Maternal periodontitis potentiates monosodium glutamate-obesity damage on Wistar offspring's fast-glycolytic muscle.

OBJECTIVE: To evaluate the effects of magnifying the damage caused by obesity induced by monosodium glutamate, using a model of maternal periodontitis, on the structure of the anterior tibialis muscle of the offspring. MATERIALS AND METHODS: Twenty-four female Wistar rats were divided into four experimental groups: control (n = 6), obese (n = 6), control with periodontitis (n = 6) and obese with periodontitis (n = 6). At 78 days of life, the rats were mated with males without any experimental intervention. The offspring of these rats (n = 1/L), at 120 days of life, were weighed and measured, then euthanized. Plasma was collected for analysis of cytokines IL-6, IL-10, IL-17 and TNF-α. Adipose tissues were collected and weighed, and the anterior tibial muscle was designated for histomorphological analyses (n = 6/group). RESULTS: Monosodium glutamate offspring showed significant muscle changes, such as a reduction in the size of fibres and neuromuscular junctions, and an increase in the nucleus and capillaries. However, all these changes were more expressed in monosodium glutamate-obese with periodontitis offspring. CONCLUSION: This leads us to suggest a magnifying effect promoted by periodontitis to the damage already well described by monosodium glutamate-obesity, determined by low-intensity inflammation, causing greater muscle damage.

The M 1 -muscarinic acetylcholine receptor subtype may play a role in learning and memory performance in the hippocampus of neonatal monosodium glutamate-obese rats.

Here, we investigate the effects of obesity induced by monosodium glutamate (MSG) on cognitive impairment and whether this model induces any alteration in the affinity, density, and subtypes of muscarinic acetylcholine receptors (mAChRs) in rat hippocampus. Healthy rats were used as controls, and MSG-obese rats were selected via the Lee index > 0.300. The effects of MSG-induced obesity on hippocampal spatial learning and memory processes were evaluated by using the working memory versions of the Morris' water maze task and the evaluation of mAChRs by binding assay and their subtypes by immunoprecipitation assays. [ 3 H]Quinuclidinyl benzilate specific binding analysis showed that the equilibrium dissociation constant (K D ) did not differ between control and MSG, indicating that affinity is not affected by obesity induced by MSG. The maximum number of binding sites (B max ) obtained in MSG subjects was lower than that obtained from control rats, indicating a decrease in the expression of total mAChRs. Immunoprecipitation assays reveal a decrease in the expression of M 1 subtype of MSG when compared with control rats (M 2 to M 5 subtypes did not differ between control and MSG). We also observed that MSG promotes a disruption of the spatial working memory which was accompanied by a decrease in the M 1 mAChR subtype in rat hippocampus, thus suggesting deleterious long-term effects besides the obesity. In conclusion, these findings provide new insights into how obesity can influence spatial learning and memory that is hippocampal-dependent. The data suggest that the M 1 mAChR subtype protein expression is a potential therapeutic target.

An Early and Sustained Inflammatory State Induces Muscle Changes and Establishes Obesogenic Characteristics in Wistar Rats Exposed to the MSG-Induced Obesity Model.

The model of obesity induced by monosodium glutamate cytotoxicity on the hypothalamic nuclei is widely used in the literature. However, MSG promotes persistent muscle changes and there is a significant lack of studies that seek to elucidate the mechanisms by which damage refractory to reversal is established. This study aimed to investigate the early and chronic effects of MSG induction of obesity upon systemic and muscular parameters of Wistar rats. The animals were exposed to MSG subcutaneously (4 mg·g-1 b.w.) or saline (1.25 mg·g-1 b.w.) daily from PND01 to PND05 (n = 24). Afterwards, in PND15, 12 animals were euthanized to determine the plasma and inflammatory profile and to assess muscle damage. In PND142, the remaining animals were euthanized, and samples for histological and biochemical analyses were obtained. Our results suggest that early exposure to MSG reduced growth, increased adiposity, and inducted hyperinsulinemia and a pro-inflammatory scenario. In adulthood, the following were observed: peripheral insulin resistance, increased fibrosis, oxidative distress, and a reduction in muscle mass, oxidative capacity, and neuromuscular junctions, increased fibrosis, and oxidative distress. Thus, we can conclude that the condition found in adult life and the difficulty restoring in the muscle profile is related to the metabolic damage established early on.

Monosodium Glutamate (MSG) Symptom Complex (Chinese Restaurant Syndrome): Nightmare of Chinese Food Lovers!

Chinese food, containing the ingredient monosodium glutamate (MSG) as the main additive agent, results in a variety of symptoms in susceptible individuals. The spectrum of symptoms ranges from headache, sweating, abdominal pain, and urticaria to angioedema in severe cases. This group of symptoms is known as MSG symptom complex or Chinese restaurant syndrome (CRS). We reported one such case with unique dermatological manifestations in a young male, developed on the consumption of Chinese food, noticed first-time as per our knowledge. An adolescent male presented to the Emergency Department with high-grade fever, cough, shock, congested throat, and generalized skin rashes. After giving the history of ingestion of Chinese food prior to symptom onset, we suspected him of a case of CRS; our diagnosis was further supported by raised absolute eosinophil count (AEC) and immunoglobulin E (IgE) levels in the blood. The patient was given intramuscular adrenaline and intravenous corticosteroid in the emergencys department for anaphylaxis, followed by oral antihistaminic.

MORPHOLOGICAL PECULIARITIES OF THE PANCREAS OF MALE RATS AFTER PROLONGED ADMINISTRATION OF MONOSODIUM GLUTAMATE DURING THE RECOVERY PERIOD.

OBJECTIVE: The aim: To study changes in the exocrine and endocrine parts of the pancreas of rats after abolition of monosodium glutamate (MSG) administered in the diet. PATIENTS AND METHODS: Materials and methods: White male laboratory rats with a baseline weight of 120 ± 5 g were randomized into 3 groups: 1 - control, 2 - animals with daily feeding of 70 mg/ kg MSG for 8 weeks, 3 - abolition of MSG with transfer of animals to a standard diet and pancreatic examination after 8 weeks. We used histological studies with morphometric analysis and statistical processing of acini and acinar cell areas, Langerhans islets, connective tissue (according to Stolte M.) and adipose tissue. Preparations of pancreas were stained with hematoxylin and eosin and azan. RESULTS: Results: The animals of groups 2 and 3 showed atrophic, degenerative and inflammatory disturbances in the exocrine and endocrine parts of the pancreas, which worsened after 8 weeks of MSG withdrawal (3 rd group). In the preparations, the Langerhans islets were of different shapes and sizes. Small islets predominated, as well as islets with low density of α- and ß-cells, different capillary filling with blood and overgrowth of connective tissue in the capillary areas. The acinar cells and acini were reduced, and degenerative abnormalities were detected in the structures. CONCLUSION: Conclusions: After daily administration of 70 mg/kg MSG for 8 weeks, atrophic and degenerative changes in the exocrine and endocrine parts of the pancreas were revealed. No recovery of pancreatic structures was observed 8 weeks after MSG withdrawal.

Could Dietary Glutamate Play a Role in Psychiatric Distress?

Glutamate is an amino acid that functions as an excitatory neurotransmitter. It has also been associated with somatic and psychiatric distress and is implicated in the pathophysiology of psychiatric disorders such as schizophrenia. Ingestion of dietary glutamate, such as monosodium glutamate (MSG), has been mechanistically linked with greater distress among patients with chronic pain conditions, though findings have been equivocal. Preliminary research suggests that an MSG-restricted diet confers beneficial effects on somatic symptoms and well-being for some individuals with chronic pain conditions. In addition to associations with somatic distress, glutamate has been associated with the onset and progression of psychiatric symptoms. Thus, the role of dietary glutamate in psychiatric distress represents an underdeveloped and potentially important area for future research aimed at clarifying pathophysiological mechanisms and identifying targets for dietary intervention in psychiatric illnesses.

The Development of Pathological Dependence after Intermittent Use of Sodium Glutamate, but Not Sucrose or Sodium Chloride Solutions.

The possibility of development of dependence was studied during the intermittent consumption of sucrose, sodium chloride, and sodium glutamate solutions. Rats were allowed to choose and consume solutions of sucrose, sodium chloride, and sodium glutamate for 28 days. On days 29-31 of the experiment, the animals were deprived of the preferred solutions. On days 32-33, the solutions of sucrose, sodium chloride, and sodium glutamate, but not water were provided again. The consumption of sucrose and sodium chloride solutions did not increase, but consumption of 0.5 and 1% sodium glutamate solutions increased after 3-days withdrawal. The consumption of 2% solution of sodium glutamate was the same before and after withdrawal. The observed effects of sodium glutamate deprivation probably indicate the development of pathological glutamate dependence.

Gender Differences in the Pharmacological Actions of Pegylated Glucagon-Like Peptide-1 on Endothelial Progenitor Cells and Angiogenic Precursor Cells in a Combination of Metabolic Disorders and Lung Emphysema.

In clinical practice, the metabolic syndrome (MetS) is often associated with chronic obstructive pulmonary disease (COPD). Although gender differences in MetS are well documented, little is known about sex-specific differences in the pathogenesis of COPD, especially when combined with MetS. Consequently, it is not clear whether the same treatment regime has comparable efficacy in men and women diagnosed with MetS and COPD. In the present study, using sodium glutamate, lipopolysaccharide, and cigarette smoke extract, we simulated lipid metabolism disorders, obesity, hyperglycemia, and pulmonary emphysema (comorbidity) in male and female C57BL/6 mice. We assessed the gender-specific impact of lipid metabolism disorders and pulmonary emphysema on angiogenic precursor cells (endothelial progenitor cells (EPC), pericytes, vascular smooth muscle cells, cells of the lumen of the nascent vessel), as well as the biological effects of pegylated glucagon-like peptide 1 (pegGLP-1) in this experimental paradigm. Simulation of MetS/COPD comorbidity caused an accumulation of EPC (CD45-CD31+CD34+), pericytes, and vascular smooth muscle cells in the lungs of female mice. In contrast, the number of cells involved in the angiogenesis decreased in the lungs of male animals. PegGLP-1 had a positive effect on lipids and area under the curve (AUC), obesity, and prevented the development of pulmonary emphysema. The severity of these effects was stronger in males than in females. Furthermore, PegGLP-1 stimulated regeneration of pulmonary endothelium. At the same time, PegGLP-1 administration caused a mobilization of EPC (CD45-CD31+CD34+) into the bloodstream in females and migration of precursors of angiogenesis and vascular smooth muscle cells to the lungs in male animals. Gender differences in stimulatory action of pegGLP-1 on CD31+ endothelial lung cells in vitro were not observed. Based on these findings, we postulated that the cellular mechanism of in vivo regeneration of lung epithelium was at least partly gender-specific. Thus, we concluded that a pegGLP-1-based treatment regime for metabolic disorder and COPD should be further developed primarily for male patients.

Monosodium Glutamate in the Diet Does Not Raise Brain Glutamate Concentrations or Disrupt Brain Functions.

The non-essential amino acid glutamate participates in numerous metabolic pathways in the body. It also performs important physiologic functions, which include a sensory role as one of the basic tastes (as monosodium glutamate [MSG]), and a role in neuronal function as the dominant excitatory neurotransmitter in the central nervous system. Its pleasant taste (as MSG) has led to its inclusion as a flavoring agent in foods for centuries. Glutamate's neurotransmitter role was discovered only in the last 60 years. Its inclusion in foods has necessitated its safety evaluation, which has raised concerns about its transfer into the blood ultimately increasing brain glutamate levels, thereby causing functional disruptions because it is a neurotransmitter. This concern, originally raised almost 50 years ago, has led to an extensive series of scientific studies to examine this issue, conducted primarily in rodents, non-human primates, and humans. The key findings have been that (a) the ingestion of MSG in the diet does not produce appreciable increases in glutamate concentrations in blood, except when given experimentally in amounts vastly in excess of normal intake levels; and (b) the blood-brain barrier effectively restricts the passage of glutamate from the blood into the brain, such that brain glutamate levels only rise when blood glutamate concentrations are raised experimentally via non-physiologic means. These and related discoveries explain why the ingestion of MSG in the diet does not lead to an increase in brain glutamate concentrations, and thus does not produce functional disruptions in brain. This article briefly summarizes key experimental findings that evaluate whether MSG in the diet poses a threat to brain function.

(p-ClPhSe)2 Reduces Hepatotoxicity Induced by Monosodium Glutamate by Improving Mitochondrial Function in Rats.

It is has been demonstrated that mitochondrial dysfunction, oxidative stress, and chronic inflammatory process are associated with progress of morbid obesity in human patients. For this reason, the searching for safe and effective antiobesity drugs has been the subject of intense research. In this context, the organic selenium compounds have attracted much attention due to their pharmacological properties, such as antihyperglycemic, antioxidant, and anti-inflammatory. The aim of this study was to evaluate the hepatoprotective action of p-chloro-diphenyl diselenide (p-ClPhSe)2 , an organic selenium compound, in a model of obesity induced by monosodium glutamate (MSG) administration in rats. Wistar rats were treated during the first ten postnatal days with MSG (4 g/kg by subcutaneous injections) and received (p-ClPhSe)2 (10 mg/kg, intragastrically) from 90th to 97th postnatal day. Mitochondrial function, purine content and the levels of proteins involved in apoptotic (poly [ADP-ribose] polymerase [PARP]) and inflammatory processes (inducible nitric oxide synthases [iNOS] and p38) were determined in the liver of rats. The present study, demonstrated that postnatal administration of MSG to male rats induced a mitochondrial dysfunction, accompanied by oxidative stress and an increase in the ADP levels, without altering the efficiency of phosphorylation in the liver of adult rats. Furthermore, the MSG administration also induces hepatotoxicity, through an increase in PARP, iNOS, and p38 levels. (p-ClPhSe)2 treatment had beneficial effects against mitochondrial dysfunction, oxidative stress, and modulated protein markers of apoptosis and inflammation in the liver of MSG-treated rats. J. Cell. Biochem. 118: 2877-2886, 2017. © 2017 Wiley Periodicals, Inc.

Taurine supplementation regulates Iκ-Bα protein expression in adipose tissue and serum IL-4 and TNF-α concentrations in MSG obesity.

PURPOSE: Obesity is usually associated with low-grade inflammation, which impairs insulin action. The amino acid, taurine (TAU), regulates glucose homeostasis and lipid metabolism and presents anti-inflammatory actions. Here, we evaluated whether inflammatory markers are altered in the serum and retroperitoneal adipose tissue of monosodium glutamate (MSG) obese rats, supplemented or not with TAU. METHODS: Male Wistar rats received subcutaneous injections of MSG (4 mg/kg body weight/day, MSG group) or hypertonic saline (CTL) during the first 5 days of life. From 21 to 120 days of age, half of each of the MSG and CTL groups received 2.5 % TAU in their drinking water (CTAU and MTAU). RESULTS: At 120 days of age, MSG rats were obese and hyperinsulinemic. TAU supplementation reduced fat deposition without affecting insulinemia in MTAU rats. MSG rats presented increased pIκ-Bα/Iκ-Bα protein expression in the retroperitoneal adipose tissue. TAU supplementation decreased the ratio of pIκ-Bα/Iκ-Bα protein, possibly contributing to the increased Iκ-Bα content in MTAU adipose tissue. Furthermore, MSG obesity or supplementation did not alter TNF-α, IL-1ß or IL-6 content in adipose tissue. In contrast, MSG rats presented lower serum TNF-α, IL-4 and IL-10 concentrations, and these alterations were prevented by TAU treatment. CONCLUSION: MSG obesity in rats was not associated with alterations in pro-inflammatory markers in retroperitoneal fat stores; however, reductions in the serum concentrations of anti-inflammatory cytokines and of TNF-α were observed. TAU treatment decreased adiposity, and this effect was associated with the normalization of circulating TNF-α and IL-4 concentrations in MTAU rats.

Effect of exclusion of frequently consumed dietary triggers in a cohort of children with chronic primary headache.

BACKGROUND: Although dietary factors are known to trigger headaches, the relationship between food and headache in children remains unclear. This prospective, observational case series aimed to evaluate the effect of exclusion of frequently-consumed foods in a cohort of children with headache. METHODS: One hundred and fifteen children aged 3-15 (mean 10.5) years with primary headache were followed in a paediatric outpatient clinic. Patients who frequently consumed foods or food additives known to trigger headaches were advised to exclude them for six weeks and to return for follow-up with headache and food diary. RESULTS: One hundred patients attended follow-up. Of these 13 (13%) did not respond to dietary exclusion; 87 (87%) achieved complete resolution of headaches by exclusion of 1-3 of the identified food(s). Caffeine was the most common implicated trigger (28), followed by monosodium glutamate (25), cocoa (22), aspartame (13), cheese (13), citrus (10) and nitrites (six). One patient was sensitive to tomatoes. CONCLUSIONS: This study demonstrates the potential scale and significance of seven frequently consumed foods or food additives as triggers for primary headache in children. Also this is the first study to show that headaches can be triggered by the cumulative effect of a food that is frequently consumed, rather than by single time ingestion.

Ginger and Propolis Exert Neuroprotective Effects against Monosodium Glutamate-Induced Neurotoxicity in Rats.

Central nervous system cytotoxicity is linked to neurodegenerative disorders. The objective of the study was to investigate whether monosodium glutamate (MSG) neurotoxicity can be reversed by natural products, such as ginger or propolis, in male rats. Four different groups of Wistar rats were utilized in the study. Group A served as a normal control, whereas group B was orally administered with MSG (100 mg/kg body weight, via oral gavage). Two additional groups, C and D, were given MSG as group B along with oral dose (500 mg/kg body weight) of either ginger or propolis (600 mg/kg body weight) once a day for two months. At the end, the rats were sacrificed, and the brain tissue was excised and levels of neurotransmitters, ß-amyloid, and DNA oxidative marker 8-OHdG were estimated in the brain homogenates. Further, formalin-fixed and paraffin-embedded brain sections were used for histopathological evaluation. The results showed that MSG increased lipid peroxidation, nitric oxide, neurotransmitters, and 8-OHdG as well as registered an accumulation of ß-amyloid peptides compared to normal control rats. Moreover, significant depletions of glutathione, superoxide dismutase, and catalase as well as histopathological alterations in the brain tissue of MSG-treated rats were noticed in comparison with the normal control. In contrast, treatment with ginger greatly attenuated the neurotoxic effects of MSG through suppression of 8-OHdG and ß-amyloid accumulation as well as alteration of neurotransmitter levels. Further improvements were also noticed based on histological alterations and reduction of neurodegeneration in the brain tissue. A modest inhibition of the neurodegenerative markers was observed by propolis. The study clearly indicates a neuroprotective effect of ginger and propolis against MSG-induced neurodegenerative disorders and these beneficial effects could be attributed to the polyphenolic compounds present in these natural products.

Homeostatic effect of p-chloro-diphenyl diselenide on glucose metabolism and mitochondrial function alterations induced by monosodium glutamate administration to rats.

The metabolic syndrome is a group of metabolic alterations considered a worldwide public health problem. Organic selenium compounds have been reported to have many different pharmacological actions, such as anti-hypercholesterolemic and anti-hyperglycemic. The aim of this study was to evaluate the effect of p-chloro-diphenyl diselenide (p-ClPhSe)2, an organic selenium compound, in a model of obesity induced by monosodium glutamate (MSG) administration in rats. The rats were treated during the first ten postnatal days with MSG and received (p-ClPhSe)2 (10 mg/kg, intragastrically) from 45th to 51 th postnatal day. Glucose, lipid and lactate levels were determined in plasma of rats. Glycogen levels and activities of tyrosine aminotransferase, hexokinase, citrate synthase and glucose-6-phosphatase (G-6-Pase) were determined in livers of rats. Renal G-6-Pase activity was also determined. The purine content [Adenosine triphosphate (ATP), adenosine diphosphate (ADP) and adenosine monophosphate] and mitochondrial functionality in the liver were also investigated. p-(ClPhSe)2 did not alter the reduction in growth performance and in the body weight caused by MSG but reduced epididymal fat deposition of rats. p-(ClPhSe)2 restored glycemia, triglycerides, cholesterol and lactate levels as well as the glucose metabolism altered in rats treated with MSG. p-(ClPhSe)2 restored hepatic mitochondrial dysfunction and the decrease in citrate synthase activity and ATP and ADP levels caused by MSG in rats. In summary, (p-ClPhSe)2 had homeostatic effects on glucose metabolism and mitochondrial function alterations induced by MSG administration to rats.

Metabolomic profiling of urinary changes in mice with monosodium glutamate-induced obesity.

Obesity with related complications represents a widespread health problem. The etiopathogenesis of obesity is often studied using numerous rodent models. The mouse model of monosodium glutamate (MSG)-induced obesity was exploited as a model of obesity combined with insulin resistance. The aim of this work was to characterize the metabolic status of MSG mice by NMR-based metabolomics in combination with relevant biochemical and hormonal parameters. NMR analysis of urine at 2, 6, and 9 months revealed altered metabolism of nicotinamide and polyamines, attenuated excretion of major urinary proteins, increased levels of phenylacetylglycine and allantoin, and decreased concentrations of methylamine in urine of MSG-treated mice. Altered levels of creatine, citrate, succinate, and acetate were observed at 2 months of age and approached the values of control mice with aging. The development of obesity and insulin resistance in 6-month-old MSG mice was also accompanied by decreased mRNA expressions of adiponectin, lipogenetic and lipolytic enzymes and peroxisome proliferator-activated receptor-gamma in fat while mRNA expressions of lipogenetic enzymes in the liver were enhanced. At the age of 9 months, biochemical parameters of MSG mice were normalized to the values of the controls. This fact pointed to a limited predictive value of biochemical data up to age of 6 months as NMR metabolomics confirmed altered urine metabolic composition even at 9 months.

Influence of diet supplementation with green tea extract on drug-metabolizing enzymes in a mouse model of monosodium glutamate-induced obesity.

PURPOSE: Consumption of dietary supplements with green tea extract (GTE) is popular for weight management, but it may be accompanied by various side effects, including interactions with drugs. The aim of the present in vivo study was to evaluate the effect of defined GTE (Polyphenon 60) in three dosage schemes on insulin, leptin and drug-metabolizing enzymes in obese mice. METHODS: Experimental obesity was induced by repeated s.c. application of monosodium glutamate to newborn mice. Green tea extract was administered in three dosage schemes in chow diet. The plasmatic levels of insulin and leptin were assayed using enzyme-linked immunosorbent assay. Enzyme activities and mRNA expressions of drug-metabolizing enzymes (totally 13) were analyzed in liver and small intestine using spectrophotometric and HPLC assays and RT-PCR, respectively. RESULTS: GTE-treatment decreased insulin and leptin levels. Eleven enzymes were significantly affected by GTE-treatment. Long-term administration of 0.01% GTE caused increase in the activity and mRNA level of cytochrome P450 3A4 (CYP3A4) ortholog in the liver as well as in the small intestine. Interestingly, short-term overdose by GTE (0.1%) had more pronounced effects on enzyme activities and mRNA expressions than long-term overdose. CONCLUSIONS: GTE-mediated induction of CYP3A4 ortholog, the main drug-metabolizing enzyme, could result in decreased efficacy of simultaneously or subsequently administered drug in obese individuals.

PGC-1α may associated with the anti-obesity effect of taurine on rats induced by arcuate nucleus lesion.

OBJECTIVE: To observe the effect of taurine treatment in rats with monosodium glutamate (MSG)-induced obesity. METHODS: Rats with MSG-induced obesity were administered taurine for five weeks. The Lee's index, food intake, blood pressure, body temperature, body mass index (BMI), fat weight, and triglyceride (TG), low density lipoprotein (LDL), and high density lipoprotein (HDL) levels were compared. The PGC-1α expression levels in white and brown adipose were measured using reverse transcription polymerase chain reaction and western blotting, and pathological changes in the arcuate nucleus and liver were examined. RESULTS: Compared with the model group, BMI, TG, and LDL in the high and low taurine dose groups were significantly lower, while HDL was higher. Body temperature in the taurine treatment groups was higher, and blood pressure was lower. The weight of brown fat in the taurine treatment groups was significantly higher than in the model group, while the white fat weight was significantly lower. Compared with the control group, the PGC-1α levels in white and brown adipose were higher in the taurine treatment groups and more significantly up-regulated in brown adipose. DISCUSSION: This study suggests that taurine prevents obesity in MSG-treated rats and may be closely associated with energy metabolism.

Does monosodium glutamate really cause headache? : a systematic review of human studies.

Although monosodium glutamate (MSG) is classified as a causative substance of headache in the International Classification of Headache Disorders 3rd edition (ICHD-III beta), there is no literature in which causal relationship between MSG and headache was comprehensively reviewed. We performed systematic review of human studies which include the incidence of headache after an oral administration of MSG. An analysis was made by separating the human studies with MSG administration with or without food, because of the significant difference of kinetics of glutamate between those conditions (Am J Clin Nutr 37:194-200, 1983; J Nutr 130:1002S-1004S, 2000) and there are some papers which report the difference of the manifestation of symptoms after MSG ingestion with or without food (Food Chem Toxicol 31:1019-1035, 1993; J Nutr 125:2891S-2906S, 1995). Of five papers including six studies with food, none showed a significant difference in the incidence of headache except for the female group in one study. Of five papers including seven studies without food, four studies showed a significant difference. Many of the studies involved administration of MSG in solution at high concentrations (>2 %). Since the distinctive MSG is readily identified at such concentrations, these studies were thought not to be properly blinded. Because of the absence of proper blinding, and the inconsistency of the findings, we conclude that further studies are required to evaluate whether or not a causal relationship exists between MSG ingestion and headache.