.2017.07.001. eCollection 2017.
Sertraline (Zoloft) and fluoxetine (Prozac) are selective serotonin reuptake inhibitors whose antidepressant mechanism of action is classically attributed to an elevation of the extracellular levels of serotonin in the synaptic cleft. However, the biological effects of these drugs seem to be more complex than their traditionally described mechanism of action. Among their actions is the inhibition of different types of Na and K channels, as well as of glutamate uptake activity. The clearance of extracellular glutamate is essential to maintain the central nervous system within physiological conditions, and this excitatory neurotransmitter is removed from the synaptic cleft by astrocyte transporters. This transport depends upon a hyperpolarized membrane potential in astrocytes that is mainly maintained by Kir4.1 K channels. The impairment of the Kir4.1 channel activity reduces driving force for the glutamate transporter, resulting in an accumulation of extracellular glutamate. It has been shown that sertraline and fluoxetine inhibit Kir4.1 K channels. Recently, we demonstrated that sertraline reduces glutamate uptake in human platelets, which contain a high-affinity Na-dependent glutamate uptake system, with kinetic and pharmacological properties similar to astrocytes in the central nervous system. Considering these similarities between human platelets and astrocytes, one might ask if sertraline could potentially reduce glutamate clearance in the synaptic cleft and consequently modulate glutamatergic transmission. This possibility merits investigation, since it may provide additional information regarding the mechanism of action and perhaps the side effects of these antidepressants.
舍曲林（左洛复）和氟西汀（百忧解）是选择性5-羟色胺再摄取抑制剂，其抗抑郁作用机制传统上被认为是由于突触间隙中细胞外5-羟色胺水平升高。然而，这些药物的生物学效应似乎比其传统描述的作用机制更为复杂。它们的作用包括抑制不同类型的钠和钾通道，以及谷氨酸摄取活性。细胞外谷氨酸的清除对于维持中枢神经系统在生理状态下至关重要，这种兴奋性神经递质通过星形胶质细胞转运体从突触间隙中清除。这种转运依赖于星形胶质细胞中主要由Kir4.1钾通道维持的超极化膜电位。Kir4.1通道活性的损害会降低谷氨酸转运体的驱动力，导致细胞外谷氨酸积累。已表明舍曲林和氟西汀会抑制Kir4.1钾通道。最近，我们证明舍曲林会降低人血小板中的谷氨酸摄取，人血小板含有一种高亲和力的钠依赖性谷氨酸摄取系统，其动力学和药理学特性与中枢神经系统中的星形胶质细胞相似。考虑到人类血小板和星形胶质细胞之间的这些相似性，有人可能会问舍曲林是否可能潜在地降低突触间隙中的谷氨酸清除，从而调节谷氨酸能传递。这种可能性值得研究，因为它可能提供有关这些抗抑郁药作用机制以及可能的副作用的更多信息。
