Ample evidence has pointed to a close link between cardiovascular diseases (CVD) and depression. Inflammatory pathways including the high-mobility-group-box-1 protein, receptor-for-advanced-glycation-end-products and toll-like-receptor-4 (HMGB1/RAGE/TLR4) and nucleotide-binding domain (NOD)–like receptor protein 3 (NLRP3) inflammasome pathways are thought to be crucial players in this link. Activation of these pathways ends by releasing of different inflammatory mediators involved in CVD and depression pathophysiology. In the brain, this inflammatory process enhanced indoleamine2,3-dioxygenase-1 (IDO-1) activation with subsequent alteration in kynurenine/tryptophan levels causing depression. Based on the favorable anti-inflammatory effects of Alirocumab, the proprotein-convertase-subtilisin/kexin-type-9 (PCSK9) inhibitor, used in different CVD, this study was designed to investigate its potential antidepressant effect. The behavioral and neurochemical effects of concomitant treatment of Alirocumab at doses of (4, 8 and 16 mg/kg/week subcutaneously) in Wistar rats exposed to chronic unpredictable mild stress (CUMS) for 6 weeks were assayed. Alirocumab prevented CUMS-induced depressive-like-behaviors exhibited in open-field and forced-swimming tests, and hypothalamus–pituitary–adrenal axis hyperactivity (adrenal gland weight and serum corticosterone). Alirocumab prevented CUMS-induced alteration in hippocampal kynurenine/tryptophan levels and pro-inflammatory cytokines tumor-necrosis-factor-alpha, interleukin-1beta (IL-1β), IL-2 and IL-6. Western blot and PCR analysis showed that Alirocumab favorably modulated the HMGB1/RAGE/TLR4 axis, nuclear-factor-kappa-beta, NLRP3 inflammasome complex and IDO-1 in the hippocampus of CUMS rats. These effects were correlated to the level of PCSK9 expression. The behavioral and biochemical findings indicated the potential antidepressant effect of PCSK9 inhibition by Alirocumab.

Graphical Abstract

中文翻译：

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PCSK9 抑制可减少 CUMS 暴露大鼠的抑郁样行为：HMGB1/RAGE/TLR4 通路、NLRP3 炎性体复合物和 IDO-1 的亮点

充足的证据表明心血管疾病（CVD）与抑郁症之间存在密切联系。炎症通路包括高迁移率组盒 1 蛋白、高级糖基化终末产物受体和 Toll 样受体 4 (HMGB1/RAGE/TLR4) 和核苷酸结合域 (NOD)–受体蛋白 3 (NLRP3) 等炎症小体通路被认为是这一环节的关键参与者。这些通路的激活最终会释放与 CVD 和抑郁症病理生理学相关的不同炎症介质。在大脑中，这种炎症过程增强了吲哚胺2,3-双加氧酶-1 (IDO-1) 的激活，随后犬尿氨酸/色氨酸水平发生变化，导致抑郁。基于Alirocumab（前蛋白转化酶枯草杆菌蛋白酶/kexin-9型（PCSK9）抑制剂）在不同CVD中的良好抗炎作用，本研究旨在探讨其潜在的抗抑郁作用。测定了暴露于慢性不可预测温和应激 (CUMS) 6 周的 Wistar 大鼠中阿利罗尤单抗 (4、8 和 16 mg/kg/周皮下注射) 联合治疗的行为和神经化学效应。Alirocumab 可预防 CUMS 诱导的旷场和强迫游泳测试中表现出的抑郁样行为，以及下丘脑-垂体-肾上腺轴过度活跃（肾上腺重量和血清皮质酮）。Alirocumab 可阻止 CUMS 诱导的海马犬尿氨酸/色氨酸水平以及促炎细胞因子肿瘤坏死因子-α、白介素-1β (IL-1β)、IL-2 和 IL-6 的变化。Western blot 和 PCR 分析显示，Alirocumab 有利地调节 CUMS 大鼠海马中的 HMGB1/RAGE/TLR4 轴、核因子-κ-β、NLRP3 炎性体复合物和 IDO-1。这些影响与 PCSK9 表达水平相关。行为和生化结果表明 Alirocumab 抑制 PCSK9 具有潜在的抗抑郁作用。

图形概要