Many controversial reports are available on the use of aspartame as it releases methanol as one of its metabolite during metabolism. The present study proposes to investigate whether long term (90 days) aspartame (40 mg/kg b.wt) administration could induce oxidative stress and alter the memory in Wistar strain male albino rats. To mimic the human methanol metabolism, methotrexate (MTX)-treated rats were included as a model to study the effects of aspartame. Wistar strain albino rats were administered with aspartame (40 mg/kg b.wt) orally and studied along with controls and MTX-treated controls. Aspartame interfered in the body weight and corticosterone levels in the rats. A marked increase in the mRNA and protein expression of neuronal nitric oxide synthase (nNOS) and induced nitric oxide synthase (iNOS) which resulted in the increased nitric oxide radical's level indicating that aspartame is a stressor. These reactive nitrogen species could be responsible for the altered cell membrane integrity and even cause death of neurons by necrosis or apoptosis. The animals showed a marked decrease in learning, spatial working and spatial recognition memory deficit in the Morris water maze and Y-maze performance task which could have resulted due to reduced hippocampal acetylcholine esterase (AChE) activity. The animal brain homogenate also revealed the decrease in the phosphorylation of NMDAR1-CaMKII-ERK/CREB signalling pathway, which well documents the inhibition of phosphorylation leads to the excitotoxicity of the neurons and memory decline. This effect may be due to methanol which may also activate the NOS levels, microglia and astrocytes, inducing neurodegeneration in brain. Neuronal shrinkage of hippocampal layer due to degeneration of pyramidal cells revealed the abnormal neuronal morphology of pyramidal cell layers in the aspartame treated animals. These findings demonstrate that aspartame metabolites could be a contributing factor for the development of oxidative stress in the brain.

中文翻译：

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在大鼠模型中，氧化应激引起的损伤导致记忆减弱和 NMDAR-CaMKII-ERK/CREB ​​信号传导对阿斯巴甜消耗的抑制

关于阿斯巴甜的使用有许多有争议的报道，因为它在新陈代谢过程中释放出甲醇作为其代谢产物之一。本研究建议调查长期（90 天）阿斯巴甜（40 mg/kg b.wt）给药是否会诱导氧化应激并改变 Wistar 品系雄性白化病大鼠的记忆力。为了模拟人类甲醇代谢，将甲氨蝶呤 (MTX) 治疗的大鼠作为模型来研究阿斯巴甜的影响。Wistar 菌株白化大鼠口服阿斯巴甜 (40 mg/kg b.wt)，并与对照组和 MTX 治疗的对照组一起研究。阿斯巴甜会干扰大鼠的体重和皮质酮水平。神经元一氧化氮合酶 (nNOS) 和诱导一氧化氮合酶 (iNOS) 的 mRNA 和蛋白质表达显着增加，导致一氧化氮自由基水平升高，表明阿斯巴甜是一种应激源。这些活性氮物种可能导致细胞膜完整性改变，甚至导致神经元因坏死或凋亡而死亡。在莫里斯水迷宫和 Y 迷宫性能任务中，动物的学习、空间工作和空间识别记忆缺陷显着减少，这可能是由于海马乙酰胆碱酯酶 (AChE) 活性降低所致。动物脑匀浆还显示 NMDAR1-CaMKII-ERK/CREB ​​信号通路的磷酸化减少，这很好地证明了磷酸化的抑制导致神经元的兴奋性毒性和记忆力下降。这种效应可能是由于甲醇也可能激活 NOS 水平、小胶质细胞和星形胶质细胞，从而诱导大脑中的神经退行性变。由于锥体细胞退化导致的海马层神经元收缩揭示了阿斯巴甜处理的动物锥体细胞层的异常神经元形态。这些发现表明，阿斯巴甜代谢物可能是大脑中氧化应激发展的一个促成因素。由于锥体细胞退化导致的海马层神经元收缩揭示了阿斯巴甜处理的动物锥体细胞层的异常神经元形态。这些发现表明，阿斯巴甜代谢物可能是大脑中氧化应激发展的一个促成因素。由于锥体细胞退化导致的海马层神经元收缩揭示了阿斯巴甜处理的动物锥体细胞层的异常神经元形态。这些发现表明，阿斯巴甜代谢物可能是大脑中氧化应激发展的一个促成因素。