Reboxetine, the first selective norepinephrine (NA) reuptake inhibitor used in the treatment of depression, mainly acts by binding to the NA transporter and blocking reuptake of extracellular NA. Recently, some other pharmacological targets beyond the NA transporter are being demonstrated for reboxetine. Peroxisome proliferator activated receptor α (PPARα) is a member of the nuclear hormone receptor family of ligand-dependent transcription factors. Previous reports have demonstrated the role of hippocampal PPARα in the pathophysiology of depression. Here we assume that hippocampal PPARα may participate in the antidepressant mechanism of reboxetine. Therefore, the chronic social defeat stress (CSDS) model of depression, various behavioral tests, the western blotting and adenovirus associated virus (AAV)-mediated genetic knockdown methods were used together in the present study. Our results showed that repeated reboxetine treatment markedly restored the decreasing effects of CSDS on the expression of hippocampal PPARα, brain-derived neurotrophic factor (BDNF) and phosphorylated cAMP response element binding protein (pCREB). Pharmacological blockade of PPARα notably prevented the antidepressant-like effects of reboxetine in the CSDS model. Furthermore, genetic knockdown of hippocampal PPARα also fully abolished the antidepressant-like effects of reboxetine in the CSDS model. Taken together, promoting the hippocampal PPARα expression participates in the antidepressant mechanism of reboxetine.

瑞波西汀是第一种用于治疗抑郁症的选择性去甲肾上腺素 (NA)再摄取抑制剂，主要通过与 NA 转运蛋白结合并阻断细胞外 NA 的再摄取而发挥作用。最近，正在证明瑞波西汀除了 NA 转运蛋白之外的一些其他药理学靶点。过氧化物酶体增殖物激活受体α（PPARα）是核激素受体配体依赖性转录因子家族。以前的报道已经证明了海马 PPARα 在抑郁症的病理生理学中的作用。在这里，我们假设海马 PPARα 可能参与瑞波西汀的抗抑郁机制。因此，抑郁症的慢性社交失败压力 (CSDS) 模型、各种行为测试、蛋白质印迹本研究同时使用了腺病毒相关病毒 (AAV) 介导的基因敲除方法。我们的结果表明，重复瑞波西汀治疗显着恢复了 CSDS 对海马 PPARα、脑源性神经营养因子 (BDNF) 和磷酸化 cAMP 反应元件结合蛋白 (pCREB) 表达的降低作用。PPARα的药理学阻断显着阻止了瑞波西汀在CSDS模型中的抗抑郁样作用。此外，海马 PPARα 的基因敲除也完全消除了瑞波西汀在 CSDS 模型中的抗抑郁样作用。总之，促进海马 PPARα 表达参与了瑞波西汀的抗抑郁机制。