Comparative evaluation of sweetener-induced changes in cognitive function, neurotransmission, and antioxidant defense mechanisms in Wistar rats

Aim: This study evaluated the comparative effects of commonly consumed artificial and natural sweeteners on cognitive function, neurotransmitter-related enzyme activities, and oxidative stress status in the brains of Wistar rats to elucidate their potential neurotoxic or neuroprotective properties under sub-chronic dietary exposure. Methods: Seventy-two male Wistar rats were randomly assigned to twelve groups and fed composite biscuits formulated with sucrose (15% and 30%), aspartame (3.5% and 7.0%), date sugar (10% and 20%), erythritol (15% and 30%), or stevia (2.5% and 5.0%) for 21 days. Control groups received either a basal diet or plain wheat biscuits. Spatial working memory was assessed using the Y-Maze spontaneous alternation test. Hippocampal tissue was harvested to determine monoamine oxidase (MAO), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) activities, lipid peroxidation (TBARS, thiobarbituric acid-reactive substances), reactive oxygen species (ROS) production, and antioxidant enzyme activities (superoxide dismutase, catalase, glutathione-S-transferase (GST), and glutathione peroxidase). Results: Sucrose (15% and 30%) and aspartame (3.5% and 7.0%) significantly reduced spontaneous alternation performance, indicating impaired working memory. Both sucrose and aspartame dosages markedly elevated MAO, AChE, and BChE activities, increased TBARS and ROS levels, and suppressed antioxidant enzyme activities in the hippocampus. In contrast, diets containing date sugar and erythritol preserved cognitive performance and maintained neurochemical and redox homeostasis. Notably, stevia (5.0%) significantly reduced MAO and AChE activities, attenuated oxidative stress markers, and enhanced endogenous antioxidant defenses. Conclusions: Sub-chronic consumption of sucrose and aspartame induces hippocampal neurotransmitter dysregulation and oxidative stress, contributing to cognitive impairment, whereas natural sweeteners, particularly stevia and date sugar, exhibit neuroprotective effects. These findings support the preferential use of natural sweeteners as safer dietary alternatives for maintaining cognitive and neurochemical health.