Plasma Concentrations and Pharmacokinetics of Phenylalanine in Rats and Mice Administered Aspartame

Hjelle, Jerry J.; Dudley, Robert; Marietta, M.; Sanders, Paul G.; Dickie, Bruce C.; Brisson, Jerry; Kotsonis, Frank N.

doi:10.1159/000138873

Cited by 21 publications

(11 citation statements)

References 16 publications

(18 reference statements)

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“…The main effect of ASP consumption in humans is to increase levels of plasma phenylalanine [ 32 ]. In rodents, levels of plasma phenylalanine and its metabolite tyrosine also increase following ASP ingestion [ 33 , 34 ] although to a lesser extent [ 35 ]. Phenylalanine competes with tyrosine, the precursor of dopamine for binding sites on the large neutral amino acid transporter (NAAT) at the blood brain barrier (BBB), with the result that brain tyrosine levels are affected and dopamine synthesis may be compromised [ 36 , 37 ].…”

Section: Introductionmentioning

confidence: 99%

Effect of developmental NMDAR antagonism with CGP 39551 on aspartame-induced hypothalamic and adrenal gene expression

et al. 2018

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RationaleAspartame (L-aspartyl phenylalanine methyl ester) is a non-nutritive sweetener (NNS) approved for use in more than 6000 dietary products and pharmaceuticals consumed by the general public including adults and children, pregnant and nursing mothers. However a recent prospective study reported a doubling of the risk of being overweight amongst 1-year old children whose mothers consumed NNS-sweetened beverages daily during pregnancy. We have previously shown that chronic aspartame (ASP) exposure commencing in utero may detrimentally affect adulthood adiposity status, glucose metabolism and aspects of behavior and spatial cognition, and that this can be modulated by developmental N-methyl-D-aspartate receptor (NMDAR) blockade with the competitive antagonist CGP 39551 (CGP). Since glucose homeostasis and certain aspects of behavior and locomotion are regulated in part by the NMDAR-rich hypothalamus, which is part of the hypothalamic-pituitary-adrenal- (HPA) axis, we have elected to examine changes in hypothalamic and adrenal gene expression in response to ASP exposure in the presence or absence of developmental NMDAR antagonism with CGP, using Affymetrix microarray analysis.ResultsUsing 2-factor ANOVA we identified 189 ASP-responsive differentially expressed genes (DEGs) in the adult male hypothalamus and 2188 in the adrenals, and a further 23 hypothalamic and 232 adrenal genes significantly regulated by developmental treatment with CGP alone. ASP exposure robustly elevated the expression of a network of genes involved in hypothalamic neurosteroidogenesis, together with cell stress and inflammatory genes, consistent with previous reports of aspartame-induced CNS stress and oxidative damage. These genes were not differentially expressed in ASP mice with CGP antagonism. In the adrenal glands of ASP-exposed mice, GABA and Glutamate receptor subunit genes were amongst those most highly upregulated. Developmental NMDAR antagonism alone had less effect on adulthood gene expression and affected mainly hypothalamic neurogenesis and adrenal steroid metabolism. Combined ASP + CGP treatment mainly upregulated genes involved in adrenal drug and cholesterol metabolism.ConclusionASP exposure increased the expression of functional networks of genes involved in hypothalamic neurosteroidogenesis and adrenal catecholamine synthesis, patterns of expression which were not present in ASP-exposed mice with developmental NMDAR antagonism.

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Section: Introductionmentioning

confidence: 99%

Effect of developmental NMDAR antagonism with CGP 39551 on aspartame-induced hypothalamic and adrenal gene expression

et al. 2018

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“…This dose was calculated according to the human dose, which is 4050-mg/kg per day, after species factor correction [7] .…”

Section: Animals Usedmentioning

confidence: 99%

Comparative Study on The Safety of Aspartame and Stevia on The Adrenal-Pituitary Axis of Adult Male Albino Rats: Histological and Immunohistochemical Study

Abdelhaliem

Mohamed

2017

Egyptian Journal of Histology

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Introduction: Aspartame is the most widely used artificial sweeteners. Stevia is a worldwide natural sweetener plant with medicinal and commercial importance. Stress responses are mediated both in the central and peripheral nervous system. The principal effectors of the stress response are localized in the hypothalamus, the anterior lobe of the pituitary gland, and the adrenal gland. This is commonly referred to as the hypothalamic-pituitary-adrenal axis. Aim: To compare the effect of aspartame and stivea on the pituitary adrenal axis. Material and Methods: A total of 30 adult male albino rats were equally divided into three groups. Group I was the Control Group. Group II (ASP Group) received aspartame (ASP), at daily oral dose 250 mg/kg for 4 weeks. .Group III (stevia Group) received stevia at daily oral dose 250 mg/kg for 4 weeks. Results: : In aspartame-treated group there was apoptosis of zona fasciculata cells with subsequent corticotrophic hyperplasia. In stevia treated groups minimal changes were observed with no significant changes in number of corticotrophes. Conclusion: As a natural sweetener, stevia is safer than aspartame on the adrenal pituitary axis.

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“…This dose used is corresponding to the human dose, which is 40-50 mg/kg/b wt. after species factor correction requiring 5-6 times higher dose than man, as rat metabolizes ASP faster than human [26]. Group 4 (P. anisum oil + ASP group): Animals of this group received .5 mL/kg/d/b wt.…”

Section: Animals and Experimental Designmentioning

confidence: 99%

Ameliorative Effect ofPimpinella anisumOil on Immunohistochemical and Ultrastuctural Changes of Cerebellum of Albino Rats Induced by Aspartame

Abdul-Hamid

Gallaly

2014

Ultrastructural Pathology

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The study aims to investigate the protective effect of Pimpinella anisum oil on aspartame (ASP) which resulted in cerebellar changes. The rats were divided into four equal groups: Group 1: (control group): served as control animals. Group 2: control P. anisum oil received .5 mL/kg/d/b wt. once daily. Group 3 (ASP group): received daily 250 mg/kg/b wt. of ASP dissolved in distilled water and given orally to the animals by intra-gastric tube for 2 months. Group 4: received .5 mL/kg/b wt. of prophylactic P. anisum oil once daily, followed by ASP after 2 h for 2 months. The histopathological approach revealed marked changes in the Purkinje cells, myleinated nerve fibers and granular cells of ASP-treated animals. Some of these cells appeared with deeply stained cytoplasm. Ultrastructural examination showed Purkinje cells with dilated rough endoplasmic reticulum and condensed mitochondria. Granular cells appeared with less c nuclei and surrounded by dissolution of most Mossy rosettes structures. Most myelinated nerve fibers showed thickening of myelinated sheath and others showed splitting of their myelin sheath. The histopathological, immunohistochemical and ultrastructural alterations were much less observed in concomitant use of P. anisum oil with ASP. Cerebellar cortex is considered target areas of ASP neurotoxicity, while P. anisum oil, when used in combination with ASP displays a protective action against neurotoxicity.

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Plasma Concentrations and Pharmacokinetics of Phenylalanine in Rats and Mice Administered Aspartame

Cited by 21 publications

References 16 publications

Effect of developmental NMDAR antagonism with CGP 39551 on aspartame-induced hypothalamic and adrenal gene expression

Effect of developmental NMDAR antagonism with CGP 39551 on aspartame-induced hypothalamic and adrenal gene expression

Comparative Study on The Safety of Aspartame and Stevia on The Adrenal-Pituitary Axis of Adult Male Albino Rats: Histological and Immunohistochemical Study

Ameliorative Effect ofPimpinella anisumOil on Immunohistochemical and Ultrastuctural Changes of Cerebellum of Albino Rats Induced by Aspartame

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