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Brain Damage in Infant Mice following Oral Intake of Glutamate, Aspartate or Cysteine
Abstract
STRIKING degenerative changes in the infant mouse retina after
subcutaneous treatment with monosodium glutamate (MSG) were reported by
Lucas and Newhouse in 19571. Other studies2-6
established that the process of retinal degeneration induced by MSG
treatment is a remarkably acute and irreversible form of neuronal
pathology. Recently it was found that a similar process of acute
neuronal necrosis occurs in several regions of the infant mouse brain
after subcutaneous treatment with MSG, and that animals treated with
high doses in infancy tend to manifest obesity and neuroendocrine
disturbances as adults7,8. The arcuate nucleus of the
hypothalamus is an area particularly vulnerable to glutamate induced
damage in infant animals of several species (mice and rats7,
rabbits and chicks and the rhesus monkey9). In mice, which
have been studied more extensively for MSG induced disturbances than
other species, the infant animal suffered hypothalamic damage from a
relatively low subcutaneous dose (0.5 g/kg of body weight)7.
... [1] Aspartic acid (aspartate) is a second excitotoxic amino acid, found in quantity in processed foods. [2] It causes brain damage just as glutamate does. It also causes the same adverse reactions, which occur with the same relative frequency in people who are sensitive to excitotoxins. ...
... [3,4] Glutamate and aspartate are structural analogs that work synergistically, working in an additive fashion to promote brain damage. [2] The synergy of MSG with Disodium 5ʹ-guanylate, Disodium 5ʹinosinate and Disodium 5ʹ-ribonucleotides, which is often referred to by industry, has to do with flavor enhancement, not toxicity. ...
... In the decade that followed, research confirmed that glutamate induces hypothalamic damage when given to immature animals after either subcutaneous [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24] or oral [2,12,18,19,[25][26][27][28][29][30] doses. In the 1980s, researchers began to focus on identifying and understanding abnormalities associated with glutamate, often for the purpose of finding drugs that would mitigate glutamate's adverse effects. ...
L-glutamate, the major neurotransmitter in humans, becomes excitotoxic when present outside of protein in excess of what the healthy human was designed to accommodate; amounts readily available to consumers who ingest multiple free-glutamate-containing ingredients during a day. Studies have demonstrated that excitotoxins ingested by a mother will pass to the fetus across the placenta and pass to the newborn through mothers’ milk. The purpose of this paper is to raise awareness of the relevance of glutamate from food additives such as MSG to human brain damage, and its possible contributions to glutamate toxicity in neurodegenerative diseases, stroke, autism, schizophrenia, depression, obsessive-compulsive disorder, epilepsy, seizures, addiction, attention-deficit/hyperactivity disorder, autism, headaches, asthma, diabetes, muscle pain, atrial fibrillation, ischemia, and trauma.
... Monosodium glutamate (MSG) is a natural constituent of human daily foods, even for infant consumption (Olney & Ho, 1970). However, more and more investigations revealed that MSG injection can damage hypothalamic neurons of both neonatal mice (Olney & Ho, 1970) and adult mice (Park et al., 2000), which eventually leads to obesity. ...
... Monosodium glutamate (MSG) is a natural constituent of human daily foods, even for infant consumption (Olney & Ho, 1970). However, more and more investigations revealed that MSG injection can damage hypothalamic neurons of both neonatal mice (Olney & Ho, 1970) and adult mice (Park et al., 2000), which eventually leads to obesity. MSG model is usually characterized by severe abdominal obesity (Ma, Zhang, Mou, Fu, & Chen, 2018). ...
... John W. Olney et al. clearly presented the hypothalamus lesion formation 3 h after a subcutaneous dose of MSG (Olney, 1969). The degree of hypothalamus damage exhibited a dose-dependent manner (Olney & Ho, 1970). Taking into consideration the medical functions of Coicis Semen, we wondered whether Coicis Semen formula could alleviate hypothalamic injury and further treat MSG-induced obesity in mice. ...
Obesity is a worldwide public health issue, however, efficient strategies to treat obesity without systemic damage is still in serious lack. Herein, we proved that a significant decrease in body weight and abdominal circumference was observed when monosodium glutamate (MSG)-induced obese mice were orally treated with Coicis Semen formula. Consistently, computed tomography and magnetic resonance imaging results showed that both whole-body fat content and subcutaneous fat thickness were lowered, which was further confirmed by hematoxylin–eosin staining. In addition, the weight ratios of adipose tissues and liver to the body weight were reduced, due to the decreased lipid accumulation. The increased triacylglycerol, total cholesterol, and inflammatory cytokines could also be downregulated after the treatment. Furthermore, the neuronal injury marker and inflammatory cytokines in the hypothalamus were obviously reduced after the treatment, revealing that the protective effect of Coicis Semen formula on MSG-induced obesity was achieved by alleviating hypothalamic injury.
... T and B cell activation is enhanced by IL-1 (Golub & Green, 1991). IL-1 stimulates T-cell to grow, and initiates the secretion of a variety of cytokines (Nossal, 1987). IL-1 activates T-cells, by enhancing the Literature Revien' recognition of T-cells, by antigen presenting cells (Dinarello & Mier, 1987). ...
... 1983; Nishiuch, ef a/. 1976; Harber, 1970;Olney & Ho, 1970), and because GSH is mostly degraded in the extracellular compartment, due to the presence of the enzyme y-glutamyl cysteine transferase, several compounds have been used as a cysteine-delivery agents. L-2oxofhiazalidine-4-carboxylate (OTC) and N-acetyl-L-cysteine (NAC), are two of the most common compounds used to serve as a cysteine-delivery agents (Sen, 1997). ...
p>The extent to which dietary intervention, by correcting deficiencies in sulphur amino acids, tryptophan, and arginine intake, improves antioxidant defences and modulates the metabolic response to infection was examined in this thesis using a young rat model. Rats were given an inflammatory challenge by intraperitoneal injection of endotoxin, and were compared with ad libitum and pair-fed controls.
Glutathione (GSH) concentrations in various organs (liver, lung, spleen and thymus), and hepatic protein content decreased in animals fed the low-protein diets. In endotoxin-treated rats, the magnitude of the increase of the acute phase protein, α-1 acid glycoprotein, was reduced in animals fed the low-protein diets.
Addition of the sulphur amino acid, methionine, to the low-protein diets, restored GSH concentrations and increased hepatic protein content in endotoxin-treated animals and in animals fed ad libitum . In endotoxin-treated rats, addition of methionine to the low-protein diets reduced (not statistically significant) the number of neutrophils in lung, while in ad libitum and in pair-fed animals, addition of methionine increased (not statistically significant) the number of neutrophils. Furthermore, before starting treatments, addition of methionine to the low-protein diets improved growth.
In general, there was no indication that addition of tryptophan or arginine had marked effects on the acute inflammatory response after exposure to the endotoxin.
To conclude, dietary methionine is the most important amino acid regarding the ability to modulate the inflammatory response.</p
... Numerous studies have shown that application of high doses of MSG (1-4 mg/g BW) especially during the neonatal period may cause lesions of the preoptic nuclei, arcuate nuclei, the circumventricular organs and the retina in different kinds of animals (mice, rats, rabbits, hamsters, dogs, and monkeys) (13,(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). During later life MSG treated animals exhibit a series of neuroendocrine disorders: stunted growth, obesity and decreased fertility (19,20,22,23,(27)(28)(29)(30). ...
... Numerous studies have shown that application of high doses of MSG (1-4 mg/g BW) especially during the neonatal period may cause lesions of the preoptic nuclei, arcuate nuclei, the circumventricular organs and the retina in different kinds of animals (mice, rats, rabbits, hamsters, dogs, and monkeys) (13,(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). During later life MSG treated animals exhibit a series of neuroendocrine disorders: stunted growth, obesity and decreased fertility (19,20,22,23,(27)(28)(29)(30). China Health and Nutrition Survey showed that MSG is responsible for development of obesity in human adults (31). ...
... 36 Two of the most insidious excitotoxins (ie, neurotoxins) in our food supply today are aspartame and monosodium glutamate (MSG). 24,[37][38][39][40][41][42] There are currently more than 6000 consumer products containing aspartame, and thousands that contain MSG in its many forms (eg, autolyzed yeast, glutamate, glutamic acid, hydrolyzed protein, monopotassium glutamate, MSG, textured protein, yeast extract, yeast food, yeast nutrient, flavors, and flavorings). The mechanism of toxicity of MSG is a very straight forward one: elevation of extracellular glutamate and excitotoxicity from overstimulation of the body's primary excitatory glutamate receptor, the NMDA-R. ...
... The mechanism of toxicity of MSG is a very straight forward one: elevation of extracellular glutamate and excitotoxicity from overstimulation of the body's primary excitatory glutamate receptor, the NMDA-R. [38][39][40][41][42] Aspartame's mechanism of toxicity is a bit more complex and is driven by the following 6 components: phenylalanine, aspartic acid, methanol, formaldehyde, formic acid, and diketopiperazine, and the list of adverse effects associated with its use is truly staggering and include fatigue, depression, anxiety, seizures, headaches, migraines, tachycardia, breathing difficulties, irritability, weight gain, metabolic syndrome, tinnitus, numbness, dizziness, endocrine disruption (ie, Graves' disease), development of phobias, vision problems, night terrors, sleep apnea, and sleep disturbances. 41,42 From a biological and toxicological perspective, all of these adverse effects make perfect sense given the fact that TBI, known as the "acute phase, " the following excitotoxic events occur: terminal membrane depolarization along with excessive release of excitatory neurotransmitters (ie, glutamate, aspartate) leading to overactivation of N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolpropionate, and voltage-dependent Ca 2+ and Na + channels. ...
Chronic, excessive exposure, and accumulation of neurotoxic agents such as heavy metals (lead, mercury, cadmium), mefloquine (Lariam), and food additives such as monosodium glutamate and aspartame cause neurotoxicity and brain damage. This chemical-induced brain damage closely resembles the pathophysiology of classical traumatic brain injury with decreased cognitive function, neurodegeneration, and increased psychiatric manifestations (depression, anxiety, sleep disturbances, and irritability). Current evidence supports a strong causal relationship between military-related exposure to specific neurotoxins, and the development of serious medical conditions and higher rates of suicide among service members. To address this current deficit in military health care, it is recommended that efficacious, nontoxic, neuroprotective, and neuroregenerative agents such as highly bioavailable magnesium, nutritional lithium, zinc, selenium, boron, ascorbate, tocopherols, heavy metal chelators, and glutathione precursors such as N-acetyl-cysteine be immediately used as a “protective shield” and to support critical healing processes in the brain and nervous system.
... This study reported by Anantharaman [47] selected mice as the experimental model, because mice were considered the most sensitive species. Repeated subcutaneous or intraperitoneal administration of MSG to new-born mice at dose levels above 0.4 up to 4 or 5 g/kg bw/day resulted in discrete brain lesions, mainly in the pre-optic and arcuate nuclei of the hypothalamus, together with scattered neurons within the median eminence [50,57,58]. Bolus oral dosing via an aqueous solution at dose levels of 0.5 up to 2.0 g MSG/kg bw to 10-12 days old mice also resulted in damage of the arcuate nuclei [57], although administration of MSG in the diet at levels up to 42 g/kg bw/day did not result in these symptoms [44,50,52]. ...
... Repeated subcutaneous or intraperitoneal administration of MSG to new-born mice at dose levels above 0.4 up to 4 or 5 g/kg bw/day resulted in discrete brain lesions, mainly in the pre-optic and arcuate nuclei of the hypothalamus, together with scattered neurons within the median eminence [50,57,58]. Bolus oral dosing via an aqueous solution at dose levels of 0.5 up to 2.0 g MSG/kg bw to 10-12 days old mice also resulted in damage of the arcuate nuclei [57], although administration of MSG in the diet at levels up to 42 g/kg bw/day did not result in these symptoms [44,50,52]. Anantharaman [47] investigated neuronal densities especially in the arcuate and other nuclei of the hypothalamus, in the basal ganglia, in the hippocampus formation and the thalamus as well as in the cortex. ...
Background:
Re-evaluation of the use of glutamic acid and glutamate salts (referred to as glutamate hereafter) by the European Food Safety Authority (EFSA) proposed a group acceptable daily intake (ADI) of 30 mg/kg body weight (bw)/day.
Summary:
This ADI is below the normal dietary intake, while even intake of free glutamate by breast-fed babies can be above this ADI. In addition, the pre-natal developmental toxicity study selected by EFSA, has never been used by regulatory authorities worldwide for the safety assessment of glutamate despite it being available for nearly 40 years. Also, the EFSA ignored that toxicokinetic data provide support for eliminating the use of an uncertainty factor for interspecies differences in kinetics. Key Messages: A 3-generation reproductive toxicity study in mice that includes extensive brain histopathology, provides a better point of departure showing no effects up to the highest dose tested of 6,000 mg/kg bw/day. Furthermore, kinetic data support use of a compound-specific uncertainty factor of 25 instead of 100. Thus, an ADI of at least 240 mg/kg bw/day would be indicated. In fact, there is no compelling evidence to indicate that the previous ADI of "not specified" warrants any change.
... Initial animal studies indicated that an extremely high dose of L-Cys could be neurotoxic [59][60][61]. However, recent studies have demonstrated that L-Cys or L-cystine is safe in rats at oral doses of less than 500 mg/kg/day for 4 weeks [62]. ...
Oxidative stress and mitochondrial dysfunction play critical roles in neurodegenerative diseases. Glutathione (GSH), a key brain antioxidant, helps to neutralize reactive oxygen species (ROS) and maintain redox balance. We investigated the effectiveness of L-cysteine (L-Cys) in preventing apoptosis induced by the ROS generator 2,3-dimethoxy-1,4-naphthoquinone (DMNQ) in mouse hippocampal neuronal HT22 cells, as well as alleviating memory and cognitive impairments caused by the GSH synthesis inhibitor L-buthionine sulfoximine (BSO) in mice. DMNQ-induced apoptotic events in HT22 cells, including elevated cytosolic and mitochondrial ROS levels, DNA fragmentation, endoplasmic reticulum stress, and mitochondrial damage-mediated apoptotic pathways were dose-dependently abrogated by L-Cys (0.5-2 mM). The reduced intracellular GSH level, caused by DMNQ treatment, was restored by L-Cys cotreatment. Although L-Cys did not significantly restore GSH in the presence of BSO, it prevented DMNQ-induced ROS elevation, mitochondrial damage, and apoptosis. Furthermore, compared to N-acetylcysteine and GSH, L-Cys had higher 2,2-diphenyl-1-picrylhydrazyl and 2,2-azino-bis-3-ethylbenzo-thiazoline-6-sulphonic acid radical-scavenging activity. L-Cys also restored mitochondrial respiration capacity in DMNQ-treated HT22 cells by reversing mitochondrial fission-fusion dynamic balance. BSO administration (500 mg/kg/day) in mice led to neuronal deficits, including memory and cognitive impairments, which were effectively mitigated by oral L-Cys (15 or 30 mg/kg/day). L-Cys also reduced BSO-induced ROS levels in the mice hippocampus and cortex. These findings suggest that even though it does not contribute to intracellular GSH synthesis, exogenous L-Cys protects neuronal cells against oxidative stress-induced mitochondrial damage and apoptosis, by acting as a ROS scavenger, which is beneficial in ameliorating neurocognitive deficits caused by oxidative stress.
... A similar result was obtained in one infant rhesus monkey (Macaca mulatta) (Olney & Sharpe, 1969). Olney and Ho (1970) also reported that orally administrated MSG (and aspartate and cystatin) induced hypothalamic damage in infant mice. ...
Umami taste was first proposed by Kikunae Ikeda in the early 1900s as the taste of glutamate. His first paper described many basic aspects of umami taste that were consolidated by later studies conducted by many researchers around the world. Since his discovery of umami taste and the development of the production process for glutamate (monosodium L-glutamate, MSG), for over 100 years, MSG has been used to improve the palatability of many foods. As the production and consumption of MSG became prevalent worldwide, the safety of MSG as a food additive was questioned. Many researchers tackled this problem, resulting in MSG now being placed in the safest category of food ingredients. In contrast, establishing umami as a unique taste by taste scientists needed much time and effort. By the 1980s, the taste of glutamate had been thoroughly investigated from physiological, behavioral, and psychological perspectives, leading many investigators to conclude that umami is a basic taste much like sweet, salty, sour, and bitter. Subsequent molecular studies identified taste receptors for glutamate, which provided conclusive evidence for umami as a basic taste. This chapter aims to provide a broad understanding of umami taste, including the historical context for umami and MSG, why umami is considered a basic taste, and differences of umami taste in different regions of the tongue and across species. This chapter closes by describing some distinctive phenomena surrounding umami taste, such as its intensity and synergism, its long-lasting effects, and the salivary secretions and feelings of mouthfullness and satisfaction elicited by umami stimuli.
... A similar result was obtained in one infant rhesus monkey (Macaca mulatta) (Olney & Sharpe, 1969). Olney and Ho (1970) also reported that orally administrated MSG (and aspartate and cystatin) induced hypothalamic damage in infant mice. ...
From an early age, humans can detect the umami taste sensation of the free amino acid glutamate, as evidenced by the facial expressions of pleasure displayed by newborns. This chapter briefly reviews the biology of umami flavor and summarizes the earliest routes of exposure to free amino acids in amniotic fluid, human milk, and infant formula, highlighting how exposure to free glutamate, and umami tastes, varies from gestation to postnatal feedings and from infant to infant. It then summarizes scientific evidence revealing that during infancy, the amount of free glutamate ingested impacts satiation and growth during milk feedings, as well as the development of preferences for similarly flavored foods. The study of umami as a basic taste during infancy and childhood has been neglected compared to other basic tastes, and gaps in knowledge are highlighted.
... A similar result was obtained in one infant rhesus monkey (Macaca mulatta) (Olney & Sharpe, 1969). Olney and Ho (1970) also reported that orally administrated MSG (and aspartate and cystatin) induced hypothalamic damage in infant mice. ...
Umami is the meaty or savory taste elicited by monosodium glutamate and other amino acids. The presence of these amino acids in foods and beverages can alter dietary intake and nutritional balance and thus the health of human and nonhuman animals. Umami has been a major culinary influence in Eastern cultures for over a century and has gradually become an important factor in Western diets. Throughout its history, research on umami, especially the unique taste elicited by monosodium glutamate and its synergistic interaction with ribonucleotides such as inosine 5′-monophosphate, has played an important role in discovering peripheral taste receptors, cellular and molecular transduction mechanisms, and the neuroanatomy of the gustatory system. Umami taste has also been a focus of study to identify brain stem and cortical structures involved in sensory processing and generating food-directed behavior. This chapter provides a brief history of umami taste, a description of the molecular receptors and cellular transduction mechanisms for umami taste stimuli in chemosensory cells in the oral cavity and gut, and an overview of the brain systems involved in umami taste perception. An understanding of these aspects of umami taste is of fundamental importance for basic science and for healthcare professions working with patient populations with dietary challenges.
... These three first-phase metabolites represent approximately 40%, 50%, and 10% of aspartame by weight, respectively [38]. The adverse neurological impacts following the consumption of aspartic acid, phenylalanine, and/or aspartame include changes in neurotransmitter levels [25,38,39] and excitotoxicity, with adverse impacts on neuron function/survival [40][41][42]. Primates, including humans, are uniquely vulnerable to methanol [43,44], the blood levels of which rise following aspartame consumption [44][45][46]. Exposures to methanol and formaldehyde resulted in increased neuronal apoptosis, neurodegeneration, and cognitive problems [43,47,48]. ...
Since its introduction, aspartame—the leading sweetener in U.S. diet sodas (DS)—has been reported to cause neurological problems in some users. In prospective studies, the offspring of mothers who consumed diet sodas/beverages (DSB) daily during pregnancy experienced increased health problems. We hypothesized that gestational/early-life exposure to ≥1 DS/day (DSearly) or equivalent aspartame (ASPearly: ≥177 mg/day) increases autism risk. The case-control Autism Tooth Fairy Study obtained retrospective dietary recalls for DSB and aspartame consumption during pregnancy/breastfeeding from the mothers of 235 offspring with autism spectrum disorder (ASD: cases) and 121 neurotypically developing offspring (controls). The exposure odds ratios (ORs) for DSearly and ASPearly were computed for autism, ASD, and the non-regressive conditions of each. Among males, the DSearly odds were tripled for autism (OR = 3.1; 95% CI: 1.02, 9.7) and non-regressive autism (OR = 3.5; 95% CI: 1.1, 11.1); the ASPearly odds were even higher: OR = 3.4 (95% CI: 1.1, 10.4) and 3.7 (95% CI: 1.2, 11.8), respectively (p < 0.05 for each). The ORs for non-regressive ASD in males were almost tripled but were not statistically significant: DSearly OR = 2.7 (95% CI: 0.9, 8.4); ASPearly OR = 2.9 (95% CI: 0.9, 8.8). No statistically significant associations were found in females. Our findings contribute to the growing literature raising concerns about potential offspring harm from maternal DSB/aspartame intake in pregnancy.
... Excessive exposure of neurons to excitatory amino acids, for example, glutamate, aspartate, and NMDA, leads to cellular damage and subsequently cell death (Olney, 1969;Olney et al., 1971;Olney & Ho, 1970), a phenomenon which was later coined excitotoxicity (Olney et al., 1974). Excitotoxicity is primarily mediated by prolonged and exacerbated glutamate activation of NMDA and AMPA glutamate receptors (Lewerenz & Maher, 2015). ...
Since it was first generally accepted that the two amino acids glutamate and GABA act as principal neurotransmitters, several landmark discoveries relating to this function have been uncovered. Synaptic homeostasis of these two transmitters involves several cell types working in close collaboration and is facilitated by specialized cellular processes. Notably, glutamate and GABA are extensively recycled between neurons and astrocytes in a process known as the glutamate/GABA‐glutamine cycle, which is essential to maintain synaptic transmission. The glutamate/GABA‐glutamine cycle is intimately coupled to cellular energy metabolism and relies on the metabolic function of both neurons and astrocytes. Importantly, astrocytes display unique metabolic features allowing extensive metabolite release, hereby providing metabolic support for neurons. Furthermore, astrocytes undergo complex metabolic adaptations in response to injury and pathology, which may greatly affect the glutamate/GABA‐glutamine cycle and synaptic transmission during disease. In this Milestone Review we outline major discoveries in relation to synaptic balancing of glutamate and GABA signaling, including cellular uptake, metabolism, and recycling. We provide a special focus on how astrocyte function and metabolism contribute to sustain neuronal transmission through metabolite transfer. Recent advances on cellular glutamate and GABA homeostasis are reviewed in the context of brain pathology, including glutamate toxicity and neurodegeneration. Finally, we consider how pathological astrocyte metabolism may serve as a potential target of metabolic intervention. Integrating the multitude of fine‐tuned cellular processes supporting neurotransmitter recycling, will aid the next generation of major discoveries on brain glutamate and GABA homeostasis. image
... Animal studies have shown that MSG administration, depending on the dose may cause degeneration in the brain, especially in the portions of the hypothalamus, which controls the secretion of several pituitary hormones, but researchers report that the most notable effects occur in the adulthood of the animals; animals were found under normal body length, obese, and have difficulty in reproductive functions [2]. Following this study, the authors proposed that feeding infants normal food containing MSG might also cause hypothalamic lesions [3]. Food-related neurotoxicity depends on the hypothesis that MSG consumption would cause plasma GLU levels to rise by increased GLU absorption by the intestine and entering the bloodstream. ...
Herein, we examined the modulatory effects of Apocynum (APO) on Monosodium Glutamate (MSG)-induced oxidative damage on the brain tissue of rats after long-term consumption of blood serum components by biochemical assays, Fourier transform infrared spectroscopy (FTIR), and machine learning methods. Sprague-Dawley male rats were randomly divided into the Control, Control + APO, MSG, and MSG + APO groups (n = 8 per group). All administrations were made by oral gavage saline, MSG, or APO and they were repeated for 28 days of the experiments. Brain tissue and blood serum samples were collected and analyzed for measurement levels of malondialdehyde (MDA), glutathione (GSH), myeloperoxidase (MPO), superoxide dismutase (SOD) activity, and Spectroscopic analysis. After 29 days, the results were evaluated using machine learning (ML). The levels of MDA and MPO showed changes in the MSG and MSG + APO groups, respectively. Changes in the proteins and lipids were observed in the FTIR spectra of the MSG groups. Additionally, APO in these animals improved the FTIR spectra to be similar to those in the Control group. The accuracy of the FTIR results calculated by ML was 100%. The findings of this study demonstrate that Apocynin treatment protects against MSG-induced oxidative damage by inhibiting reactive oxygen species and upregulating antioxidant capacity, indicating its potential in alleviating the toxic effects of MSG.
... Aspartame and its constituent amino acids have been studied for their impact on baby development. Infant mice were demonstrated to have brain damage after being intragastrically intubated with high doses of aspartate [42]. The women are deficient in an enzyme that permits them to digest the amino acid phenylalanine, which is a component of aspartame. ...
Scientific evidence is mounting that synthetic chemicals used as food additives may have harmful impacts on health. Food additives are chemicals that are added to food to keep it from spoiling, as well as to improve its colour and taste. Some are linked to negative health impacts, while others are healthy and can be ingested with little danger. According to several studies, health issues such as asthma, attention deficit hyperactivity disorder (ADHD), heart difficulties, cancer, obesity, and others are caused by harmful additives and preservatives. Some food additives may interfere with hormones and influences growth and development. It is one of the reasons why so many children are overweight. Children are more likely than adults to be exposed to these types of dietary intakes. Several food additives are used by women during pregnancy and breast feeding that are not fully safe. We must take specific precaution to avoid consuming dangerous compounds before they begin to wreak havoc on our health. This study is intended to understand how the preservatives induce different health problem in the body once it is consumed. This review focuses on some specific food additives such as sodium benzoate, aspartame, tartrazine, carrageenan, and potassium benzoate, as well as vitamin A. Long-term use of food treated with the above-mentioned food preservatives resulted in teratogenicity and other allergens, according to the study. Other health issues can be avoided in the future by using natural food additives derived from plants and other natural sources.
... L'équipe de Lucas et al montrent par la suite que l'administration parentérale de glutamate chez la souris contrôle ou présentant une dystrophie rétinienne héréditaire entraînent une destruction des neurones de la couche interne de la rétine (Lucas and Newhouse, 1957). De nombreuses études réalisées chez différentes espèces et pour différentes structures du système nerveux central ont par la suite confirmé cette toxicité du glutamate (Olney, 1986;Olney and Ho, 1970;Olney and Sharpe, 1969). C'est en 1969 que Olney nomma pour la première fois ce phénomène de toxicité ou excitotoxicité médié par le glutamate sur différentes régions du cerveau de souris (Olney and Sharpe, 1969). ...
La mitochondrie centrale énergétique de nos cellules possède son propre génome ou ADN mitochondrial (ADNmt) présent en de nombreuses copies par cellule. Les mutations de l’ADNmt sont responsables de maladies mitochondriales comme le syndrome neurovasculaire MELAS. La coexistence de copies d’ADNmt mutées et normales définit le concept d’hétéroplasmie en lien direct avec la symptomatologie et la sévérité de cette maladie. Parmi les mutations MELAS de l’ADNmt, le variant m.3243A>G est le plus fréquemment rencontré. Afin de mieux comprendre la physiopathologie de ce syndrome et proposer des approches thérapeutiques, nous disposons d’un modèles cybrides neuronal qui porte différents niveaux d’hétéroplasmies pour le variant m.3243A>G. Nous avons montré une dysfonction sévère de la chaine respiratoire, associée à un défaut sévère d’assemblage en particulier du complexe I mitochondrial. L’utilisation d’une approche multi-omiques nous a permis d’identifier un profil biochimique spécifique au syndrome MELAS avec une modification de la voie du glutamate conduisant à une accumulation significative de ce métabolite au niveau extra et intra-cellulaire. L’exposition de corps cétoniques comme stratégie métabolique à visée thérapeutique entraine une réduction majeure du glutamate et une amélioration significative des fonctions mitochondriales, modulant également les métabolites intermédiaires du cycle de Krebs. La stratégie multi-omiques nous a aidé à comprendre les mécanismes de la dysfonction mitochondriale, et a permis d’identifier le glutamate comme marqueur potentiel de ce syndrome. Cela démontre aussi l’intérêt de stratégies métaboliques comme thérapies dans le syndrome MELAS et les maladies mitochondriales.
... Later, Pizzi et al. [66] reported that BLU:Ha(ICR) mice display reduced fertility. In the present study, we used similar MSG concentration as previously published [43,50,51,67] and found that the animals were infertile. Therefore, differences in the experimental design likely contribute to this discrepancy among studies. ...
Growth hormone (GH) deficiency is a common cause of late sexual maturation and fertility issues. To determine whether GH-induced effects on reproduction are associated with alterations in hypothalamic kisspeptin system, we studied the male reproduction in two distinct GH deficiency mouse models. In the first model, mice present GH deficiency secondary to arcuate nucleus of the hypothalamus (ARH) lesions induced by posnatal monosodium glutamate (MSG) injections. MSG-induced ARH lesions led to significant reductions in hypothalamic Ghrh mRNA expression and consequently growth. Hypothalamic Kiss1 mRNA expression and Kiss1-expressing cells in the ARH were disrupted in the MSG-treated mice. In contrast, kisspeptin immunoreactivity remained preserved in the anteroventral periventricular and rostral periventricular nuclei (AVPV/PeN) of MSG-treated mice. Importantly, ARH lesions caused late sexual maturation and infertility in male mice. In our second mouse model, we studied animals profound GH deficiency due to a loss-of-function mutation in the Ghrhr gene (Ghrhrlit/lit mice). Interestingly, although Ghrhrlit/lit mice exhibited late puberty onset, hypothalamic Kiss1 mRNA expression and hypothalamic kisspeptin fiber density were normal in Ghrhrlit/lit mice. Despite presenting dwarfism, the majority of Ghrhrlit/lit male mice were fertile. These findings suggest that spontaneous GH deficiency during development does not compromise the kisspeptin system. Furthermore, ARH Kiss1-expressing neurons are required for fertility, while AVPV/PeN kisspeptin expression is sufficient to allow maturation of the hypothalamic-pituitary-gonadal axis in male mice.
... 33 Research has shown that MSG causes toxic effects involving increased oxidative stress and cytotoxicity on various organs and systems, otherwise known as Chinese restaurant MSG administered orally caused neuron deaths in the arcuate nucleus in the brain of newborn mice. 34 Small doses of MSG have also been used to trigger epileptic attacks in rats. Death rates and attack severity were shown to increase in direct association with the rats' age. ...
... Meaning that some of the neural cell death due to hypoxia-ischemic (HI) insult was mediated by excess production of the excitatory neurotransmitter "glutamate" and elevation of intracellular Ca 2þ concentration by N-methyl-D-aspartate glutamatergic receptor (NMDA GluR), AMPA/Kainate GluR (A/K GluR), and metabolic GluR(mGluR) in different ways. 7,8 We summarize the mechanism of "excitotoxicity" in ►Fig. 1. Glutamate (Glu) is converted to Glutamine (Gly) by the action of glutamine synthetase (GS) in astrocyte, and shuttled from astrocyte to neurons, then converted to Glu by glutaminases (GLS). Energy depletion in presynaptic site of neurons activates release of Glu into synapse. ...
Objective Neonatal hypoxic–ischemic encephalopathy (HIE) causes permanent motor deficit “cerebral palsy (CP),” and may result in significant disability and death. Therapeutic hypothermia (TH) had been established as the first effective therapy for neonates with HIE; however, TH must be initiated within the first 6 hours after birth, and the number needed to treat is from 9 to 11 to prevent brain damage from HIE. Therefore, additional therapies for HIE are highly needed. In this review, we provide an introduction on the mechanisms of HIE cascade and how TH and cell therapies such as umbilical cord blood cells and mesenchymal stromal cells (MSCs), especially umbilical cord-derived MSCs (UC-MSCs), may protect the brain in newborns, and discuss recent progress in regenerative therapies using UC-MSCs for neurological disorders.
Results The brain damage process “HIE cascade” was divided into six stages: (1) energy depletion, (2) impairment of microglia, (3) inflammation, (4) excitotoxity, (5) oxidative stress, and (6) apoptosis in capillary, glia, synapse and/or neuron. The authors showed recent 13 clinical trials using UC-MSCs for neurological disorders.
Conclusion The authors suggest that the next step will include reaching a consensus on cell therapies for HIE and establishment of effective protocols for cell therapy for HIE.
Key Points
... Glutamate is both the principal excitatory neurotransmitter and a potent neurotoxin (at high concentrations) in the mammalian CNS (Choi 1988;Fonnum 1984;Krnjevic 1970;Nicholls 1993;Olney and Ho 1970). Indeed, extracellular glutamate levels are tightly regulated for precise control of neurotransmission at glutamatergic synapses, and to prevent neuronal cell death from excitotoxicity (Danbolt 2001). ...
Hypoxia is a critical pathological element in many human diseases, including ischemic stroke, myocardial infarction and solid tumors. Of particular significance and interest of ours are the cellular and molecular mechanisms that underlie susceptibility or tolerance to low O2. Previous studies have demonstrated that Notch signaling pathway regulates hypoxia tolerance in both Drosophila melanogaster and humans. However, the mechanisms mediating Notch-conferred hypoxia tolerance are largely unknown. In the current study, we delineate the evolutionarily conserved mechanisms underlying this hypoxia tolerant phenotype. We determined the role of a group of conserved genes that were obtained from a comparative genomic analysis of hypoxia-tolerant Drosophila melanogaster populations and human highlanders living at the high-altitude regions of the world (Tibetans, Ethiopians and Andeans). We developed a novel dual-UAS/Gal4 system that allows us to activate Notch signaling in the Eaat1-positive glial cells, which remarkably enhances hypoxia tolerance in Drosophila melanogaster, and, simultaneously, knock down a candidate gene in the same set of glial cells. Using this system, we discovered that the interactions between Notch signaling and bnl (fibroblast growth factor), croc (forkhead transcription factor C) or Mkk4 (mitogen-activated protein kinase kinase 4) are important for hypoxia tolerance, at least in part, through regulating neuronal development and survival under hypoxic conditions. Since these genetic mechanisms are evolutionarily conserved, this group of genes may serve as novel targets for developing therapeutic strategies and have a strong potential to be translated to humans to treat/prevent hypoxia-related diseases.
... ; J.W.Olney, 1969;J.W. Olney & Ho, 1970; J. W. Olney & Sharpe, 1969; S. M. Rothman, 1983; S. M. Rothman & Olney, 1986) and the high sensitivity of CNS neurons to the toxic effects of GLU (M.B. Robinson, Djali, & Buchhalter ...
Cocaine, amphetamine, and methamphetamine abuse disorders are serious worldwide health problems. To date, there are no FDA-approved medications for the treatment of these disorders. Elucidation of the biochemical underpinnings contributing to psychostimulant addiction is critical for the development of effective therapies. Excitatory signaling and glutamate homeostasis are well known pathophysiological substrates underlying addiction-related behaviors spanning multiple types of psychostimulants. To alleviate relapse behavior to psychostimulants, considerable interest has focused on GLT-1, the major glutamate transporter in the brain. While many brain regions are implicated in addiction behavior, this review focuses on two regions well known for their role in mediating the effects of cocaine and amphetamines, namely the nucleus accumbens (NAc) and the ventral tegmental area (VTA). In addition, because many investigators have utilized Cre-driver lines to selectively control gene expression in defined cell populations relevant for psychostimulant addiction, we discuss potential off-target effects of Cre-recombinase that should be considered in the design and interpretation of such experiments.
... Si des concentrations anormalement hautes de glutamate s'accumulent dans l'espace i te ellulai e, l'a ti atio e essi e et l'e t e assi e de Ca 2+ dans les cellules qui en résulte, vont mener à la mort de celle-ci. La toxicité du glutamate a été observée pour la première fois sur la rétine de souris par Lucas et Newhouse en 1957, puis sur le cerveau en 1970 dans la p e i e tude e tio a t le te e d'e itoto i it (Olney and Ho, 1970). ...
Les défauts de translation des études précliniques vers les essais cliniques dans le domaine des AVC ischémiques et l'échec des développements thérapeutiques pourraient être expliqués par trois aspects : (1) le manque de compréhension des mécanismes des deux formes de rtPA, le traitement pharmacologique de l'AVC; (2) le manque d'outils adaptés d'imagerie de perfusion chez le petit animal et (3) l'influence de l'anesthésie sur l’effet des traitements testés dans les modèles animaux.Le tPA utilisé en clinique (Actilyse®) est un mélange de deux formes de tPA: une forme chaîne simple (sc-rtPA) et une double chaîne (tc-rtPA). Malgré des activités fibrinolytiques similaires, ces deux formes de tPA exercent des fonctions cérébrales distinctes influençant différemment la récupération des patients. Ainsi, nous avons décidé d'étudier en détail dans un modèle murin d'AVC thromboembolique les mécanismes pouvant expliquer ces effets divergents. Nous avons confirmé ces observations à savoir que sc-rtPA est bénéfique lorsqu'il est perfusé tôt après le début de l'AVC, alors que le tc-rtPA est délétère en raison d'une altération de la barrière hémato-encéphalique.L'imagerie en temps réel de la perfusion de l'ensemble du cerveau est un atout pour les études cliniques et précliniques. L'émergence des ultrasons ultra-rapides a conduit au développement du Doppler ultra-rapide et de la Microscopie de Localisation à Ultrasons (ULM), deux méthodes avec différents profils de résolutions spatio-temporelles et une excellente sensibilité aux petits flux sanguins. Nous avons combiné ces deux méthodes pour fournir un suivi longitudinal en 3D de la perfusion cérébrale dans un modèle murin d’AVC thromboembolique avec fibrinolyse par rtPA. Nos données montrent que le FUS et l’ULM présentent un intérêt majeur pour le pronostic précoce de l'AVC ischémique et de la réponse au traitement, avec une corrélation étroite entre la reperfusion précoce à 2h et la récupération tissulaire à 24h.Enfin, l’anesthésie utilisée en laboratoire interfère sur la lésion ischémique et les effets des molécules thérapeutiques testées. Nous nous sommes affranchis de ces effets en développant un nouveau modèle d’AVC ischémique chez des souris totalement éveillées. Le débit sanguin cérébral régional a été suivi par laser Doppler avant, pendant et 45min après le début de l’AVC. Le traitement par rtPA (à 20 min) est bénéfique dans les modèles d’AVC vigile et anesthésié, mais l'anesthésie est associée à un manque de corrélation entre la recanalisation et les volumes de lésion post-ischémie. Nous testons actuellement une molécule neuroprotectrice, qui était prometteuse avant d’échouer lors des essais cliniques (NXY-059), afin d’évaluer la pertinence de ce modèle novateur d’AVC pour les futures études pharmacologiques. Dans l’ensemble, ce travail fournit un panel de données précliniques innovantes pour améliorer nos chances de translation en clinique, incluant un modèle pertinent d'AVC thromboembolique chez des animaux vigiles et une méthode d'imagerie du pronostic précoce de réponse aux traitements vasculaires.
... In his 1970 publication, J.W. Olney showed that high extracellular levels of glutamate act as a neurotoxin in mice, by flooding neurons with calcium, triggering a downstream neurotoxic cascade and generating intracellular free radicals, resulting in enzyme activation and eventually apoptosis. 24 This excitotoxicity mechanism is believed to be a culprit in a range of neurological diseases, including stroke. In this same publication, Olney showed that glutamate plays a key role in ischemic brain damage and that drugs which decrease the accumulation of glutamate or block its postsynaptic effects may be a rational therapy for stroke, giving the medical community hope for effective stroke therapy. ...
Mechanical thrombectomy (MT) has revolutionized the treatment of large-vessel occlusion stroke and markedly improved patient outcomes. Unfortunately, there remains a large proportion of patients that do not benefit from this technology. This review takes a look at recent and upcoming technologies that may help to increase the number of MT-treated patients, thereby improving their outcomes. To that end, an overview of digital health solutions, innovative pharmacological treatment, and futuristic robotic endovascular interventions is provided.
... 44 An analogue between ingestion of drug (addict) and overconsumption of palatable foods in obese individuals is based on the issue of palatable food, a daily reinforcer, which causes molecular adaptations favoring food consumption ( Figure 2). 45 Excessive food consumption can be harmful not only because of weight gain and its associated health risk, but also because of the adaptation that may occur in the neurobiology of the individual leading to a preference and "excessive intake" of palatable foods, far from a voluntary control and directing it to a compulsive consumption (Figure 2). 32 The adaptations in the food reward system generate a positive feedback loop to improve signals that stimulate the favoring of food intake and events that block negative feedback. ...
... Recently, pheomelanin has been suggested to have evolved because of its potential role in removing excess cysteine (Galván et al. 2012b). Although cysteine is an essential component of GSH, thereby being important for antioxidant protection, it can cause a variety of problems when in excess, including poor growth, pregnancy complication and brain damage (Olney and Ho 1970;Orth et al. 1992;El-Khairy et al. 2003;. Therefore, under low levels of environmental oxidative stress-i.e., when cysteine is not needed for GSH-mediated antioxidant protection and can potentially be in excess-, pheomelanogenesis may be advantageous as it consumes toxic cysteine (Galván et al. 2012b). ...
In several species, the rusty color of hair or feathers is due to pheomelanin pigments, whose adaptive function is unknown. Pheomelanin may be costly because it is phototoxic and its production consumes a key intracellular antioxidant. Pheomelanin-based traits are, however, positively associated with individual quality in several bird species, where they have thus been suggested to have evolved through sexual selection. Here we investigated the signaling potential of the pheomelanin-based coloration of the crown feathers in the blue petrel. Although this pelagic seabird is nocturnal at the breeding colony and breeds within deep burrows, it might use visual communication when settled on the water during daytime. We tested the correlation between crown color and several fitness-related traits, and we found that higher-quality females displayed less-orange crown than poorer-quality females. This result is inconsistent with an adaptive function of pheomelanin-based coloration in inter-, or intra-, sexual selection in females. We suggest that it might, however, be in line with a signaling function of eumelanin-based coloration, if inter-individual variations in orange coloration are mainly due to eumelanin-to-pheomelanin ratio, rather than to pheomelanin quantity. In contrast to females, we did not find strong evidence for associations between melanin-based coloration and individual quality in males, suggesting sex-specific selective pressures on melanin-based traits in this species.
... Loss of interest in food intake was possibly due to neuropathic changes as suggested by other researcher. [16][17] Our finding of smaller kidney ( Fig. 6 and 7) has been supported by others. 8, 14 We had not found any interstitial fibrosis, though literature is available referring to interstitial fibrosis of renal parenchyma. ...
Monosodium Glutamate (MSG) is a commonly used food additive. Scientists have found that MSG has toxic effects in several tissues and organs like neurons, liver, testes, ovary, kidneys etc due to oxidative stress both after exposure in neonatal period as well as in adult animal models. Although various reports have suggested that MSG has damaging effect in kidneys only few histological studies are available. This study was done to observe any histological changes in kidneys of albino mice after neonatal exposure with MSG. Study showed significant changes in weight and volume of kidneys in gross morphology. Increased urinary space and dilatation of proximal convoluted tubules (PCT) and distal convoluted tubules (DCT) were constant finding in experimental animals. There were loss of luminal microvilli and reduced height of lining cells of both PCT and DCT.
... 24,36 In an earlier study, it was observed that infant mice, on account of poorly developed blood brain barrier, showed neurological lesion even when MSG was given in lower dose. 42 From the results, tissue sections of the normal control rats (Plates 1, 6 and11) showed normal histological structures of the liver, brain and kidney. The effects observed in both the liver (Plate 2-5) and kidneys (12-15) of treated rats could have occurred because these organs are involved in the metabolism of glutamate. ...
... WATs: PT, parietal; RP, retroperitoneal; EP, periepidydimal; PM, parametrial; PR, perirenal; OM, omental. Tables indicate percentage of increasing of WATs between MSG-LIPEC and MSG-SHAM groups arcuate nucleus of hypothalamus (ANH), an important area in the control of orexigenic and anorectic mechanisms [18,21,[28][29][30][31][32][33][34]. Studies of Shi et al. (2007,35] observed different approaches to reduce fat mass by caloric restriction or surgical fat removal (LIPEC) male and female rats affected food intake behavior, which can implicate directly in the capability to restore visceral fat. ...
Background
Mobility of fat deposited in adipocytes among different fatty territories can play a crucial role in the pathogenesis of obesity-related diseases. Our goal was to investigate which of the remaining fat pads assume the role of accumulating lipids after surgical removal of parietal WAT (lipectomy; LIPEC) in rats of both sexes displaying MSG-induced obesity.
Methods
The animals entered the study straight after birth, being separated according to gender and randomly divided into CON (control, saline-treated) and MSG (monosodium glutamate-treated) groups. Next, the animals underwent LIPEC or sham-operated surgery (SHAM). Obesity was induced by the injection of MSG (4 mg/g/day) during neonatal stage (2nd to 11th day from birth). LIPEC was performed on the 12th week, consisting in the withdrawal of parietal WAT. On the 16th week, the following WATs were isolated and collected: peri-epididymal-WAT (EP-WAT); parametrial-WAT (PM-WAT); omental-WAT (OM-WAT); perirenal-WAT (PR-WAT) and retroperitoneal-WAT (RP-WAT).
Results
The adiposity index was significantly increased in both male (3.2 ± 0.2** vs 1.8 ± 0.1) and female (4.9 ± 0.7* vs 2.6 ± 0.3) obese rats compared to their respective control groups. LIPEC in obese animals produced fat accumulation in visceral fat sites in a more accentuated manner in female (3.6 ± 0.3** vs 2.8 ± 0.3 g/100 g) rather than in male (1.8 ± 0.2* vs 1.5 ± 0.1 g/100 g) rats compared to obese non-lipectomized animals. Among the visceral WATs, the greater differences were observed between gonadal WATs of obese lipectomized rats, with higher accumulation having been observed in PM-WAT (2.8 ± 0.3* vs 2.1 ± 0.2 g/100 g) rather than in EP-WAT (1.0 ± 0.1 ± 0.9 ± 0.1 g/100 g) when compared to obese non-lipectomized animals.
Conclusions
The results of the present study led us to conclude that obesity induced by MSG treatment occurs differently in male and female rats. When associated with parietal LIPEC, there was a significant increase in the deposition of visceral fat, which was significantly higher in obese female rats than in males, indicating that fat mobility among WATs in lipectomized-obese rats can occur more expressively in particular sites of remaining WATs.
... At the time, the author speculated that MSG ingestion by pregnant women might imperil the normal development of the fetal nervous system [1]. In subsequent studies, the author suggested that weaning infants onto normal food containing MSG might also lead to hypothalamic lesions [2]. ...
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.
... Olney and Ho and others have described the toxic effect of subcutaneous administration of large doses of monosodium glutamate (MSG) in young mice (1,2). Degenerative changes in the retina of the infant mouse after subcutaneous treatment with MSG was reported earlier by Lucas and Newhouse (3). ...
The glutathione precursor cysteine is not contained in most total parenteral nutrition (TPN) formulations, and premature infants may not be capable of synthesizing cysteine because of a deficiency of cystathionase. Glutathione depletion may have negative effects on host defense against oxidative damage. Several studies have suggested that glutathione depletion induces ornithine decarboxylase activity and increases in polyamine concentrations. Since an inverse relationship between polyamine and glutathione concentrations has been suggested, the concentrations of both of these compounds may be altered in premature infants receiving TPN. We measured glutathione and polyamine concentrations of the small intestine and colon of prematurely delivered newborn rabbits administered TPN for 7 days after birth with or without added cysteine (75 or 150 mg kg ‐ 1 day ‐ 1 ). Maternally reared kits were also studied. Total glutathione concentrations in the gastrointestinal tract were significantly lower in kits administered cysteine‐free TPN than in kits receiving cysteine or who were maternally reared. Polyamine concentrations did not differ among groups. Glutathione depletion of the small intestine and colon does occur during cysteine‐free parenteral nutrition and may compromise intestinal defense against oxidant damage.
Worldwide more than one million babies die annually from perinatal asphyxia and its associated complications such as neonatal encephalopathy – one of the major causes of cerebral palsy and cognitive deficiencies in children aside from prematurity. Cooling the head – or the entire body – minimizes neuronal death, enabling the neonatal brain to be 'rescued' thus greatly improving developmental outcomes. Hypothermic neural rescue therapy has revolutionized the treatment of this condition and is a major recent achievement in neonatal medicine. This landmark book provides a brief scientific underpinning of hypothermic neural rescue therapy and lays out the evidence base for good practice. Internationally recognized authorities give practical advice, drawn from personal experience, on how to deliver hypothermia in the neonatal intensive care unit. A valuable addition to any neonatal unit, this is essential reading for neonatologists, neonatal nurses and paediatric neurologists.
Development of the brain and the emergence of the mind constitute some of the most important concerns of contemporary biology. Disturbances during fetal life may have profound implications for a child's future neurological and psychological development, which can in turn impact society. The new edition of this highly respected work presents a comprehensive review of the basic mechanisms of brain development and the pathophysiology of disorders of the infant brain, written by a team of distinguished neuroscientists, neonatologists, and neuropediatricians. The book follows the main milestones of brain development, from formation of the neural tube and wiring of the neurons in the brain. Neurotrophic factors, neurotransmitters, glial cell biology, cerebral circulation development of sensory functions are all described in detail. Furthermore, there are more philosophical chapters on the evolution of the brain and the emergence of consciousness. Clinical considerations are highlighted where relevant.
Development of the brain and the emergence of the mind constitute some of the most important concerns of contemporary biology. Disturbances during fetal life may have profound implications for a child's future neurological and psychological development, which can in turn impact society. The new edition of this highly respected work presents a comprehensive review of the basic mechanisms of brain development and the pathophysiology of disorders of the infant brain, written by a team of distinguished neuroscientists, neonatologists, and neuropediatricians. The book follows the main milestones of brain development, from formation of the neural tube and wiring of the neurons in the brain. Neurotrophic factors, neurotransmitters, glial cell biology, cerebral circulation development of sensory functions are all described in detail. Furthermore, there are more philosophical chapters on the evolution of the brain and the emergence of consciousness. Clinical considerations are highlighted where relevant.
Development of the brain and the emergence of the mind constitute some of the most important concerns of contemporary biology. Disturbances during fetal life may have profound implications for a child's future neurological and psychological development, which can in turn impact society. The new edition of this highly respected work presents a comprehensive review of the basic mechanisms of brain development and the pathophysiology of disorders of the infant brain, written by a team of distinguished neuroscientists, neonatologists, and neuropediatricians. The book follows the main milestones of brain development, from formation of the neural tube and wiring of the neurons in the brain. Neurotrophic factors, neurotransmitters, glial cell biology, cerebral circulation development of sensory functions are all described in detail. Furthermore, there are more philosophical chapters on the evolution of the brain and the emergence of consciousness. Clinical considerations are highlighted where relevant.
Esta obra aborda el descubrimiento del gusto umami, las evidencias científicas de su existencia y los compuestos químicos responsables por este gusto, en particular el glutamato monosódico (GMS), su papel en el metabolismo de los aminoácidos y su uso como aditivo alimentario. También se discute la asociación del GMS con las dietas, su influencia en la aceptabilidad de los alimentos y aspectos químicos, biológicos y sensoriales involucrados en este proceso. Se abordan aspectos de la seguridad alimentaria y tecnológica del GMS, los principales organismos reguladores y comités científicos relacionados.
Esta obra es el resultado de la colaboración de académicos y expertos de la industria, así respaldada por sólidas referencias científicas. Su contenido está dirigido a estudiantes de pregrado y posgrado, académicos y profesionales que trabajan en las áreas de la salud, ciencia y tecnología de alimentos, nutrición, gastronomía, culinaria y regulación alimentaria.
Phụ gia thực phẩm gồm các nhóm: nhóm phụ gia bảo quản (gồm chống vi sinh vật, chống oxy hóa và chống sẫm màu); Nhóm phụ gia dinh dưỡng (gồm vitamin, khoáng, acid amin, xơ,…); Nhóm phụ gia màu, mùi, vị; Nhóm phụ gia cải thiện cấu trúc (gồm 3 nhóm chính phụ gia tạo nhũ, phụ gia ổn định, phụ gia làm đông đặc, làm dầy); Nhóm phụ gia khác (chất làm chắc, các enzyme, các chế phẩm tinh bột, chống tạo bọt, chất chống đông vón, chất điều chỉnh độ acid,…).
Quyển sách này giới thiệu các loại phụ gia được sử dụng trong thực phẩm, mô tả chi tiết tính chất của các phụ gia, xác định liều lượng và phạm vi sử dụng phụ gia trên cơ sở tiêu chuẩn Việt Nam.
Ischemic stroke is the leading cause of long-term disability in adults. The primary reason for the disability is the death of neurons in the cortex or subcortical nuclei. Following cerebral ischemia, neurons may die of accidental cell death (necrosis) or regulated cell death such as apoptosis, necroptosis, or ferroptosis. In this chapter, we summarize recent progress in the molecular and cellular mechanisms of ischemic neuronal death. A better understanding of the mechanisms of ischemic neuronal death, especially regulated cell death, may promote the development of therapeutic intervention of ischemic stroke.
Glutaryl‐CoA dehydrogenase deficiency is an inherited organic acid disorder with predominantly neurological presentation. The biochemical hallmark of this disease is an accumulation and enhanced urinary excretion of two key organic acids, glutaric acid and 3‐hydroxyglutaric acid. If untreated, acute striatal damage is often precipitated by febrile illnesses during a vulnerable period of brain development in infancy or early childhood, resulting in a dystonic dyskinetic movement disorder. 3‐Hydroxyglutaric and glutaric acids are structurally similar to glutamate, the main excitatory amino acid of the human brain, and are considered to play an important role in the pathophysiology of this disease. 3‐Hydroxyglutaric acid induces excitotoxic cell damage specifically via activation of N‐methyl‐D‐aspartate receptors. It has also been suggested that secondary amplification loops potentiate the neurotoxic properties of these organic acids. Probable mechanisms for this effect include cytokine‐stimulated NO production, a decrease in energy metabolism, and reduction of cellular creatine phosphate levels. Finally, maturation‐dependent changes in the expression of neuronal glutamate receptors may affect the vulnerability of the immature brain to excitotoxic cell damage in this disease.
Glaucoma is a disease that causes irreversible blindness. Reducing intraocular pressure (IOP) is the main treatment at present. Nitric oxide (NO), an endogenous gas signaling molecule, can increase aqueous humor outflow facility, inhibit aqueous humor production thereby reducing IOP, as well as regulate eye blood flow and protect the optic nerve. Therefore, NO donating anti-glaucoma drugs have broad research prospects. In this review, we summarize NO-mediated therapy for glaucoma, and the state of the art of some NO donating molecules, including latanoprostene bunod in market and some other candidate compounds, for the intervention of glaucoma, as well as prospects and challenges ahead in this field.
Insulin‐like Growth Factor‐1 (IGF‐1) has been studied extensively for its ability to promote neuronal growth and excitability. Declining levels of IGF‐1 have been correlated with impaired learning and memory as well as an increased risk of neurodegenerative diseases. While neuronal regulation by IGF‐1 is well understood, the role of IGF‐1 in influencing astrocyte function requires further exploration. Astrocytes regulate many aspects of the brain microenvironment, including controlling glutamate‐glutamine cycling, which ultimately supports neuronal metabolism, neurotransmission, and protection from over stimulation. In this study, we examined whether IGF‐1 acts through its cognate receptor, IGFR, to alter astrocytic glutamate handling. We utilized both small molecule IGFR inhibitors and Cre‐driven genetic approaches to reduce IGFR in vivo and in cultured rodent astrocytes. When IGFR was knocked out of primary astrocytes derived from igfrf/f mice using AAV5‐CMV‐Cre, significant reductions in glutamate uptake were observed. Similarly, inhibition of IGFR with picropodophyllotoxin for 2 h, as well as 24 h, reduced glutamate uptake in vitro. Mechanistically, short‐term inhibition of IGFR resulted in a significant decrease in glutamate transporter availability on the cell surface, as assessed by biotinylation. Long‐term inhibition of IGFR led to significant reductions in mRNA expression of glutamate transport machinery, as assessed with qPCR. Reduced glutamate transporter mRNA was also observed in the brains of astrocyte‐specific IGFR‐deficient mice, three to four months after knock‐out was induced with tamoxifen. Interestingly, long‐term IGF‐1 inhibition also resulted in an increase in adenosine triphosphate‐stimulated glutamate release, though no change in adenosine triphosphate‐stimulated calcium flux was observed nor were any changes in purinergic receptor protein expression. Together, these data suggest that reduced IGF‐1 signaling will favor an accumulation of extrasynaptic glutamate, which may contribute to neurodegeneration in disease states where IGF‐1 levels are low.
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Cover Image for this issue: doi: 10.1111/jnc.14534.
Glutathione (GSH) is a critical endogenous antioxidant found in all eukaryotic cells. Higher GSH concentrations protect against cellular damage, tissue degeneration, and disease progression in various models, so there is considerable interest in developing interventions that augment GSH biosynthesis. Oral GSH supplementation is not the most efficient option due to the enzymatic degradation of ingested GSH within the intestine by γ-glutamyltransferase, but supplementation of its component amino acids—cysteine, glycine, and glutamate—enhances tissue GSH synthesis. Furthermore, supplementation with some non-precursor amino acids and micronutrients appears to influence the redox status of GSH and related antioxidants, such as vitamins C and E, lowering systemic oxidative stress and slowing the rate of tissue deterioration. In this review, the effects of oral supplementation of amino acids and micronutrients on GSH metabolism are evaluated. And since specific dietary patterns and diets are being prescribed as first-line therapeutics for conditions such as hypertension and diabetes, the impact of overall diets on GSH homeostasis is also assessed.
The present study was designed to investigate the effect of ascorbic acid (AA) treatment on the anxiety related behavioral and neurochemical alterations. AA (50, 100 and 200 mg/kg, i.p.) was administered to the mice and anxiety related behavior and levels of glutamate and nitrite in the brain of mice were determined. The results obtained revealed that the administration of AA (100 mg/kg, i.p.) significantly reduced the anxiety related behavior and the levels of nitrite in the brain of mice. Nitrergic interactions were further determined by the pretreatment of mice with nitric oxide (NO) modulator and AA treatment followed by behavioral and neurochemical measurements. The results obtained suggested that NO inhibition potentiated the anxiolytic like activity of AA in mice. It was also observed that the glutamate and nitrite level in the brain of mice were significantly reduced by the NO inhibitor pretreatment. Thus, the present study demonstrated the possible nitrergic pathways modulation in the anxiolytic like activity of AA in mice.
Sodium-L-glutamate was administered to post-natal Swiss albino and agouti C3H/HeJ “rodless” mice. In both cases there was at two months a marked reduction in myelinated axons of the optic nerve from about 25,000 to less than 225 axons but Swiss mice had more ganglion cell somas than axons. Glutamate-treated eyes seemed smaller and the lenses were 65% of the weight of control lenses. The inner nuclear layer of Swiss-glutamate retinas was reduced from 5–7 nuclei deep to 1–2. In treated Swiss mice the receptor concentration appears unchanged and electron microscopy revealed that both spheroidal and pedicular receptor terminals were contacted by presumed neurites of second order neurons. There was a small, relative increase in terminals of bipolar neurons in the markedly reduced inner plexiform layer. Relative to these findings a description is given of normal synaptic arrangements. In glutamate-treated “rodless” mice at two months the retina contained two rows of nuclei. Imbricated processes of glial cells of Müller faced the pigment epithelium and the retina contained scattered ganglion cells, bipolar cells, and other neurons less readily characterized. At two months most glutamate-treated mice, rod containing or “rodless,” had a direct pupillary response and a detectable but obviously weaker consensual response. Preliminary examinations of animals one year after glutamate treatment showed receptor deterioration in albino animals and further retinal deterioration in both groups. The two surviving C3H-glutamate animals possessed milky cataractous lenses, however full but sluggish direct iris constrictions could be elicited.
In newborn mice subcutaneous injectionis of monosodium glutamate induced acute neuronal necrosis in several regions of developing
brain including the hypothanamus. As adults, treated animals showed stunted skeletal development, marked obesity, and female
sterility. Pathological changes were also found in several organs associated with endocrine function. Studies of food consumption
failed to demonstrate hyperphagia to explain the obesity. It is postulated that the aduls syndrome represents a multifacted
nueroendocrine disturbance arising from the disruption of developing nueral centers concered in the mediation of endocrine
function.
In an infant rhesus monkey brain damage resulted from subcutaneously administered monosodium glutamate. Although a relatively high dose of monosodium glutamate was used, the infant was asymptomatic for a 3-hour observation period during which time hypothalamic neurons were undergoing a process of acute cell death. With the electron microscope it was observed that dendrites and cell bodies of neurons are the tissue components primarily affected in brain damage induced by monosodium glutamate.
L-Glutamic acid and its sodium salt have been widely used in the oral treatment of petit mal and mental deficiency (e. g., Zimmerman, Burgemeister, and Putnam, 1949; Milliken and Standen, 1951). Single doses of 20-30 gm. have also been administered intravenously without permanent illeffects (Sapirstein, 1943; Elman, 1946; Mayer-Gross and Walker, 1949; Weil-Malherbe, 1949).
During an investigation of the influence of various substances of biochemical importance upon the progress in the mouse of an hereditary retinal dystrophy it was observed that the parenteral administration of sodium L-glutamate damaged the inner layers of the retina, which are not themselves involved in the genetic lesion. Since this lesion could also be produced in normal mice, a limited study was made of its histological development and the conditions necessary for its appearance in mouselings and adults of the Strong A2 (Glaxo) strain. Among substances related chemically or physiologically to glutamate, which were also
1. 1. Inhibition of the formation of the inner retinal layers in newborn mice by the method of Lucas and Newhouse was repeated by us. 2. 2. Such animals whose retinas are essentially a pure culture of receptor cells show an ERG consisting of a negative a-wave only. 3. 3. In animals receiving inadequate doses of glutamate and showing a normal ERG, the intermediate cell layers are always present. 4. 4. This is considered strong evidence for the origin of the b-wave in the intermediate cell layer. 5. 5. A new hypothesis for the mechanism of glutamate toxicity is proposed.
Neioborn albino rats show the same loss of inner retinal layers and of b-wave on treatment with sodium i,-glutamate as do mice. Values for four enzymes metabolizing glutamate or glutamine have been determined on normal and glutamate-treated rats. The retinas of normal rats contain almost twice as much glutaminase I per unit weight as those of glutamate-treated animals. There is no measurable "glutaminase II" activity in rat retina. There is no difference between retinas of normal and treated animals in content of glutamosynthetase and glutamo- transferase. These findings are consonant with our hypothesis that glutamate action on the retina of the newborn rat is by repression of synthesis of an enzyme whose reaction product is glutamate itself. They do not eliminate the possibility that direct competitive inhibition by glutamate may play a role.