OBJECTIVE Letrozole, a next-generation aromatase inhibitor, has become a favored drug for the treatment of breast cancer in postmenopausal women. Although letrozole is generally well tolerated, its adverse effects on the central nervous system have been reported. The present study aimed to assess the behavioural outcomes of letrozole administration in mice to determine its side effects. METHODS C57BL/6J female ovariectomized mice received administration of letrozole (2.5 mg/kg per day) or vehicle by gavage for 3 weeks. Behavioural tasks were used to assess anxiety, depression, as well as learning and memory in mice. RESULTS Letrozole-treated mice showed an increased latency to enter the inner area of the chamber on the third day of the open field test, and traveled a shorter distance in the open arms of the elevated plus maze. No significant difference was found in the light-dark box or forced swimming task between letrozole-treated and vehicle-treated mice. Besides, letrozole did not change the spontaneous alternation behaviour of mice in the Y-maze. In the Morris water maze, mice administered with letrozole exhibited an improvement in spatial learning and memory compared with the vehicle-treated mice. CONCLUSION Our results indicate that the inhibition of oestrogen biosynthesis results in mild anxious behaviour, which may be a consideration in the treatment of breast cancer in postmenopausal women using aromatase inhibitors.
目的: 来曲唑作为新一代芳香化酶抑制剂已广泛用于治疗妇女绝经后的乳腺癌。 虽然来曲唑治疗具有良好的耐受性, 但其对中枢神经系统的副作用还需要更多的研究。
方法: 将卵巢摘除的C57BL/6J雌性小鼠每天给予来曲唑(2.5 mg/kg)或赋形剂灌胃处理, 共持续3周。 给药结束后, 对小鼠自主运动、探索、焦虑、抑郁以及学习和记忆行为进行分析。
结果: 与对照小鼠相比, 来曲唑处理小鼠的体重显著增加, 海马组织匀浆中的雌激素水平显著降低。 旷场实验中, 来曲唑处理小鼠在第3天任务中进入旷场中央区域的潜伏期显著增长。 高架十字迷宫中, 来曲唑处理小鼠在开放臂上运动距离变短。 在明暗箱、强迫游泳和Y-迷宫任务中, 来曲唑处理小鼠行为未有显著改变。 在Morris水迷宫中, 来曲唑给药小鼠的空间学习和记忆能力有所提高。
结论: 系统性芳香化酶抑制剂降低了小鼠中枢神经系统中雌激素的含量, 并且导致了焦虑样行为的增加, 提示使用芳香化酶抑制剂治疗乳腺癌可能对中枢神经系统产生副作用。