Background

Chronic inorganic arsenic (iAs) exposure induces deleterious effects on CNS including oxidative stress, cognitive deficits and altered brain neurochemistry. Little is known about the association between iAs and estrogen receptor expression in brain regions.

Aims and objectives

Owing to the neuroprotective and estrogenic activities of resveratrol (RES), we examined the combined effects of arsenic trioxide (As₂O₃) and RES on neurobehavioural functions, estrogen signalling and associated neurochemical changes in mouse hippocampus.

Materials and methods

As₂O₃ alone (2 and 4 mg/kg bw) or along with RES (40 mg/kg bw) was administered orally for 45 days to adult female mice. From days 33 to 45, open field, elevated plus maze and Morris water maze tests were conducted to evaluate locomotion, anxiety and learning and memory. On day 46, animals were euthanized and brain tissue and hippocampi obtained therefrom were processed for atomic absorption spectrophotometry and western blotting respectively.

Results

As₂O₃ alone exposure resulted in enhanced anxiety levels, reduced locomotion and impaired learning and memory. As₂O₃-induced behavioural deficits were accompanied by downregulation of estrogen receptor (ERα) expression with a concomitant reduction of BDNF and NMDAR 2B levels in the hippocampus. However, the behavioural alterations and expression of these markers were restored in RES-supplemented mice. Moreover, a dose-dependent iAs accumulation was observed in serum and brain tissues of mice receiving As₂O₃ alone whereas simultaneous administration of As₂O₃ with RES facilitated iAs efflux.

Conclusions

These results suggest that reduced ERα expression with associated downregulation of BDNF and NMDAR 2B levels could be a mechanism by which iAs induces cognitive impairment; hence, the modulation of estrogen-NMDAR-BDNF pathway by RES represents a potential avenue to recover behavioural deficits induced by this neurotoxin.

Graphical abstract

中文翻译：

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白藜芦醇通过调节雌性小鼠海马中的雌激素-NMDAR-BDNF 信号通路减轻砷诱导的认知缺陷

背景

慢性无机砷 ( iAs ) 暴露会对 CNS 产生有害影响，包括氧化应激、认知缺陷和脑神经化学改变。关于iAs与大脑区域中雌激素受体表达之间的关联知之甚少。

目的和目标

由于白藜芦醇 (RES) 的神经保护和雌激素活性，我们检查了三氧化二砷 (As ₂ O ₃ ) 和 RES 对小鼠海马神经行为功能、雌激素信号传导和相关神经化学变化的综合影响。

材料和方法

将₂ O ₃单独（2 和 4 毫克/千克体重）或与 RES（40 毫克/千克体重）一起口服给药至成年雌性小鼠 45 天。从第 33 天到第 45 天，进行旷场、高架十字迷宫和莫里斯水迷宫测试以评估运动、焦虑和学习记忆。在第46天，对动物实施安乐死，并分别处理从中获得的脑组织和海马用于原子吸收分光光度法和蛋白质印迹法。

结果

由于₂ O ₃单独暴露导致焦虑水平增强、运动减少以及学习和记忆受损。As ₂ O ₃诱导的行为缺陷伴随着雌激素受体(ERα)表达的下调，伴随着海马中BDNF和NMDAR 2B水平的降低。然而，这些标志物的行为改变和表达在补充 RES 的小鼠中得到了恢复。此外，在单独接受 As ₂ O ₃的小鼠的血清和脑组织中观察到剂量依赖性iAs积累，而同时施用 As ₂ O ₃和 RES 促进了iAs 流出。

结论

这些结果表明，与 BDNF 和 NMDAR 2B 水平的下调相关的 ERα 表达降低可能是iAs诱导认知障碍的机制。因此，RES 对雌激素-NMDAR-BDNF 通路的调节代表了恢复由这种神经毒素引起的行为缺陷的潜在途径。

图形概要