Electrophysiology Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran; Neuroscience and Addiction Studies Department, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Electrophysiology Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran; Neuroscience and Addiction Studies Department, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran; Cognitive and Behavioral Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran.
Neurobiol Learn Mem. 2020 Nov;175:107300. doi: 10.1016/j.nlm.2020.107300. Epub 2020 Aug 31.
Hippocampal aromatase is responsible for local synthesis of 17β-estradiol (E2) that has much higher concentrations than serum levels in males and females. Letrozole, an aromatase inhibitor, passes through the brain barriers, distributes to the brain, and affects local E2 synthesis. Here, the effects of intra-cerebroventricular (ICV) letrozole administration in the presence and absence of gonads were examined on the cognitive abilities of male and female rats.
Animals received intra-ICV injection of letrozole or vehicle for 14 consecutive days. Spatial working memory, novel object recognition memory, and anxiety-related behavior, were evaluated using Y-maze, object recognition test, and elevated plus maze, respectively. The E2 levels in the serum and hippocampal tissue were measured by the ELISA technique. RT-PCR was performed to assess the hippocampal estrogen receptors (ER) expression. Moreover, letrozole effect on neuronal activity of CA1 pyramidal neurons was studied by in vivo single-unit recording.
Letrozole (0.2, 0.4, and 0.8 µg) significantly decreased the hippocampal E2 levels compared to the vehicle group. Letrozole caused cognitive impairments in a dose-dependent manner in male and female rats in the presence or absence of gonads. Dose-response analysis revealed that the minimum effective dose of letrozole on the behavioral measures was 0.4 μg. Letrozole also caused an up-regulation of ERα and ERβ and a down-regulation of GPR30 gene expression. The firing rate of pyramidal neurons was reduced by letrozole in gonadal-intact animals.
The detrimental effects of letrozole treatment on cognitive abilities in the presence and absence of gonads indicate that local E2 synthesis in the hippocampus is a crucial factor in normal cognitive performance. The suppressive effect of letrozole on hippocampal neuronal firing might alter synaptic plasticity that is critical for memory formation. These data potentially suggest that memory deficits following letrozole administration should be monitored.
海马体芳香酶负责局部合成 17β-雌二醇（E2），其在雄性和雌性中的浓度远高于血清水平。来曲唑是一种芳香酶抑制剂，可穿透血脑屏障，分布到大脑，并影响局部 E2 合成。在这里，研究了在有性腺和无性腺的情况下，脑室内（ICV）给予来曲唑对雄性和雌性大鼠认知能力的影响。
动物连续 14 天接受 ICV 注射来曲唑或载体。使用 Y 迷宫、物体识别测试和高架十字迷宫分别评估空间工作记忆、新物体识别记忆和焦虑相关行为。通过 ELISA 技术测量血清和海马组织中的 E2 水平。通过 RT-PCR 评估海马雌激素受体（ER）的表达。此外，通过在体单细胞记录研究来曲唑对 CA1 锥体神经元活性的影响。
来曲唑（0.2、0.4 和 0.8μg）与载体组相比，显著降低了海马体 E2 水平。来曲唑在有性腺和无性腺的雄性和雌性大鼠中以剂量依赖的方式引起认知障碍。剂量反应分析表明，来曲唑对行为测量的最小有效剂量为 0.4μg。来曲唑还引起 ERα 和 ERβ 的上调和 GPR30 基因表达的下调。来曲唑在有性腺的动物中降低了锥体神经元的放电率。
来曲唑治疗对有性腺和无性腺大鼠认知能力的有害影响表明，海马体局部 E2 合成是正常认知表现的关键因素。来曲唑对海马神经元放电的抑制作用可能改变了对记忆形成至关重要的突触可塑性。这些数据可能表明，应监测来曲唑给药后出现的记忆缺陷。
