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Aspartame and Soft Drink-Mediated Neurotoxicity in Rats: Implication of Oxidative Stress, Apoptotic Signaling Pathways, Electrolytes and Hormonal Levels

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Abstract

A significant association between fructose corn syrup in sweetened beverages consumption and increased risk of detrimental central nervous system effects has been recently reported. We hypothesized that the aspartame and soft drink induced disturbances in energy production and endocrine function, which play a role in the induction of brain damage. Therefore, we aimed to assess the effect of aspartame and soft drink on brain function and the link between energy status in the brain, oxidative stress and molecular pathways of apoptosis. Thirty rats were randomly assigned to drink water, aspartame (240 mg/kg orally) and cola soft drinks (free access) daily for two months. Subchronic intake of aspartame and soft drink significantly disrupted the brain energy production, as indicated by inhibited serum and brain creatine kinase, specifically in soft drink-received rats. Moreover, they substantially altered serum electrolytes (increased Ca and Na, and depleted Cu, Fe, Zn and K levels), and accordingly the related hormonal status (increased T4 and PTH, and lowered T3 and aldosterone levels), particularly in soft drink-received rats reflecting brain damage. Additionally, significant increment of acetylcholine esterase activity concomitant with the reduction of antioxidant molecules (SOD, CAT, GSH-Px and GSH), and induction of malondialdehyde level are precisely indicative of oxidative brain damage. Brain mRNA transcripts of target genes showed that aspartame and soft drink induced upregulation of BAX, Casp3, P27 and Mdm2 (1.5-fold) and down-regulation of Bcl2, suggesting an activation of cellular apoptosis. Collectively, subchronic aspartame and soft drink-induced brain damage in rats may be driven via a mechanism that involves energy production disruption, electrolytes and hormonal imbalance, increased oxidative stress and activation of molecular pathway of neuronal apoptosis.

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Fig. 1

Abbreviations

AChE:

Acetylcholine esterase

ADI:

Acceptable daily intake

ANOVA:

Analysis of variance

BAX:

Bcl-2 like protein 4

Bcl-2:

B-cell lymphoma 2

Casp3:

Caspase-3

CAT:

Catalase

CDNB:

1-chloro-2,4-dinitrobenzene

CK:

Creatine kinase

CK-BB:

Brain-type CK

CK-MB:

Cardiac-type CK

CK-MM:

Muscle-type CK

DTNB:

5,5′-dithiobis 2 nitrobenzoic acid

GSH:

Reduced glutathione

GSH-Px:

Glutathione peroxidase

GST:

Glutathione-S-transferase

H2O2 :

Hydrogen peroxide

MDA:

Malondialdehyde

Mdm2:

Mus musculus transformed mouse 3 T3 cell double minute 2

mPTP:

mitochondrial permeability transition pore

NIH:

National Institutes of Health

P27:

Cyclin-dependent kinase inhibitor 1B (Cdkn1b)

PBS:

Phosphate buffer saline

PK:

Pyruvate kinase

PTH:

Parathyroid hormone

SEM:

Standard error of means

SOD:

Superoxide dismutase

T3:

Triiodothyronine

T4:

Thyroxine

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Acknowledgements

All of the authors declare that they have no competing interests to disclose. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The authors are solely responsible for the design and conduct of the study and the collection, management, analysis, and interpretation of the data, and the preparation of the manuscript. All authors had full access to the data and take responsibility for its integrity. All authors have read and agreed with the manuscript as written.

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Authors and Affiliations

  1. Department of Biochemistry, Faculty of Veterinary Medicine, Alexandria University, Edfina, 22758, Egypt

    Mohamed A. Lebda

  2. Department of Biochemistry, Faculty of Veterinary Medicine, Damanhour University, Damanhour, 22511, Egypt

    Kadry M. Sadek

  3. Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, Damanhour University, Damanhour, 22511, Egypt

    Yasser S. El-Sayed

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  1. Mohamed A. Lebda
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  2. Kadry M. Sadek
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  3. Yasser S. El-Sayed
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Correspondence to Yasser S. El-Sayed.

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Lebda, M.A., Sadek, K.M. & El-Sayed, Y.S. Aspartame and Soft Drink-Mediated Neurotoxicity in Rats: Implication of Oxidative Stress, Apoptotic Signaling Pathways, Electrolytes and Hormonal Levels. Metab Brain Dis 32, 1639–1647 (2017). https://doi.org/10.1007/s11011-017-0052-y

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