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Year : 2012  |  Volume : 2  |  Issue : 3  |  Page : 251-257

Monosodium glutamate modulates the circadian rhythms of biochemical variables and behavioral activity in rats under constant light

1 Department of Biotechnology, Faculty of Science, Vysya College, Salem, India
2 Department of Chemistry, Velammal Engineering College, Velammal Nagar, Ambattur-Red Hills Road, Chennai, India
3 Department of Biotechnology, Faculty of Science, Periyar University, Salem, India
4 Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Tamilnadu, India

Date of Web Publication8-Aug-2012

Correspondence Address:
Perumal Subramanian
Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar - 608 002, Tamil Nadu
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2231-0738.99479

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Introduction: Suprachiasmatic nuclei (SCN) contained a variety of neurotransmitters and neuropeptides, and many of them could influence the activities of the circadian pacemaker. Glutamate was the major excitatory neurotransmitter in the mammalian central nervous system (CNS) and in SCN. Materials and Methods: Monosodium glutamate (MSG) (50 mg / kg body weight) was administered subcutaneously for 60 days to Wistar rats; open-field behavioral activity and 24-hour rhythms of glucose, cholesterol, total protein, phospholipids, aspartate transaminase (AST), and alkaline phosphatase (ALT) were studied under conditions of constant light (LL). Results: An open-field behavioral test showed that peripheral movement, central movement, rearing and grooming, were significantly decreased in LL, MSG and LL (MSG-treated) rats when compared with the control rats . The study revealed that the acrophase, amplitude, and mesor values of the glucose, protein, lipid profile, and liver marker enzymes of these rhythms were found to be altered in the experimental group rats when compared with the control rats. Conclusion: Monosodium glutamate, under constant light, modulated the circadian rhythms of lipid profiles and liver marker enzymes, which could be due to glutamate conveying the photic information to the SCN.

Keywords: Circadian rhythm, constant light, monosodium glutamate, suprachiasmatic nucleus

How to cite this article:
Kumaravel P, Subash S, Seethalakshmi KS, Murugan N, Yuvarajan R, Subramanian P. Monosodium glutamate modulates the circadian rhythms of biochemical variables and behavioral activity in rats under constant light. Int J Nutr Pharmacol Neurol Dis 2012;2:251-7

How to cite this URL:
Kumaravel P, Subash S, Seethalakshmi KS, Murugan N, Yuvarajan R, Subramanian P. Monosodium glutamate modulates the circadian rhythms of biochemical variables and behavioral activity in rats under constant light. Int J Nutr Pharmacol Neurol Dis [serial online] 2012 [cited 2023 Feb 1];2:251-7. Available from:

   Introduction Top

The circadian clock is an evolutionary, highly conserved feature of bacteria, plants, and animals that allows organisms to adapt their physiological processes to the time of day in an anticipatory fashion. [1],[2] This internal timing mechanism coordinates the biochemical, physiological, and behavioral processes, to maintain synchrony with the environmental cycles of light, temperature, and nutrients. Circadian rhythms reflect the extensive programming of biological activities that meet and exploit the challenges and opportunities offered by the periodic nature of the environment. [2]

In mammals, circadian rhythms are driven by a timing system comprised of a master pacemaker in the SCN of the hypothalamus and peripheral oscillators located throughout the organism. Independent circadian oscillators exist within each cell of almost every tissue and / or organ investigated, including the liver and heart. [3],[4] The SCN adjusts its phase in response to this photic and nonphotic input, thereby maintaining its synchronization with the external world, by communicating the phase information to oscillators in tissues elsewhere in the brain, and in nearly all other tissues. [5]

Light is the most relevant cue for circadian entrainment, although nonphotic stimuli also function as zeitgebers or time givers. [6],[7] More recently, epidemiological studies have cited associational evidence that night shift work and exposure to light at night are risk factors for breast cancer. [8],[9] The suppression of melatonin by light exposure during shifts extending over the usual hours of nighttime darkness, have been postulated, and are supported by some experimental evidence in animals. [10] Constant light (LL) causes the release of glutamate, which initiates a signal transduction cascade in the SCN neurons that ultimately results in a phase shift of the circadian system. [11] Continuous exposure of bright light strongly suppresses the circadian rhythms of the sleep-wake cycle, drinking, locomotion, and body temperature. [12] Behavioral arousal or activation as well as the emotionality elicited by a novel environment is frequently analyzed by the open-field procedure. Behavioral arousal can be quantified by exploratory behaviors such as sniffing, walking, and rearing. [13],[14]

Monosodium glutamate is the sodium salt of an amino acid, glutamic acid. It has another name ajinomoto. It is used as a food additive, which causes only minor alterations in adults. Glutamic acid is one of the most abundant amino acids found in nature and exists as a free glutamate. [15] Glutamate is a major excitatory neurotransmitter in the brain and the most abundant amino acid in our daily diet. Excitatory action may, however, also lead to toxic effects related to excessive accumulation of extracellular glutamate. [16],[17] In vivo concentration of both the excitatory amino acid aspartate and glutamate have been seen to be higher during the dark phase than during the light phase in the rat SCN, in the LD (light-dark) cycle, and these are the major stimulatory neurotransmitters in the mammalian nervous system. [18] Glutamate in high doses produces neuroendocrine abnormalities, [19] neurodegeneration, neurotoxicity, [20] and oxidative damage in different organs. [21],[22]

   Materials and Methods Top

Adult male Wistar rats (180 - 200 g) were obtained from the Central Animal House, Faculty of Medicine, Annamalai University. The rats were housed in polypropylene cages at room temperature (30 ± 2° C) under semi-natural conditions. [23] The animals were maintained in natural light-dark cycles (12 : 12 hours) in an experimental room, under natural conditions. [24] All the animals were fed with the standard pellet diet (Hindustan Lever Ltd., Bangalore, India) and water was available ad libitum. Food and water were replenished daily. The experimental protocol was approved by the Committee for Research and Animal Ethics, Annamalai University (Vide No: 587/2008) and were in accordance with the guidelines of the National Institute of Nutrition (NIN), Indian Council of Medical Research (ICMR), Hyderabad, India.

The animals were randomized and divided into four groups (n = 6 in each group). MSG (50 mg / kg) was injected subcutaneously in group III and group IV rats, once a day, for 60 days. MSG was obtained from Himedia, Mumbai, India. Group - I Control (LD 12:12), Group - II Constant light (LL), Group- III MSG administration (50 mg / kg, subcutaneously), Group - IV Constant light condition + MSG administration (50 mg / kg, subcutaneously).

Open-field behavior is a simple test to evaluate the status of the animal by placing the animal in a brightly lit rectangular box (100 x 100 cm) with 40 cm height, made with walls of plywood. The floor consists of a clean plastic material painted in black dividing the field into 25 (5 x 5) equal squares. The rats are placed in the corner of the rectangular box and their behavior is observed for five minutes. This elicits a series of behavior-like peripheral and central movements and motor activity like grooming and rearing, related to the emotional status of the animal. [25]

After the experimental period, blood samples were collected after every four hours from each group of experimental and control rats (00:00, 04:00, 08:00, 12:00, 16:00, 20:00 and 24:00 hours) throughout the 24-hour period continuously. Minimal amount of blood was collected from the orbital sinus, with great care, using heparinized tubes. [26] Blood glucose was determined by using the O-toluidine method of Fings et al. [27] Briefly, 0.1 ml of blood was precipitated with 1.9 ml of 10% trichloro acetic acid (TCA), and the precipitate was removed after centrifugation. Next, 1 ml of supernatant was mixed with 4 ml of O-toluidine reagent and kept in a boiling water bath for eight minutes and cooled. The absorbance was read at 640 nm. Glucose was expressed as milligrams per deciliter of blood. Plasma cholesterol was estimated by the method of Zak et al. [28] Plasma of 0.1 ml and 4.9 ml of ferric chloride acetic acid reagent were mixed well and allowed to stand for 15 minutes to flocculate. Centrifuged and 3 ml of sulfuric acid was added to the supernatant. The chlolesterol in acetic acid gave a purple color with ferric chloride and sulfuric acid; the color developed was read at 560 nm.

Subsequently, the protein in the enzyme extract was determined using the method of Lowry et al. [29] The CO-NH group (peptide bond) present in the protein molecule reacted with the copper sulfate in the alkaline medium to give a blue color, which was read at 620 nm. Phospolipids in the serum were estimated by the method of Zilversmit et al. [30] This involved the conversion of organic phosphorus to inorganic phosphorus, which reacted with the ammonium molybdate to form phosphomolybdic acid. This on treatment with amino naphthol sulfonic acid (ANSA) formed a stable blue color, which was read at 680 nm.

The activities of AST were assayed by the method of Reitman and Frankel. [31] A 0.2 ml aliquot of serum with 1 ml of substrate (aspartate and α-ketoglutarate (KG) in phosphate buffer (pH 7.4)) was incubated for one hour. A 1 ml aliquot of 2,4-dinitrophenylhydrazine (DNPH) solution was added to arrest the reaction, and kept for 20 minutes at 25°C. After incubation, 1 ml of 0.4 N NaOH was added and the absorbance was read at 540 nm. The activities were expressed as IU / L. The ALP was assayed by the method of King and Armstrong. [32] The ALP activity was assayed using disodium phenylphosphate as a substrate. After preincubation of the buffer (0.1 M bicarbonate buffer, pH 10) with the substrate for 10 minutes, 0.2 ml of serum was added and incubated for 15 minutes at 25°C. The liberated phenols from the substrate reacted with a Folin-Phenol reagent (1 ml). The suspension was centrifuged and collected as the supernatant. An aliquot of 10% sodium bicarbonate 2 ml was added to the supernatant and the color that developed was read at 680 nm after 10 minutes. Activities of the ALP were expressed as IU / L.

The values of the variables (mean ± SD) were plotted versus the time of blood collection. Measurements of the acrophase (φ - measure of the peak time of the variable studied), amplitude (A - corresponded to half the total rhythmic variability in a cycle), mesor (M - rhythm adjusted mean), and 'r' values were calculated by the cosinor analysis using the 'cosinorwin' computer software program. [23]

Yti = M + A Cos (ωt - φ)

Where, Yti - Cosine function at the time point, M - Mesor, A - Amplitude, t - Time, φ - Phase.

   Results Top

The glutamate level was found to be increased in the brain tissues of group II animals (15.56 ± 0.18 μ mole / g tissue) and group IV animals (13.23 ± 0.78 μ mole / g tissue) compared to the control animals. However, there was no alteration in the levels of LL (MSG-treated rats). [Figure 1] shows the open-field behavioral activity as a peripheral movement where central movement, grooming, and rearing were significantly decreased in groups II, III, and IV, when compared with the control rats.
Figure 1: Open-field behavioral activity of Peripheral movement, Central movement, Grooming, and Rearing in control and experimental rats. Values are given as mean ± S.D from six rats in each group. Values not sharing a common superscript differ significantly at P < 0.05 (DMRT).

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The biochemical variables measured in this study showed marked fluctuations over a 24-hour period in all the groups. The characteristics of rhythm with the r and p values indicated a detectable rhythmicity or non-significant temporal variation over a 24-hour period. The acrophase of the circadian rhythm of glucose was found at 00:32 hours in group I rats; in the case of group II, group III, and group IV rats maximum glucose levels were found at 22:57, 01:33, and 02:10 hours, respectively [Table 1]. The significantly increased mesor and decreased amplitude values were seen in groups II, III, IV rats, when compared with group I rats. Cholesterol activity showed peaking at 18:27 hours in normal and at 17:59 hours in MSG-treated rats, respectively. Acrophase was delayed in groups III and IV when compared to control rats. Increased mesor was found in groups III and IV, whereas, group II animals show decreased mesor values when compared to control rats, as shown in [Table 1].
Table 1: Temporal variation of glucose, cholesterol, and total protein in control and experimental rats

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Peak activities of total protein were found during 07:29 and 08:10 hours in normal and MSG-treated rats, respectively. The acrophase was advanced in groups III and IV and a delay in group II, when compared to group I rats [Table 1]. The level of phospholipid was found to be at the peak at 11:18 hours in group I rats and maximum value of phospholipid in groups II, III, and IV rats was seen at 02:48, 09:55, and 12:12 hours, respectively. The amplitude and mesor values were altered significantly in groups ii, iii, 0 and IV, when compared with group I rats [Table 2]. Acrophase of AST activity revealed maximum activity in group I animals at 23:19 hours and in groups ii0 , III, and IV animals at 17:32, 02:43, and 21:17 hours, respectively. Increased mesor values were seen in groups II, III, and IV rats when compared with group I rats. The significant temporal variations of ALP over the 24-hour period. The acrophase of ALP was delayed in groups II, III, and IV, when compared to group I rats. The mesor value was increased in groups III and IV and decreased in group II, when compared to group I rats, as shown in [Table 2].
Table 2: Rhythmic pattern of Phospholipid, AST and ALP in control and experimental rats

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   Discussion Top

Open-field behavioral test revealed that peripheral movement, central movement, rearing, and grooming, were significantly decreased in LL, MSG, and LL (MSG-treated) rats, when compared with control rats. LL-induced changes in circadian behaviour paralleled changes in the neuronal discharge of the SCN wherein high neuronal discharge occurred when locomotor activity was at its minimal level. [33] MSG or hypertonic saline treatment resulted in decreased intensity of locomotor activity, and a slow down of its uninterrupted habituation in the open-field test was observed in adult male rats. Reduced behavioral (locomotor) activities in MSG-treated rats might be due to excess activation of NMDA receptor cause lipid peroxidation in the brain and tissues. In LL-exposed and LL (MSG-treated) rats reduced locomotor activities were seen, which might be due to the (i) changes in the levels of acetylcholine and also modified cortisol, serotonin, GABA, and NPY in rat SCN, (ii) increased lipid peroxidation, (iii) modulates the pituitary and pineal glands, which leads to neuroendocrine hormonal level changes such as, melatonin, norepinephrine, and so on. [34],[35],[36],[37]

The peak and nadir values of glucose over a 24-hour period are well correlated with the temporal pattern of food intake, digestion, and accumulation of glucose in blood, [38] with the pervious reports demonstrating peak activity of glycolytic enzymes [39] during the night. Elevated levels of glucose in group II treated rats is due to increased peroxidation of lipids in red blood cells yielding free radicals. [40] Increased mesor of glucose in groups II and IV rats may be due to constant light, which can cause elevated catecholamines and / or corticosterone from the adrenal gland [41] and a peak level of glucagons. [42]

In addition free cholesterol of plasma low-density lipoproteins and high-density lipoproteins of the rats were high during the dark period. [43] Increased mesor of cholesterol in groups I i0 and IV might be due to the elevated lipid contents, which resulted in increased peroxidation in red blood cells. [40] LL caused elevated levels of corticosterone leading to decreased cholesterol synthesis, [44] this could be the reason for decreased amplitude and mesor values of cholesterol in group II rats. In rats, the rate-limiting enzyme (HMG CoA reductase) activity was shown to be high, [45, 46] and those of cholesterol biosynthesis precursors such as squalene and lanosterol were found to be higher [43] at midnight. LL caused elevated levels of corticosterone leading to decreased cholesterol synthesis. [44] This could be the reason for decreased amplitude and mesor values of cholesterol in group II rats.

The present study showed the peak time of total protein at 07:29 hours in group I rats; which corroborated with the previous reports. [47] Total protein rhythmicity was mainly attributed to the positive and negative balance between synthesis and degradation of protein. [48] Decreased mesor of total protein rhythm in groups II and IV, due to continuous light, caused restricted food access and acted directly upon the overt rhythm, without affecting the circadian oscillator. [49] A circadian rhythm of the content of total and individual phospholipids was found in the albino rat liver by biochemical methods. The phospholipid content and enzyme activity were higher during the daytime, 09:00 to 15:00 hours. The level of phospholipid was found to be at the peak at 11:18 hours in normal rats, which was corroborating with the previous reports. [50] The amplitude and mesor values were altered significantly in groups ii, iii, 0 and IV, when compared with group I rats.

The diurnal rhythms of many enzymes, including lactate dehydrogenase, aspartate transaminase, alanine transaminase, alkaline phosphatase, and acid phosphatase were well-documented. [51] Increased ALP activity in neonatal MSG-treated rats suggested that despite sustained hypophagia, their increased body fat content could also be caused by changes in the intestinal function. [52] The diurnal rhythms of plasma alkaline phosphatase were well-established in Wistar rats, the rhythms of ALP were not affected by the activity status of the animal, but they were synchronized by the environment factors like LD cycles. [23] Increased AST activity in the serum was generally accepted as an index of liver damage. [53] It was generally believed that one of the most important functions of AST was to transport reducing equivalents from cytosolically reduced NAD into the mitochondria by the 'malate-aspartate shuttle,' for production of energy. AST catalyzed the reversible transamination between aspartate and 2-oxoglutarate, to yield glutamate and oxaloacetate. [54]

Glutamate levels in the brain were increased in MSG-treated rats when compared to control rats. MSG administration did increase the glutamate levels within the arcuate nucleus dialysates, and plasma glutamate might be involved in the regulation of the blood brain barrier (BBB) permeability. [55] When the glutamate receptors, which were also demonstrated in cerebral capillaries, were overstimulated, a breakdown of the BBB could occur. [56],[57] A high dose of glutamate, particularly in young rats, was found to induce convulsions leading to increased cerebrovascular permeability. [58] Acute and chronic intake of relatively high doses of MSG, in adult rats, on the extracellular glutamate levels were altered in the hippocampus and hypothalamus, two brain areas particularly susceptible to glutamate-induced neurotoxicity. [59]

   Conclusion Top

The present study concludes that the administration of MSG under constant light treatment was found to cause acrophase delays in the glucose, phospholipid, aspartate transaminase rhythms, and advances in acrophases of cholesterol, alkaline phosphatase, and total protein levels. Glutamate levels in the brain were found to be significantly increased, which could alter these biochemical rhythms by modulating transmission in the retinohypothalamic tract and in the hypothalamic nuclei, probably including suprachiasmatic nuclei.

However, to elucidate the mechanisms, further research on neuroendocrine rhythms is needed.

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