Aalborg University, Department of Health Science and Technology, Aalborg, 9220, Denmark.
Aarhus University, Department of Clinical Medicine, Risskov, 8240, Denmark.
Sci Rep. 2017 May 19;7(1):2158. doi: 10.1038/s41598-017-02343-6.
Major depressive disorder is a complex and common mental disease, for which the pathology has not been elucidated. The purpose of this study is to provide knowledge about the importance of mitochondrial dysfunction, dysregulated lipid metabolism and inflammation. Mitochondrial carnitine palmitoyl transferase 1a (CPT1a) is a key molecule involved in lipid metabolism and mutations in CPT1a causing reduced function is hypothesized to have a protective role in the development of depression. Moreover, CPT1a is found to be upregulated in suicide patients with history of depression. Therefore, we hypothesized that inhibition of CPT1a activity can be developed as an innovative treatment strategy for depression. Stress exposure combined with different pharmacological treatment regimens; Etomoxir, CPT1 blocker, and Escitalopram, a favoured antidepressant drug, was applied in state-of-the-art chronic mild stress model. Etomoxir treatment induced statistical significant reduction of anhedonic behavior compared to vehicle treatment (p < 0.0001) and reversed depression-like phenotype in 90% of the rats (p = 0.0007), whereas Escitalopram only proved 57% efficacy. Moreover, Etomoxir revealed downregulation of interferon-γ, interleukin-17α and tumor necrosis factor-α. This indicate that alteration in metabolism is pivotal in the pathogenesis of depression, since CPT1 blockage is highly efficient in treating anhedonia and inflammation, thereby opening up for a novel class of antidepressant medication.
重度抑郁症是一种复杂且常见的精神疾病，其病理尚未阐明。本研究旨在提供有关线粒体功能障碍、脂质代谢失调和炎症的重要性的知识。线粒体肉碱棕榈酰转移酶 1a（CPT1a）是参与脂质代谢的关键分子，假设 CPT1a 功能降低的突变在抑郁症的发展中具有保护作用。此外，在有抑郁病史的自杀患者中发现 CPT1a 上调。因此，我们假设抑制 CPT1a 活性可以开发为治疗抑郁症的创新治疗策略。应激暴露结合不同的药物治疗方案；CPT1 抑制剂 Etomoxir 和抗抑郁药 Escitalopram 在最先进的慢性轻度应激模型中应用。与对照组相比，Etomoxir 治疗诱导快感缺失行为统计学显著减少（p<0.0001），并使 90%的大鼠（p=0.0007）的抑郁样表型逆转，而 Escitalopram 仅证明了 57%的疗效。此外，Etomoxir 显示干扰素-γ、白细胞介素-17α 和肿瘤坏死因子-α下调。这表明代谢改变在抑郁症的发病机制中至关重要，因为 CPT1 阻断在治疗快感缺失和炎症方面非常有效，从而为一类新的抗抑郁药物开辟了道路。
