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Effects of Aspartame Metabolites on Astrocytes and Neurons

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Effects of Aspartame Metabolites on Astrocytes and Neurons Review paper Effects of aspartame metabolites on astrocytes and neurons Karol Rycerz, Jadwiga Elżbieta Jaworska-Adamu Department of Animal Anatomy and Histology, Faculty of Veterinary Medicine, University of Life Sciences, Lublin, Poland Folia Neuropathol 2013; 51 (1): 10-17 DOI: 10.5114/fn.2013.34191 Abstract Aspartame, a widespread sweetener used in many food products, is considered as a highly hazardous compound. Aspar - tame was discovered in 1965 and raises a lot of controversy up to date. Astrocytes are glial cells, the presence and functions of which are closely connected with the central nervous system (CNS). The aim of this article is to demonstrate the direct and indirect role of astrocytes participating in the harmful effects of aspartame metabolites on neurons. The artificial sweetener is broken down into phenylalanine (50%), aspartic acid (40%) and methanol (10%) during meta - bolism in the body. The excess of phenylalanine blocks the transport of important amino acids to the brain contributing to reduced levels of dopamine and serotonin. Astrocytes directly affect the transport of this amino acid and also indi - rectly by modulation of carriers in the endothelium. Aspartic acid at high concentrations is a toxin that causes hyper - excitability of neurons and is also a precursor of other excitatory amino acid - glutamates. Their excess in quantity and lack of astrocytic uptake induces excitotoxicity and leads to the degeneration of astrocytes and neurons. The methanol metabolites cause CNS depression, vision disorders and other symptoms leading ultimately to meta - bolic acidosis and coma. Astrocytes do not play a significant role in methanol poisoning due to a permanent consumption of large amounts of aspartame. Despite intense speculations about the carcinogenicity of aspartame, the latest studies show that its metabolite – dike - topiperazine – is cancirogenic in the CNS. It contributes to the formation of tumors in the CNS such as gliomas, medul - loblastomas and meningiomas. Glial cells are the main source of tumors, which can be caused inter alia by the sweet - ener in the brain. On the one hand the action of astrocytes during aspartame poisoning may be advantageous for neuro-protection while on the other it may intensify the destruction of neurons. The role of the glia in the pathogenesis of many CNS dis - eases is crucial. Key words: aspartame, aspartate, diketopiperazine, phenyloalanine, receptors, transporters, neurodegeneration. medicines and particularly in diet beverages. It was Introduction found that aspartame is present in 68% of comestible Aspartame (APM) is an artificial sweetener wide - assortment among sugar-free products in Poland [28] . spread in the world which is used in many food prod - It is applied by diabetics as tablets instead of sugar ucts like chewing gum, desserts, yoghurts, vitamins, (NutraSweet, Equal, Sugar Free, Canderel). The sweet - Communicating author: lek. wet. Karol Rycerz, Department of Animal Anatomy and Histology, Faculty of Veterinary Medicine, University of Life Sciences, ul. Akademicka 12, 20-950 Lublin, Poland, e-mail: [email protected] 10 Folia Neuropathologica 2013; 51/1 Effects of aspartame metabolites on astrocytes and neurons ener was accidentally discovered by James Schlatter This naturally essential amino acid after applied with during his attempts to obtain a gastric ulcer drug in nutrients to an organism joins the general pool of ami - 1965 [9]. This white, crystalline and odourless powder no acids present in the blood. It is partly transform ed is 180-200 times sweeter than sucrose. The intense sen - into tyrosine by phenylalanine hydroxylase and then sation of sweetness allows the use of such small dos - to L-3,4-dihydroxyphenylalanine (DOPA), dopamine es so that the product is almost non-caloric although (DA), noradrenaline (NA) and adrenaline (A) in the its energy value is 4 kcal/g of aspartame. The sweet - liver. Phe nylalanine may be used in protein synthesis ener is a chemical agent, N-L-alpha-Aspartyl-L-phe nyl - and also to convert into phenylpyruvic acid present in alanine methyl ester (C14H18N2O5) [26]. This substance high concentration in patients with phenylketonuria is hydrolysed completely to the three main breakdown (PKU) [21]. products: phenylalanine (50%), aspartic acid (40%) and The remaining pool of phenylalanine crosses to methanol (10%) in the intestinal lumen. The use of as - the brain by neutral amino acid transporters (NAAT) partame as a sweetening agent has been controversial mainly situated in capillary vessels, a part of blood- for years due to the harmful effects of high concen - brain barrier (BBB). These transporters are used to trations of the metabolites. Hence the European Food transport various amino acids: glutamine, histidine, Safety Authority established an acceptable daily in - me thio nine, serine, threonine, tyrosine and trypto - take of 40 mg/kg b.w./day [8,17]. phan, which are important for neurotransmitters’ syn - Most articles about harmful effects of the artificial thesis. Astrocytes are involved in the modulation of sweetener are focused primarily on its negative influ - the blood-brain barrier and thus influence the trans - ence on the nerve cells [2,3,5,7,19]. And only in a few port of amino acids by the endothelium. Under the studies the effect of aspartame on glial tissue, which influence of astrocytic factors in the endothelial cell inextricably accompanies neurons, has been described cultures derived from rat’s brain using an RT-PCR [15,29]. Therefore, the aim of this article is to show the method, the expression of one of the subunits build - direct and indirect role of astrocytes which participa- ing amino acid transporters (4F2hc – heavy chain) was te in the harmful effects of aspartame metabolites. shown. These glial cells can modulate transport of Among many functions of astrocytes one is to nour - inter alia phenylalanine through the wall of the cap - ish the nerve cells and compose a stroma in the form illaries. Na +-independent (L1 system – transport of of neu ropil for them. They set up the blood-brain bar - large essential neutral amino acids) and Na +-depen - rier and also regulate the homeostasis of ions (Ca 2+ , K +), dent endothelial transporters hold a subunit in the maintain water balance (AQP4 – aquaporin 4), provide form of 4F2hc heavy chain. This suggests that astro - substrates for the synthesis of neurotransmitters (par - cytes are involved in the uptake of neutral amino acids ticularly glutamate – Glu, γ-amino butyric acid – GABA , (NAAs) through functional changes of many NAAT and serotonin – 5-HT) and are involved in their uptake transporters. and metabolism [20]. Aspartame interference in these Astrocytic end feet reaching the basilemma of the functions may directly or indirectly evoke the develop- endothelium contain many membrane transporters ment of many adverse symptoms such as headaches, which participate in the entry of phenylalanine into dizziness, seizures, nausea, numbness, muscle spasms, the CNS. It was shown that the Na +-dependent large rashes, depression, fatigue, irritability, insomnia, vision neutral amino acid transporters (Na +-LNAA system) are problems, hearing loss, heart palpitations, anxiety at- present in the astrocytes and therefore they may be tacks, slurred speech, tinnitus, memory loss, learning involved in the penetration of Phe across the blood- disabilities and joint pain [1]. Astrocytes can presum - brain barrier. Presumably, astrocytes are directly in volved ably take part in positive and negative effects of aspar - in the transport of phenylalanine and in the increase tame metabolites in view of their functions and par - of its concentration in the brain after consumption of ticipation in metabolism of neurons. aspartame [4,14,23]. All amino acids which can pass through the BBB compete for the transporter. The affin - Astrocytes influence on the transportation ity of the carriers is proportional to the concentration of phenylalanine of amino acids in the blood. Higher concentrations of One of the major metabolite of aspartame is phe- the amino acid in the blood enhance the ability to bind nylalanine (Phe), the sweetener’s breakdown product. a transporter. Consuming aspartame increases the pool Folia Neuropathologica 2013; 51/1 11 Karol Rycerz, Jadwiga Elżbieta Jaworska-Adamu Aspartame acids necessary for proteins and neurotransmitters syn - thesis cannot pass to the brain. One of the essential amino acids delivered to the CNS by the BBB is tyro - sine (Tyr) required for the synthesis of dopamine (DA) Trp, Tyr Phe (50%) and nonessential amino acid – tryptophan (Trp) in - volved in the formation of serotonin (5-HT). As a re - sult of lack of neutral amino acid transporters after endothelium binding phenylalanine to them, there is a deficiency NAAT 4 F 2 of other amino acids resulting in decreased produc - h c tion of these two neurotransmitters (Fig. 1). Low do - astrocytic pamine levels in neurons of the substantia nigra in the ↑Phe factors midbrain forming neural pathways reaching the stria - tum (globus pallidus, putamen and nucleus caudatus) and brain cortex, lead to a reduction in mobility, bal - 5-HT Clinical ance and walking. These alterations are the first symp - ↓ symptoms ↓DA toms of Parkinson’s disease [3,15,30]. In adult mice it was shown that the low concentrations of dopamine in the dopaminergic system also cause disorders in Astrocyte exploratory behaviour, adipsia and aphagia [32]. Presynaptic Lower levels of serotonin in the hippocampus, raphe neuron nucleus of the brain stem and substantia nigra in the midbrain affect sleep, memory, sensory perception, con - trol of mood, temperature regulation disorders, depres - GABA GABA transporter sion and anxiety in adults. The reduction of serotonin levels in the development of CNS can affect cell pro - Depolarisation liferation, differentiation and migration of neurons and inhibition synaptogenesis. Serotonin deficiency in the prenatal period leads to developmental disorders of the respi - Postsynaptic ratory system [6,11,15]. Astrocytes may be involved in neuron the above alterations caused by phenylalanine derived from aspartame because they capture, break up, me - Fig.
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