|
 
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| ORIGINAL ARTICLE |
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| Year : 2021 | Volume
: 6
| Issue : 1 | Page : 17-23 |
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Comparative effect of neonatal and adult exposure to monosodium glutamate
Akataobi Uche Stephen, Awusha Moses Ushie, Obio Arong Wilson
Department of Biochemistry, Faculty of Basic Medical Sciences, University of Calabar, Nigeria
| Date of Submission | 05-Aug-2020 |
| Date of Decision | 30-Nov-2020 |
| Date of Acceptance | 21-Jan-2021 |
| Date of Web Publication | 30-Mar-2021 |
Correspondence Address:
Akataobi Uche Stephen
Department of Biochemistry, Faculty of Basic Medical Sciences, University of Calabar, P.M.B. 1115, Calabar, Cross River State
Nigeria
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/ed.ed_24_20
Purpose: Exposure to monosodium glutamate (MSG) is reported to have different effects on exposed rats depending on the age of exposure, believed to be as a result of its ability to pass the blood–brain barrier and affect the level and function of neurotransmitters in the central nervous system.
Aim: The present study is aimed at understanding the differential effect of MSG in rats exposed either as neonate, neonate plus adult or adult only by measuring the metabolism of selected neurotransmitters in the brain.
Materials and Methods: Neonates were grouped into 2 administered 4 mg/g body weight MSG and Saline (control) on postnatal days 2, 4, 6, 8, and 10. The rats were allowed to mature for 30 weeks afterwards the MSG group were further divided into three groups (n = 6) and administered saline, 5 and 10 mg/g of MSG. Two other groups, not exposed to MSG at neonatal age, were similarly administered 5 and 10 mg/g of MSG, administration lasted for 6 weeks. Key enzymes of acetylcholine and tyrosine metabolisms as well as alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured in whole brain homogenates.
Results: Showed an increase in acetylcholinesterase and tyrosine hydroxylase activities which occurred similarly in both neonatal and adult administered groups. AST and ALT showed a similar activity significantly higher adult groups.
Conclusion: MSG affected both neonate and adult administered groups similarly in a dose dependent manner.
Keywords: Brain homogenate, monosodium glutamate, neonate, neurotransmitter, postnatal
How to cite this article:
Stephen AU, Ushie AM, Wilson OA. Comparative effect of neonatal and adult exposure to monosodium glutamate. Environ Dis 2021;6:17-23 |
| Introduction | |  |
Monosodium glutamate (MSG) is a white crystal salt of glutamic acid made-up of 2% water, 20% sodium and 78% glutamate.[1] It was first used as additive to improve flavor and taste, previously in Chinese and Japanese foods[2] and presently been used around the world.[3] Adding MSG to food gives it a flavoring taste, similar to that of naturally occurring free glutamate.[4] MSG is present in a good number of commercially packaged foods including sausages, snacks, vegetable burgers, prepared meals, soup and sauces, seasoned chicken,[5] foods served in restaurants as well as in household cooking.[6] MSG enhances food flavor by stimulation of orosensory receptor and by improving the palatability of foods,[7] influencing appetite positively and result in consumption of more of the food.[8] It has been shown that MSG affects brain activity,[1],[5] by increasing the concentration of certain neurotransmitters in the central nervous system.[2] Exposure to MSG have different effect in experimental animals depending on the age of exposure,[9] this idea is employed in studies involving MSG administration to rat at neonatal stage while the effect is studied when the rats get to adult stage.[10],[11] This is due to reports that glutamate from MSG when digested easily penetrate a developing blood–brain barrier at neonatal stage than it does in adulthood.[1],[2] In some industrial foods and other consumable products, MSG in allowable limits may be listed and/or described on the food label as flavoring agent or as a hydrolyzed vegetable protein.[12] However, when present in higher than recommended concentration, the quantity of MSG is usually concealed or given unconventional names for disguise in the labels of the products.[13],[14] Such names include – glutamic acid, glutaccyl, autolyzed yeast extract, glutarene, calcium caseseinate, sodium caseinate, E621, and no added MSG.[1]
Despite the effective role of MSG in foods, studies have indicated that its consumption results to an increased level of excitatory neurotransmitter[3] which can be toxic to the brain in accumulated level[15] and lead to brain damage through continuous excitation of brain cells to death[8] and conditions such as “attention deficit disorder, attention deficit hyper active disorder, Asperger's Syndrome and Autism.[12],[16] Neurotransmitters are small endogenous chemical messengers responsible for transmitting chemical or electrical signals across chemical synapses like the neuromuscular junctions.[17] According to Webstar,[18] they are substances released at the end of a nerve fiber on arrival of an impulse and by diffusing across the synapse effect the transfer of impulse to another never fiber (or muscle fiber or some receptor).[9] Classified into four major groups, the biogenic amines, the neuropeptides, other ligands and the small molecule neurotransmitters,[19] which are low molecular weight substances synthesized in the presynaptic terminals, including glycine, glutamate (the major component of MSG), γ-aminobutir acid[11],[18] and acetylcholine that can function as both excitatory and inhibitory signal neurotransmitters.[18],[19] Studies have shown that acetylcholine act at various sites in the central nervous system where it function as a neurotransmitter as well as a neuromodulator[7] and plays a vital role in motivation, arousal, attention, learning and memory,[9] its role in promoting REM sleep have been recorded.[20] MSG administration to Wistar rats have been reported to cause an increase in activity of acetylcholinesterase responsible for the breakdown of acetylcholine in the brain.[21] This report points to an increase in acetylcholine concentration following MSG administration in the brain.[22]
MSG administration have also been shown to influence the activity of tyrosine hydroxylase in brain of matured Wistar rats[18] responsible for the conversion of tyrosine to L- dihydroxyphenylalanine (L-DOPA) using molecular oxygen and Fe2+ as well as tetrahydropterin (BH-4) cofactor[18] in a reaction representing the rate limiting step in the biosynthesis of catecholamines.[19] Impairment in the metabolism of tyrosine and synthesis of catecholamines leads to the development of Parkinson's and other neurodegenerative disease.[4],[7]
| Materials And Methods | | |
Experimental animals
Male and female adult Wistar rats were obtained from the animal house of the college of Medical Sciences, University of Calabar, P. M. B. 1115, Calabar, Cross River State, Nigeria. The rats were co-habited (two males and four females). The females were allowed to become pregnant (identified physically by the change in the size of their stomach), before they were separated to different cages where they littered and raised their offspring (neonate). The principles of Laboratory Animal Care (NIH publication No: 83-23 reversed 1985) were followed as well as specific national laws where applicable. All experiments were approved by the Faculty of Basic Medical Science University of Calabar and ethics committee (November 04, 2018).
Distribution of experimental animal
Neonates rats were used as experimental animals. The animals were divided into six groups with six animals per group and exposed to different concentrations of MSG as neonates only, neonate plus adults, and adult only [Table 1]. The sample size used in this study were chosen to represent groups capable of identifying an effect where present and not too large to prevent errors that may occur in the process of handling, administration as well as collection of results.
Monosodium glutamate administration
Following the day of delivery neonates were divided into two groups and administered drinkable water (group one) and a single dose of 4 mg/g MSG (group two) intra-peritoneally, on postnatal days 2, 4, 6, 8, and 10 according to the method of Akataobi US.[6] The rats were weaned on the 21st day and raised normally for 30 weeks. At the end of which, group one were divided into three groups and administered drinkable water (control), 5 mg/g and 10 mg/g MSG orally using oral gavage (adult only groups) and group two divided into three and administered drinkable water (neonate only group), 5 mg/g and 10 mg/g MSG (neonate plus adult groups) orally using an oral gavage, according to the method of Akataobi US.[1] All the groups were given water and MSG orally, twice a day in the morning and the evening (12 h apart). Treatment lasted for 6 weeks. All the animals were giving free access to feed (rat chow) and water ad libitum.
Termination of the experiment and collection of samples
At the end of the 6 weeks' study, all groups were fasted overnight and sacrificed under ketamine. The animals were decapitated, the skull were opened and whole brain removed and suspended in an ice cold phosphate buffer saline of pH 7.4 in preparation for biochemical assays.
Preparation of brain homogenate
Whole brain was thoroughly homogenized in phosphate buffer of pH 7.4, using a laboratory mortar and pestle and centrifuged at 2,000 rpm for 30 min. After centrifugation, the supernatant was withdrawn into a plain tube and used for biochemical analysis.
Statistical analysis
Data obtained were analyzed by one way analysis of variance followed by least significant difference post hoc test. The Statistical Package for the Social Science (200 West Madison Street Suite 2300 Chicago, IL 60606 United State) version 21.0 was used for the analysis. Differences were considered significant at P < 0.05 and expressed as mean ± standard error of mean (SEM).
Acetylcholinesterase activity assay
Acetylcholinesterase, activity was analyzed by Ellman's method as described in 2017 by Khalil and Kasim.[11] Based on the principle of measuring the rate of thiocholine production when acetylthiocholine is hydrolyzed due to continuous reaction of thiol with 5-dithiobbis-2-nitrobenzoate-2-nitrobenzoate ion-1 to form a yellow anion of 5-thio-2-nitro-bezoic acid-11. The activity is measured following increase of yellow color produced when the thio anion produced by the enzymatic hydrolysis of the substrate (acetylthiocholine) reacts with dithiobis-nitrobenzoic acid (DTNB) in a spectrophotometer at 412 nm.
Methods
Brain tissue homogenized as described above was used. Exactly, 10 μl aliquot of the homogenate was pipetted into a test tube containing 2 ml 0.1 M phosphate buffer of pH 8.0 and mixed with 100 μl Ellman's reagent (containing 0.01 M DTNB in 5:5-dithiobis-2-nitrobenzoic acid prepared by dissolved 39.6 mg in 10 ml 0.1 M phosphate buffer of pH 7.0 and 15 mg of sodium bicarbonate and made up with buffer of pH 7). The mixture was properly mixed and preincubated for 30 min. 20 μl of 1 mM acetylthiocholine iodide used as substrate (prepared in a solution containing 2 ml 0.01M tris-HCl, (pH 7.4), 2 ml 1M NaCl, 4 ml 0.01MeGTA, 4 ml 1% Trion X-100), stored in ice until used was then added into the test tube allowed to stand for 10 min, to develop a yellow-colored mixture after which spectrophotometric reading was taken at 412 nm twice over for 2 min at 60 s interval. The enzyme activity was determined by change in absorbance and expressed in μmol/min/mg according to the method of,[1] from the formula,
Enzyme activity (μmol/min/mg) = 
ɛDTNB = extinction coefficient of DTNB (13,600 M─1 cm─1)
Tw = tissue weight (gm)
△A = change in absorbance
TV = total volume of reaction mixture (ml)
SV = volume of test sample in reaction mixture (ml)
Tyrosine hydroxylase activity assay
Reagents
0.020 M L-phenylalanine, 1.0 M potassium phosphate buffer, pH 6.8, 0.0025 M TPN, 25 M glucose, glucose dehydrogenase in excess, partially purified cofactor, enzyme solution to be assayed. The enzyme activity assay was analyzed using the method described in “Enzymes of protein metabolism.”[6] The reaction mixture is prepared by mixing exactly 0.1 ml of each solution with water up to 1.0 ml and incubated at 25°C for 30 min with shaking. Afterward, 2.0 ml of 12% trichloroacetic acid was added to stop the reaction. The mixture was then centrifuged for 5 min at 2,000 rpm to remove the precipitate and tyrosine hydroxylase activity measured on a 2.0 ml aliquot of supernatant. A zero time control were TCA was added prior to the enzyme served as the blank. While a tyrosine standard containing the same amount of trichloroacetic acid as the experiment tube is carried through each assay. One unit of the hyroxylase enzyme is defined as the amount which catalyzes the formation of 0.1 micromole of tyrosine in 30 min under the condition of the assay. Enzyme activity were determined spectrophotometrically at 280 nm.
Alanine aminotransferase activity
ALT analysis was done according to the method provided by Randox, which involved mixing the reagent provided by the industry with serum of the animals, incubation, and absorbance reading using a spectrophotometer (Randox Laboratories United Kingdom).
Procedure
Exactly 0.1 ml serum was pipette in a test tube and mixed with 0.5 ml of reagent 1, into a second test tube 0.5 ml of reagent 1 was mixed with 0.1 ml of distilled water (reagent blank). Both mixtures was incubated for 30 min at 37°C after which 0.5 ml of reagent 2 were added into each of the test tubes and mixed properly and allowed to stand for 20 min at room temperature. After which 5.0 ml each of sodium hydroxide were to both mixtures. Using a spectrophotometer, the absorbance of the mixtures was read at 546 nm after 5 min following addition of sodium hydroxide.
Calculation
ALT (IUL) = 2742 × △A 546 nm/min, where 2742, = extinction coefficient; △A 564 nm/min = change in absorbance per minute for the homogenate sample.
Aspartate aminotransferase activity
AST analysis was done according to the method provided by Randox, which involved mixing the reagent provided by the industry with serum of the animals, incubation and absorbance reading using a spectrophotometer (Randox Laboratories United Kingdom).
Procedure
AST is measured by monitoring the concentration of oxaloacetate hydrazine formed with 2,4-dinitrophydrazene
Measurement against reagent blank
Exactly 0.1 ml serum was pipette in a test tube and mixed with 0.5 ml of reagent 1, into a second test tube 0.5 ml of reagent 1 was mixed with 0.1 ml of distilled water (reagent blank). Both mixtures was incubated for 30 min at 37°C after which 0.5 ml of reagent 2 were added into each of the test tubes and mixed properly and allowed to stand for 20 min at room temperature. After which 5.0 ml each of sodium hydroxide were to both mixtures. Using a spectrophotometer the absorbance of the mixtures was read at 546 nm after 5 min following addition of sodium hydroxide.
Calculation
AST (IUL) = 2742 × △A 546 nm/min, where 2742, = extinction coefficient; △A 564 nm/min = change in absorbance per minute for the homogenate sample
| Results | | |
Effect monosodium glutamate administration on acetyl-cholinesterase activity
MSG administration caused a significant (P < 0.05) increase in acetylcholinesterase activity versus control. The 4 mg/g body weight neonate plus 10 mg/g body weight adult showed the highest increase in activity though not significant (P > 0.05) versus 10 mg/g body weight adult only and 4 mg/g body weight neonate only. While a similar trend of activity was shown in 4 mg/g body weight neonate plus 5 mg/g body weight adult and 5 mg/g-body weight adult-only [Figure 1]a. | Figure 1: (a) Bar graph showing the effect of MSG administration on acetylcholinesterase activity. Values are expressed as mean ± SEM, n = 6. &P < 0.05 versus normal control, #P < 0.05 versus 4 mg/g-neonate plus 5 mg/g-adult, *P > 0.05 versus 5 mg/g-adult. (b) Bar graph showing the effect of MSG administration on tyrosine hydroxylase activity. All values are expressed as mean ± SEM, n = 6. %P < 0.05 versus normal control, #P < 0.05 versus 4 mg/g-neonate plus 10 mg/g-adult, &P < 0.05 versus 10 mg/g-adult and 4mg/g-neonate. (c) Bar graph showing the effect of MSG administration on alanine aminotransferase activity. All values are expressed as mean ± SEM, n = 6. &P < 0.05 versus normal control and 4 mg/g-neonate plus 10 mg/g-adult, *P > 0.05 versus 5 mg/g-adult. (d) Bar graph showing the effect of MSG admonition aspartate aminotransferase activity. Values are expressed as mean ± SEM, n = 6. #P < 0.05 versus normal control. *P < 0.05 versus 4 mg/g-neonate plus 10 mg/g-adult. $P < 0.05 versus 10 mg/g
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Effect monosodium glutamate administration on tyrosine hydroxylase activity
The administration of MSG caused a significant (P < 0.05) increase in tyrosine hydroxylase activity in all MSG administered groups when compared with the control group. The adult administered groups showed a higher increased activity versus neonate plus adult groups, followed by the neonate only group. In the adult groups, the increase in activity was not significantly different (P > 0.05) [Figure 1]b.
Effect of monosodium glutamate administration on alanine aminotransferase activity
MSG administration caused a dose dependent difference (P < 0.05) in alanine aminotransfaraes activity in all MSG groups versus control group. 10 mg/g-adult group showed the highest activity significantly not different versus 4 mg/g-neonate plus10 mg/g-adult, followed by 4 mg/g-neonate only. MSG administration also caused a nonsignificant (P > 0.05) effect in 4 mg/-neonate plus 5 mg/g-adult and 5 mg/g-adult [Figure 1]c.
Effect of monosodium glutamate administration on aspartate aminotransferase activity
The administration of MSG caused an increase in aspartate aminotransferase activity in the administered groups versus normal control. The adult only groups indicated a higher MSG effect significantly (P < 0.05) higher in 5 mg/g-adult group. MSG administration caused a dose dependent increase in neonate and neonate plus adult administered groups [Figure 1]d.
| Discusion | | |
In this study, the administration of MSG caused a significant effect in the activities of measured enzymes in both neonate, neonate plus adult and adult only administered groups similarly. An indication that MSG from the blood can cross the blood–brain barrier into the brain,[4] even after been fully developed in a similar manner it does during brain development.[11] This result further indicated that MSG administration caused an increase in the activities of enzymes measured in the whole brain when compared with the control, suggesting a possible increase in the level their substrate following MSG administration.[2] Moreover, the enzymes abilities to breakdown and convert the respective substrates into forms that promote their usage as well as clearance from the brain, a sort of defensive measure to protect itself against MSG effects.[11] The difference observed in enzyme activities in whole brain of exposed and control Wistar rats suggests that the blood–brain barrier may not be the major determinate that determine the effect of MSG in the brain of neonate or adult MSG exposed rats.[18] Furthermore, following administration and breakdown of MSG in the liver, substances carried in the blood crossed the blood–brain barrier of the rats into the brain despite age of exposure.[8] This agrees with the report that there exist a direct relationship between the liver and the brain.[9] In this study, the results obtained indicated that MSG administration caused a buildup of substances in the blood,[23] which finds its way across the blood–brain barrier into the central nervous system and lead to increased activities of the measured enzymes when compared to the level obtained in the control group but in neonatal and adult exposed groups this MSG effect occurred similarly.[24] This non differential effect of MSG in both developing brain (neonate) and fully developed brain (adult) have been reported to result in neurological malfunctions.[1] ALT and AST activities were increased in the MSG exposed groups when compared with the control both in neonatal and adult exposed caused by MSG exposure and their role in glutamate metabolism which is the major component of MSG.[25] AST is involved in the synthesis of aspartate during glutamate metabolism, a neurotransmitter which has been shown to increase in rat brain following MSG exposure.[21] A similar result has been reported by Russell,[24] in the ability of toxic substances from MSG used as food additives to pass the blood–brain barrier into the central nervous system (CNS) of infants which is suggested to occur during brain development with little protection from the blood–brain barrier and in adult through unprotected regions of the brain. This is in agreement with the results obtained in ALT and AST in this study which showed an increased in enzymes activities following MSG administration during (in neonate) and after (in adult) development of the blood–brain barrier. Furthermore, these elevation suggests that peripheral MSG exposure may contribute to the accumulation of toxic substances in the CNS and there toxic effects, which are kept very low for proper functioning of the brain.[19]
Acetylcholinesterase is involved in the termination of impulse transmission by rapid hydrolysis of the neurotransmitter acetylcholine in numerous cholinergic pathways in the central and peripheral nervous system[5] and is solely responsible for the breakdown of acetylcholine in the brain.[26] In this report, its activity following the 6 weeks MSG exposure, increased in all the administered groups (both neonate and adult) similarly. An indication that age of exposure or the level of brain barrier development did not affect the activity of acetylcholinesterase. This result is in line with the report of Russell[27] on the effects of MSG in the brain of both young and adult. Furthermore, elevation in activity of actylcholinesterase following chronic intra-peritoneal exposure of MSG through unprotected regions of the brain such as the hypocampus in mouse has been reported.[28] Pointing to the fact that metabolism of MSG caused a buildup substances in the bloodstream which entered the brain through these regions of the matured brain in adult rats and during development in neonates similarly.[21],[29] Tyrosine hyroxylase (TH), plays an important role in the regulation of catecholamine levels in the brain.[7] And have been reported to serve as a rate limiting enzyme in the catecholaime biosynthetic pathway.[20] Using tetrahydrobiopterin in addition to molecular oxygen to convert tyrosine into L-dihydoxyphnyalanine (DOPA) resulting in the breakdown of tyrosine from the CNS.[30] Reports have suggested that TH may play a key role in development of Parkinson's disease via oxidative stress as well as through pro-inflammatory mechanism.[6] In this study, TH activity increased in whole brain of MSG administered groups versus control while among the groups exposed to MSG the enzyme activity occurred similarly and was not determined by the level of blood–brain barrier or age of exposure.[21] This is in contrast to the study of Michael et al.[27] which reported, the in ability of TH to convert tyrosine in a sliced and homogenated rat brain in an appreciable extent following exposure to food additives that cause elevation in tyrosine concentration after exposure. In this study, the sample size were chosen to represent groups capable of identifying an effect where present and not influence the results obtained, and also not too large in other to prevent errors that may come from handling and collection of the results, which indicated that MSG affected both neonatal and adult exposed rats by producing a differential effect when compared with the control.
Study limitation
This current study is limited to the comparative effect of MSG on rats exposed either as neonate, neonate plus adult and adult only, through the measurement of AChE, TH, AST, and ALT activities in the whole brain.
| Conclusion | | |
From the result obtained in this study, it can be concluded that MSG administration caused an increase in the level of AchE, TH, AST, and ALT activities, in the whole brain of neonate and adult exposed Wistar rats. Moreover, the increase in enzyme activities occurred in the same manner indicating the ability of toxic substances from the blood to cross the blood–brain barrier of both in neonate and adult exposed rats in the manner.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1]
[Table 1]
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