Microcystin-leucine-arginine (MCLR) is the most common form of microcystins, which are environmental toxins produced by cyanobacteria, and its hepatotoxicity has been well-documented. However, the neurotoxic potential of MCLR remains to be further elucidated. In the present study, we investigated whether intracerebroventricular (i.c.v.) infusion of MCLR induces mortality and neuronal loss in the hippocampus of mice. Because we found that MCLR impairs memory function in the hippocampus at a low dose (4 ng/μl/mouse, i.c.v.) without a significant neuronal loss, we focused on this dose for further analyses. Results showed that MCLR (4 ng/μl/mouse, i.c.v.) significantly increased oxidative stress (i.e., malondialdehyde, protein carbonyl, and synaptosomal ROS) in the hippocampus. In addition, MCLR significantly increased superoxide dismutase (SOD) activity without corresponding induction of glutathione peroxidase (GPx) activity, and thus led to significant decrease in the ratio of GPx/SODs activity. The GSH/GSSG ratio was also significantly reduced after MCLR treatment. GPx-1 overexpressing transgenic mice (GPx-1 Tg) were significantly protected from MCLR-induced memory impairment and oxidative stress. The DNA binding activity of nuclear factor erythroid-derived 2-related factor 2 (Nrf2) in these mice was significantly enhanced, and the ratios of GPx/SODs activity and GSH/GSSG returned to near control levels in the hippocampus. Importantly, memory function exhibited a significant positive correlation with the ratios of GPx/SODs activity and GSH/GSSG in the hippocampus of MCLR-treated non-transgenic (non-Tg)- and GPx-1 Tg-mice. Combined, our results suggest that MCLR induces oxidative stress and memory impairment without significant neuronal loss, and that GPx-1 gene constitutes an important protectant against MCLR-induced memory impairment and oxidative stress via maintaining antioxidant defense system homeostasis, possibly through the induction of Nrf2 transcription factor.

微囊藻毒素-亮氨酸-精氨酸（MCLR）是微囊藻毒素的最常见形式，它们是蓝细菌产生的环境毒素，其肝毒性已有大量文献证明。但是，MCLR的神经毒性潜力仍有待进一步阐明。在本研究中，我们调查了MCLR的脑室内（icv）输注是否会引起小鼠海马的死亡和神经元丢失。因为我们发现低剂量（4 ng /μl/小鼠，icv）的MCLR会损害海马的记忆功能，而没有明显的神经元丢失，因此我们集中于此剂量进行进一步分析。结果表明，MCLR（4 ng /μl/小鼠，icv）显着增加了海马体的氧化应激（即丙二醛，蛋白质羰基和突触体ROS）。此外，MCLR显着增加了超氧化物歧化酶（SOD）的活性，而没有相应地诱导谷胱甘肽过氧化物酶（GPx）的活性，因此导致GPx / SODs活性的比值显着降低。在MCLR治疗后，GSH / GSSG比也显着降低。GPx-1过表达的转基因小鼠（GPx-1 Tg）受到了MCLR诱导的记忆障碍和氧化应激的显着保护。在这些小鼠中，核因子类红细胞衍生的2相关因子2（Nrf2）的DNA结合活性显着增强，并且海马中GPx / SODs活性和GSH / GSSG的比率恢复到接近控制水平。重要的是，记忆功能与MCLR治疗的非转基因（non-Tg）-和GPx-1 Tg-小鼠的海马中GPx / SODs活性和GSH / GSSG的比率呈显着正相关。