Department of Structural and Functional Biology, Institute of Biosciences, UNESP - São Paulo State University, Botucatu, Brazil.
Department of Morphology, Stomatology and Physiology, USP - University of São Paulo, Ribeirão Preto, Brazil.
Basic Clin Pharmacol Toxicol. 2020 Dec;127(6):525-532. doi: 10.1111/bcpt.13467. Epub 2020 Jul 21.
Sibutramine is a non-selective serotonin-norepinephrine reuptake inhibitor orally administered for weight loss. In a previous study, we showed pharmacological mechanisms involved in the reduction of sperm quality and fertility of rats exposed for 30 days to this anorexigen in the light phase of the light-dark (l/d) cycle. It is already known that rodents are nightlife animals, with higher metabolic activity during the dark phase than in the light phase of the light-dark (l/d) cycle. Thus, the present study aimed to investigate whether the deleterious effects on reproductive parameters after sibutramine administration would be enhanced after a shorter period of exposure during the dark phase of the l/d cycle. For this, adult male Wistar rats were treated with sibutramine (10 mg/kg/d) or vehicle for 15 days during the dark phase of the l/d cycle. Sibutramine treatment decreased final body and reproductive organ weights, as well as serum testosterone levels. Sperm transit time through the epididymis was accelerated, and sperm concentration and motility were diminished in the sibutramine-exposed rats. The decrease in sperm concentration was also verified in the epididymal histological sections. In conclusion, the deleterious effects of sibutramine on reproductive parameters of male rats were enhanced when the exposure occurred in the dark phase of the l/d cycle, even after a short exposure duration. Our results reinforce the impact of timing on drug therapeutic action.
西布曲明是一种非选择性 5-羟色胺和去甲肾上腺素再摄取抑制剂，口服用于减肥。在之前的一项研究中，我们展示了这种厌食药在光照-黑暗（l/d）周期的光照阶段暴露 30 天后，对大鼠精子质量和生育能力下降所涉及的药理机制。已知啮齿动物是夜行性动物，其代谢活动在黑暗阶段比在光照-黑暗（l/d）周期的光照阶段更高。因此，本研究旨在探讨在 l/d 周期的黑暗阶段进行更短时间的暴露后，西布曲明给药对生殖参数的有害影响是否会增强。为此，成年雄性 Wistar 大鼠在 l/d 周期的黑暗阶段接受西布曲明（10mg/kg/d）或载体处理 15 天。西布曲明处理降低了终身体重和生殖器官重量，以及血清睾酮水平。精子通过附睾的转运时间加快，精子浓度和活力在暴露于西布曲明的大鼠中降低。在附睾组织学切片中也验证了精子浓度的降低。总之，即使暴露时间较短，当暴露发生在 l/d 周期的黑暗阶段时，西布曲明对雄性大鼠生殖参数的有害影响会增强。我们的结果强调了时间对药物治疗作用的影响。
