Department of Physiology and Pharmacology, Faculty of Medicine, University of Salamanca, Salamanca, Spain.
Laboratory of Neuroendocrinology, Institute of Neurosciences of Castilla y León (INCyL), and Laboratory of Neuroendocrinology and Obesity, Institute of Biomedical Research of Salamanca (IBSAL), University of Salamanca, Salamanca, Spain.
J Physiol Biochem. 2023 May;79(2):415-425. doi: 10.1007/s13105-023-00950-8. Epub 2023 Feb 23.
The antidepressant drug opipramol has been reported to exert antilipolytic effect in human adipocytes, suggesting that alongside its neuropharmacological properties, this agent might modulate lipid utilization by peripheral tissues. However, patients treated for depression or anxiety disorders by this tricyclic compound do not exhibit the body weight gain or the glucose tolerance alterations observed with various other antidepressant or antipsychotic agents such as amitriptyline and olanzapine, respectively. To examine whether opipramol reproduces or impairs other actions of insulin, its direct effects on glucose transport, lipogenesis and lipolysis were investigated in adipocytes while its influence on insulin secretion was studied in pancreatic islets. In mouse and rat adipocytes, opipramol did not activate triglyceride breakdown, but partially inhibited the lipolytic action of isoprenaline or forskolin, especially in the 10-100 μM range. At 100 μM, opipramol also inhibited the glucose incorporation into lipids without limiting the glucose transport in mouse adipocytes. In pancreatic islets, opipramol acutely impaired the stimulation of insulin secretion by various activators (high glucose, high potassium, forskolin...). Similar inhibitory effects were observed in mouse and rat pancreatic islets and were reproduced with 100 μM haloperidol, in a manner that was independent from alpha2-adrenoceptor activation but sensitive to Ca release. All these results indicated that the anxiolytic drug opipramol is not only active in central nervous system but also in multiple peripheral tissues and endocrine organs. Due to its capacity to modulate the lipid and carbohydrate metabolisms, opipramol deserves further studies in order to explore its therapeutic potential for the treatment of obese and diabetic states.
抗抑郁药奥匹哌醇已被报道在人体脂肪细胞中具有抗脂解作用，这表明除了其神经药理学特性外，该药物还可能调节外周组织的脂质利用。然而，用这种三环化合物治疗抑郁症或焦虑症的患者并没有表现出与其他各种抗抑郁药或抗精神病药（如阿米替林和奥氮平）观察到的体重增加或葡萄糖耐量改变。为了检查奥匹哌醇是否复制或损害胰岛素的其他作用，在脂肪细胞中研究了其对葡萄糖转运、脂肪生成和脂肪分解的直接影响，而在胰岛中研究了其对胰岛素分泌的影响。在小鼠和大鼠脂肪细胞中，奥匹哌醇不会激活甘油三酯分解，但部分抑制异丙肾上腺素或 forskolin的脂肪分解作用，特别是在 10-100 μM 范围内。在 100 μM 时，奥匹哌醇还抑制了葡萄糖向脂质的掺入，而不会限制小鼠脂肪细胞中的葡萄糖转运。在胰岛中，奥匹哌醇急性损害了各种激活剂（高葡萄糖、高钾、 forskolin 等）刺激胰岛素分泌的作用。在小鼠和大鼠胰岛中观察到类似的抑制作用，并用 100 μM 氟哌啶醇复制，其方式独立于α2-肾上腺素能受体激活，但对 Ca 释放敏感。所有这些结果表明，抗焦虑药物奥匹哌醇不仅在中枢神经系统中活跃，而且在多种外周组织和内分泌器官中活跃。由于其调节脂质和碳水化合物代谢的能力，奥匹哌醇值得进一步研究，以探索其治疗肥胖和糖尿病状态的治疗潜力。
