García-Fuster M Julia, García-Sevilla Jesús A
Neurobiology of Drug Abuse Group, IUNICS/IdISPa, University of the Balearic Islands, Cra. Valldemossa km 7.5, E-07122, Palma de Mallorca, Spain.
Redes Temáticas de Investigación Cooperativa en Salud-Red de Trastornos Adictivos (RETICS-RTA), ISCIII, Madrid, Spain.
Psychopharmacology (Berl). 2016 Aug;233(15-16):2955-71. doi: 10.1007/s00213-016-4342-6. Epub 2016 Jun 3.
Fas-associated death domain (FADD) is an adaptor of death receptors that can also induce anti-apoptotic actions through its phosphorylated form (p-FADD). Activation of monoamine receptors, indirect targets of classic anti-depressant drugs (ADs), reduced FADD and increased p-FADD and p-FADD/FADD ratio in brain.
To ascertain whether ADs, which indirectly regulate monoamine receptors, modulate FADD protein forms to promote anti-apoptotic actions.
The effects of selected norepinephrine transporter (NET), serotonin transporter (SERT), monoamine oxidase (MAO) inhibitors, atypical ADs, and electroconvulsive shock (ECS) or behavioral procedures (forced swim test, FST) on FADD forms and pro-survival FADD-like interleukin-1β-converting enzyme-inhibitory protein (FLIP-L) and phosphoprotein enriched in astrocytes of 15 kDa (p-PEA-15) contents were assessed in rat brain cortex by western blot analysis.
Acute NET (e.g., nisoxetine) but not SERT (e.g., fluoxetine) inhibitors decreased cortical FADD (up to 37 %) and increased p-FADD/FADD ratio (up to 1.9-fold). Nisoxetine effects were prevented by α2-antagonist RX-821002, suggesting the involvement of presynaptic α2-autoreceptors. Immobility time in the FST correlated with increases of pro-apoptotic FADD and decreases of anti-apoptotic p-FADD. The MAO-A/B inhibitor phenelzine decreased FADD (up to 33 %) and increased p-FADD (up to 65 %) and p-FADD/FADD (up to 2.4-fold). Other MAO inhibitors (clorgyline, Ro 41-1049, rasagiline), atypical ADs (ketamine and mirtazapine), or ECS did not modulate cortical FADD. Chronic (14 days) desipramine and fluoxetine, but not phenelzine, increased p-FADD (up to 59 %), p-FADD/FADD ratio (up to 1.8-fold), and pro-survival p-PEA-15 (up to 46 %) in rat brain cortex.
Multifunctional FADD protein, through an increased p-FADD/FADD ratio, could participate in the mechanisms of anti-apoptotic actions induced by ADs.
Fas相关死亡结构域（FADD）是死亡受体的衔接蛋白，其磷酸化形式（p-FADD）也可诱导抗凋亡作用。经典抗抑郁药（ADs）的间接靶点单胺受体激活后，可降低大脑中的FADD水平，增加p-FADD水平及p-FADD/FADD比值。
确定间接调节单胺受体的ADs是否通过调节FADD蛋白形式来促进抗凋亡作用。
通过蛋白质免疫印迹分析，评估所选去甲肾上腺素转运体（NET）、5-羟色胺转运体（SERT）、单胺氧化酶（MAO）抑制剂、非典型ADs以及电休克（ECS）或行为学程序（强迫游泳试验，FST）对大鼠大脑皮质中FADD形式、促生存的FADD样白细胞介素-1β转化酶抑制蛋白（FLIP-L）以及15 kDa富含星形胶质细胞的磷蛋白（p-PEA-15）含量的影响。
急性给予NET抑制剂（如尼索西汀）而非SERT抑制剂（如氟西汀）可降低皮质FADD水平（降低达37%），并增加p-FADD/FADD比值（增加达1.9倍）。α2拮抗剂RX-821002可阻断尼索西汀的作用，提示突触前α2自身受体参与其中。FST中的不动时间与促凋亡FADD的增加及抗凋亡p-FADD的减少相关。MAO-A/B抑制剂苯乙肼可降低FADD水平（降低达33%），增加p-FADD水平（增加达65%）及p-FADD/FADD比值（增加达2.4倍）。其他MAO抑制剂（氯吉兰、Ro 41-1049、雷沙吉兰）、非典型ADs（氯胺酮和米氮平）或ECS均未调节皮质FADD水平。慢性（14天）给予地昔帕明和氟西汀可增加大鼠大脑皮质中的p-FADD水平（增加达59%）、p-FADD/FADD比值（增加达1.8倍）以及促生存的p-PEA-15水平（增加达46%），但苯乙肼无此作用。
多功能FADD蛋白可通过增加p-FADD/FADD比值，参与ADs诱导的抗凋亡作用机制。
