Oxidative stress evoked damages leading to attenuated memory and inhibition of NMDAR–CaMKII–ERK/CREB signalling on consumption of aspartame in rat model

Abstract

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.

Effects of dietary sweeteners supplementation on growth performance, serum biochemicals, and jejunal physiological functions of broiler chickens

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Induction of Brain Injury and Depression in Rats by Chronic Unpredictable Stress Associated with the Augmentation of Nitrosative Stress and Apoptosis

“…In cell signalling, nitrosative and oxidative stress are located upstream of the apoptotic and the survival biomarkers caspas-3 and Bcl-2 upon activation in many cases such as tissue injury (Iyaswamy et al, 2018;Liang & Su, 2019). Our data that points to the induction of brain tissue injury, nitrosative and oxidative stress, and inhibition of SOD and Bcl-2 by CUS Fig.…”

Could aspartame exacerbate caffeine effects on renal maturation in rat's offspring? A biochemical and histological study

“…Aspartame is metabolized in the body to methanol which can be detected even after 24 hr of exposure. Methanol is primarily metabolized by oxidation to formaldehyde and then to formic acid which induce increased production of free radicals and increased oxidative damage in multiple tissues and may be responsible for the formation of superoxide anion and hydrogen peroxide (Humphries, Pretorius, & Naudé, 2008) and (Iyaswamy et al, 2018).…”