Relationship between Aspartame-Induced Cerebral Cortex Injury and Oxidative Stress, Inflammation, Mitochondrial Dysfunction, and Apoptosis in Sprague Dawley Rats

Jureeporn U-Pathi; Yen-Chia Yeh; Chia-Wen Chen; Eddy E Owaga; Rong-Hong Hsieh

doi:10.3390/antiox13010002

Relationship between Aspartame-Induced Cerebral Cortex Injury and Oxidative Stress, Inflammation, Mitochondrial Dysfunction, and Apoptosis in Sprague Dawley Rats

Antioxidants (Basel). 2023 Dec 19;13(1):2. doi: 10.3390/antiox13010002.

Authors

Jureeporn U-Pathi¹, Yen-Chia Yeh¹, Chia-Wen Chen², Eddy E Owaga³, Rong-Hong Hsieh^{1

2

4}

Affiliations

¹ School of Nutrition and Health Sciences, College of Nutrition, Taipei Medical University, Taipei 11031, Taiwan.
² Research Center of Nutritional Medicine, College of Nutrition, Taipei Medical University, Taipei 11031, Taiwan.
³ Institute of Food Bioresources Technology, Dedan Kimathi University of Technology, Nyeri P.O. Box 657-10100, Kenya.
⁴ Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan.

Abstract

There are emerging concerns about the potential cerebral cortex injury from aspartame due to the accumulation of the various neurotoxic metabolic components in the central nervous system after long-term dietary exposure. The aim of this study was to evaluate the effect of oral aspartame consumption on cerebral cortex injury in the rat brain, and further evaluate the various underlying molecular mechanisms, with a special focus on oxidative stress, inflammation, mitochondrial dysfunction, and apoptosis pathways. Sprague Dawley rats (nineteen, female) were randomly sub-divided into three groups: (i) normal diet with vehicle: control group (five rats), (ii) low dose of aspartame group (LA): seven rats received 30 mg/kg body weight (bw) daily doses of aspartame, (iii) high dose of aspartame group (HA): seven rats received 60 mg/kg bw daily doses of aspartame. After 8 weeks, the LA and HA groups showed lower expression levels of brain-derived neurotrophic factor (BDNF), antioxidant enzyme activity (SOD2, CAT), antioxidant marker (Nrf2), inflammatory response (IκB), mitochondrial biogenesis (Sirt1, PGC1α, Nrf1, TFAM), mitochondrial DNA (mtDNA) copy number, and apoptosis-related proteins (Bax, Caspase-3) expressions. Aspartame administration also elevated oxidative stress levels (Malondialdehyde, MDA), 8-hydroxy-2-deoxy guanosine (8-OHdG), PGE₂ and COX-2 expressions, pro-inflammatory cytokines (TNFα, IL6, IL1β), antioxidant marker expression (Keap1), inflammatory responses (iNOS, NFκB), and glial fibrillary acidic protein (GFAP) levels in the cerebral cortex of the rats, thereby contributing to the reduced survival of pyramidal cells and astrocyte glial cells of the cerebral cortex. Therefore, these findings imply that aspartame-induced neurotoxicity in rats' cerebral cortex could be regulated through four mechanisms: inflammation, enhanced oxidant stress, decreased mitochondrial biogenesis, and apoptosis pathways.

Keywords: apoptosis; aspartame; inflammation; mitochondrial biogenesis; oxidative stress.

Grants and funding

This research was funded by grants (MOST 109-2314-B-038-058, MOST110-2314-B-038-157, MOST 111-2314-B-038-005) from the National Science Council, Taiwan.