Glutamic Acid, Twenty Years Later

This review examines progress in understanding the physiologic functions of glutamic acid in the body since the first symposium on glutamic acid physiology and biochemistry was held at the Mario Negri Institute in Milan in 1978. The topics reviewed, although not exhaustive, include the metabolism of glutamic acid, umami taste, the role of glutamic acid as a neurotransmitter, glutamate safety and the development of new drugs resulting from the knowledge of the neurodegeneration induced by high doses of glutamic acid.

Twenty years ago (in May 1978) the Mario Negri Institute for Pharmacological Research in Milan organized a symposium on glutamic acid; the proceedings were published in an “orange book” (Fig. 1). It is now interesting to assess the changes that have taken place in our knowledge of specific glutamate functions (e.g., its metabolism, roles in the central nervous system, participation in taste perception, as well as its safety as a food additive and as a source of new drugs). This review, although not exhaustive, attempts to highlight some of the many advances made in the years between the two symposia.


Cover of 1979 symposium proceedings: Glutamic Acid: Advances in Biochemistry and Physiology.

Metabolism of glutamic acid

L-glutamic acid (GA)2 is an ubiquitous amino acid present in most foods in either the free form or bound to peptides and proteins. It has been calculated that a 70-kg man has a daily GA intake of ∼28 g that is derived from the diet and from the breakdown of gut proteins. The daily GA turnover in the body is ∼48 g. Despite this large turnover, the total pool of GA in blood is quite small, ∼20 mg, because of its rapid extraction from and utilization by various tissues, particularly muscle and liver (Munro 1979).

The sodium salt of glutamic acid (MSG) is added to several foods to enhance flavor. The 1978 meeting thus presented considerable information, new at the time, on the fate of MSG, administered by various routes, in numerous animal species including humans. GA is transformed in intestinal mucosal cells to alanine, and in the liver to glucose and lactate (Stegink et al. 1979). Peak plasma GA levels achieved in adult animals after a 1 g/kg oral dose of MSG are lowest in rabbits and progressively higher in rhesus monkeys, dogs, mice, rats and guinea pigs (see Table 1) (Garattini 1979). Several factors influence peak plasma GA levels, including the route of MSG administration (oral < subcutaneous < intraperitoneal), the MSG concentration of the ingested solution (2% < 10%), the ingestion of MSG with food [peak levels are attenuated when MSG is consumed with food, particularly carbohydrates (Stegink et al. 1979)], and age [newborn animals metabolize GA slower than adults (Garattini 1979)]. However, there appear to be no circadian variations in plasma and whole blood GA concentrations in humans fed a diet with or without added MSG.


Kinetic parameters of oral monosodium glutamate (MSG) in different animal species1

Species Age Dose2 Peak plasma concentration Plasma AUC3 T1/2
d g/kg μmol/(L · mL) μmol/(L · mL) × min min
Mouse 7 0.25 0.72 ± 0.04 103 79
1.00 2.10 ± 0.06 375 111
90 1.00 2.08 ± 0.02 309 98
1.004 0.27 ± 0.01 48
Rat 7 1.00 2.89 ± 0.11 1391 241
90 1.00 1.91 ± 0.09 288 88
Guinea pig 7 1.00 1.91 ± 0.02 321 101
90 1.00 2.28 ± 0.03 487 173
Rabbit adult 1.00 0.29 ± 0.14 13 53
Dog (beagle) adult 1.00 1.78 ± 0.315 143 49
Monkey (rhesus) adult 1.00 1.58 ± 0.334 53 99
Human (male) adult 0.06 0.19 ± 0.09 6.2 68
(female) adult 0.06 0.19 ± 0.09 4.7 68
1 Modified from Garattini (1979).
2 By gavage (10% concentration for animal species, 2% solution for humans).
3 AUC, area under the curve.
4 With a meal.
5 Vomiting occurred.
The metabolism of GA is very complex; a large number of pathways are involved (Meister 1979). But a metabolite of GA that has received little attention is pyroglutamate (pyroGA) (Fig. 2), a heterocyclic compound present in the plasma of several species, including humans (Ghezzi et al. 1983). PyroGA is also present in tissues (Meister 1974, van der Werf and Meister 1975), particularly the skin (Marstein et al. 1973), and is known to enter the brain (in rats and mice) (Caccia et al. 1983).
Conversion of pyroglutamic acid to glutamate by 5-oxoprolinase.

The placenta is considered virtually impermeable to GA, although breast milk concentrations are high. However, breast milk GA concentrations are influenced only modestly by the ingestion of MSG (Pitkin et al. 1979).

Glutamic acid in the central nervous system

The metabolism of GA in the central nervous system (CNS) has been studied extensively in relation to nitrogen metabolism, the energy supply, its role as a neurotransmitter and as a precursor to another neurotransmitter (γ-amino acid, GABA), and more recently, its metabolic compartmentalization within different cellular elements in brain.

Shank and Aprison (1979) in the “orange book” reviewed the hypothesis that GA may be an excitatory neurotransmitter, suggesting that the precursors of neurotransmitter GA are glucose, glutamine and/or α-ketoglutarate. It was also established that there is active GA uptake by glia and neurons; this uptake process terminates the excitatory actions of GA after its release into synapses. Despite this information, Curtis (1979) concluded at the 1978 symposium that the role of GA as a transmitter was far from convincing, particularly because of the technical limitations of the experiments at the time. Similarly, Wurtman (1979), in summarizing the 1978 meeting, accepted that “GA is a CNS neurotransmitter,” but admitted that “we lack understanding about the locations of the specific synapses where GA is released.”

Today, 20 years later, it is widely accepted that GA is the major excitatory transmitter within the brain, mediating fast synaptic transmission and active in perhaps one third of all CNS synapses (Watkins and Evans 1981). The concept of GA as an exclusively excitatory transmitter has been challenged recently on the basis of evidence that that it mediates an inhibitory postsynaptic potential in dopamine neurons (Cleland 1996, Fiorillo and Williams 1998).

All of the conditions that establish GA as a neurotransmitter have now been satisfied, although much remains to be clarified. Several symposium papers reviewed recent progress on this issue.

Neuronal GA is released by many stimuli and can be measured not only in vitro, but also in vivo by microdialysis. Once released, GA acts at multiple subtypes of postsynaptic and presynaptic receptors (McGehee and Role 1996). As illustrated in Table 2, there are two major groups of glutamate receptors: ionotropic and metabotropic. The ionotropic receptors include the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors containing iGluR1 and iGluR4 subtypes, kainate receptors (iGLUR5, iGLUR7 and KA1, KA2 subtypes) and N-methyl-D-aspartate (NMDA) receptors (NR1, NR2A-D, NR3 subtypes).


Schematic classification of glutamic acid receptors1

Class of receptors Groups Effect
Ionotropic receptors
AMPA iGluR1; iGluR4 influx of Na+
Kainate iGluR5; iGluR7 influx of Na+
KA1; KA2
NMDA NR1; NR2A–D; NR3 influx of Ca++
Metabotropic receptors
1. mGluR1a–c; mGluR5 phosphoinositide hydrolysis activation
2. mGluR2; mGluR3 cAMP inhibition
3. mGluR4,6,7,8 cAMP inhibition
1 AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazole propionate; NMDA, N-methyl-D-aspartate.

AMPA and kainate receptors, also called non-NMDA receptors, mediate fast excitatory synaptic transmission and “are associated with voltage-independent channels that gate a depolarizing current primarily carried by an influx of Na+ ions” (Cotman et al. 1995). In addition to AMPA itself, other AMPA agonists include α-amino-3-hydroxy-5-tert-butyl-4-isoxazole propionate (ATPA) and aniracetam (Tang et al. 1991); acromelic acid and domoic acid are potent agonists for kainate receptors.

NMDA receptor activation results in the “development of a relatively slow-rising, long-lasting current mediated primarily by the influx of Ca++ ions” (Cotman et al. 1995). In addition to NMDA, agonists of these receptors (trans-ABCD) are S-sulfo-L-cysteine and trans-1-aminocyclobutane,1,3 dicarboxylate.

The metabotropic receptors are coupled to intracellular second messengers via G proteins and fall into three groups as follows: the first group contains mGluR1a,b,cand mGluR5a,b; the second group contains mGluR2,3; and the third group, mGluR4,6,7,8 (Nakanishi and Masu 1994). This classification is based on the transduction mechanisms that each of these mediate (Conn and Pin 1997). Group 1 receptors stimulate phospholipase C and phosphoinositide (PI) hydrolysis, resulting in two second messengers, i.e., diacylglycerol, which activates protein kinase C, and inositol-1,4,5-triphosphate, which elicits the release of Ca++ from intracellular stores. Group 2 receptors inhibit forskolin- or Gs-coupled receptor-stimulated cAMP formation. Members of group 3 have the same action as group 2 receptors, but are notably weaker inhibitors of cAMP formation.

An enormous amount of work has focused on identifying selective agonists and antagonists at mGlu receptors. Examples include quisqualate, the most potent agonist for group 1; 2,3-dicarboxycyclopropyl-glycol, an agonist at the group 2 receptors, and L-amino-4 phosphobutyrate (L-AP4) and L-serine-O-phosphate (O-SOP), agonists at group 3 receptors (Conn and Pin 1997). The mGlu receptors in each group are distinct in their selectivity to agonists, although most of the results on agonist potency have been obtained from cloned receptors inserted into heterologous cells, a condition that may not mimic accurately the mGlu receptor microenvironment in neuronal cells.

Once released into synapses, excess GA is taken up by both neuronal and glial cells. Several transport proteins have been identified; they are glycoproteins and demonstrate high affinity for GA. They are dependent on the presence of Na+ ions and reside in and around excitatory GA synapses. Four transporters have been identified to date; they are named GLAST-1 (Storck et al. 1992), GLT-1 (Pines et al. 1992), EAA C-1 (Kanai and Hediger 1992) and EAA T-4 (Fairman et al. 1995). Their distribution among cell types and brain regions is not uniform, i.e., GLAST-1 is present in oligodendrocytes in the hippocampus and cerebral cortex, GLT-1 is found in astrocytes throughout the brain, EAAT-4 is expressed primarily in cerebellum, whereas EAAC-1 is located principally on neurons.

The absence or inhibition of these GA transport proteins has been postulated to be a cause of neurodegeneration (because abnormally high extracellular GA levels cause hyperexcitation of neurons, leading to their death). However, mice made deficient in EAAC-1 do not develop neuronal lesions, although they exhibit behavioral abnormalities (Peghini et al. 1997). This finding may indicate that glial GA transporters are more important than neuronal transporters in the etiology of neuronal death. Several GA transport inhibitors have been identified, including L-trans-pyrrolidine-2,4-dicarboxylic acid (Massieu et al. 1995Rawls and McGinty 1997)

There are numerous interactions between GA and other neurotransmitters. For example, results from this Institute (Consolo et al. 1996) revealed that bilateral electrical stimulation in vivo of the prefrontal cortex or the parafascicular nucleus of the thalamus facilitates the release of acetylcholine into the dorsal striatum. This effect is mediated in the cortex by the nontonic activation of AMPA-type GA receptors [it is blocked by DNQX or NBQX, but not dizolcipine (MK801)] and in the parafascicular nucleus through the tonic activation of NMDA receptors (blocked by MK801, but not DNQX or NBQX). In turn, acetylcholine is known tonically to regulate GA release in the striatum (Rawls and McGinty 1998).

Glutamate activity may also be modulated by other chemicals in nonclassical ways; for example, arachidonic acid blocks GA uptake (Manzoni and Mennini 1997), serotonin modulates 3H-GA binding to receptors (Mennini and Miari 1991), and interleukin-1β (Mascarucci et al. 1998, Vezzani et al. 1998) and neuropeptide Y (Schwarzer et al. 1996) all increase neuronal GA release.

Taste perception

At the time of the 1978 glutamate symposium, psychometric studies had established that MSG imparts a unique taste of its own, termed “umami” (delicious or savory taste) (Yamaguchi and Kimizuka 1979). However, it was also known to enhance the perception of sweetness and saltiness, and to diminish that of sourness and bitterness. As suggested by Cagan et al. (1979), the flavor-enhancing properties of MSG were thought to offer important clues to understanding the biochemical basis of taste sensation.

Since the first symposium, considerable progress has been made in this area of investigation. For example, members of the Monell Chemical Senses Center in Philadelphia have systematically studied the taste properties of GA. Cagan et al. (1979) observed that 3H-GA binding to preparations of bovine circumvallate papillae (taste cells) is several times higher than that found with preparations of tongue epithelium (nontaste cells), using millimolar concentrations of MSG (KD = 17–20 mmol/L). Further, GA binding has been found to be enhanced several-fold by coincubation with the nucleotide GMP; other mononucleotides produce smaller responses, suggesting specificity for GMP. The interpretation of these results lies in the possibility that GMP exposes hidden receptors to GA. In this regard, it is of interest to note that both MSG and GMP are present in the popular Japanese condiments, seaweed sea tangles (Laminaria sp.) and black mushrooms (shiitake), respectively, (Sohn et al. 1998).

In addition, work has moved forward on the basic MSG taste (umami) to the point that it has now been proposed to be a fifth primary taste (Kurihara 2000). As a corollary, it is clear that the MSG taste cannot be attributed to the sodium moiety of MSG. Dogs, monkeys, certain strains of mice, but not rats all resemble humans in possessing the ability to taste umami. Two molecular mechanisms appear to be involved in umami taste transduction; one is based on an NMDA-type GA ion-channel receptor, the other on a GA metabotropic receptor, mGluR4 (Brand 2000), which utilizes IP3 and cAMP as second messengers. Regardless of mechanism, however, it appears clear that fibers can be identified in the chorda tympani as well as in glossopharyngeal nerves that are selectively sensitive to MSG (and not to stimuli for the other basic tastes) (Ninomiya 2000).

The identification of two mouse strains that differ markedly in their preference for MSG creates an opportunity to identify genes that modulate MSG taste. Other studies are examining sensory pathways that project from MSG-sensitive papillae to the brain. In primates, umami sensing is “localized” in the secondary taste cortex in connection with neurons also sensitive to olfactory stimuli. Nishijo et al. (2000) found that the taste preference for MSG may also be located in neurons of the lateral hypothalamic area (LHA) and possibly also in the ventromedial hypothalamus (VMH).

Neurotoxicity of glutamate, safety evaluation

Some years ago, Lucas and Newhouse (1957) observed that subcutaneous injections of GA in infant mice caused degeneration of neurons in the inner layers of the retina. Later, Olney (1969a and 1969b) confirmed and extended these findings, determining that neuronal lesions also occur in brain, particularly in the arcuate nucleus of the hypothalamus (NAH). Brain lesions occurred in most animal species (although rhesus monkeys may be an exception) (Reynolds et al. 1979), and particularly in rodents in which infants were more susceptible than adults (Olney 1979). These observations led to the concept of GA as an “excitotoxic agent” (i.e., a compound that so overstimulates excitatory GA receptors on neurons as to precipitate their death). Because of this property, GA has been used widely as a tool to investigate the processes of neuronal degeneration, both in vivo and in vitro. In vitro, for example, numerous studies have used cell culture models to establish that not only GA but also NMDA agonists (e.g., quinolinic acid or ibotenic acid) and AMPA/kainate agonists (kainic, quisqualic and domoic acids) induce neuronal degeneration (Choi 1988). One of the most convincing bits of in vitro evidence regarding the necessity of GA receptor stimulation for the occurrence of neurotoxicity is the demonstration that NMDA receptor expression in nonneuronal cells normally insensitive to GA toxicity (by transfecting them with a gene containing the receptor) transforms them into GA-susceptible cells (Cik et al. 1993).

Another neurotoxic mechanism linked to GA release (Campochiaro and Coyle 1978, Rothman 1983) is the excessive entry of sodium (Meldrum and Garthwaite 1990) and/or calcium (Iacopino et al. 1992, Mills and Kater 1990, Nedergaard 1988) into cells, which also induces neuronal degeneration. Neuronal death, depending on the model system, results from necrosis (e.g., Sohn et al. 1998) or apoptosis (e.g., Du et al. 1997). Numerous studies have outlined the biochemical events related to apoptosis and indicate the importance of post-translational activation of caspase 3 (cysteine proteases), at least for cultured cerebellar granule neurons (Du et al. 1997). In addition, and more generally, several lines of evidence also indicate that “metabolic inhibition predisposes neurons to GA excitotoxic damage” (Greene and Greenamyre 1996).

Observations concerning GA neurotoxicity have raised questions about the possible harm induced by this amino acid as a food additive. In fact, it is currently used (as MSG) as a flavor enhancer in foods throughout the world, with a range of oral intakes varying between 0.4 g/(person·d) in Italy and 3 g/(person·d) in Taiwan (Giacometti, 1979). Despite its safe use in food, however, there is no doubt, as discussed by Olney (1979) that in several animal species, particularly infants, oral GA induces neuronal degeneration in brain. Takasaki et al. (1979) studied this issue quantitatively, showing, for example, in weanling mice (the most sensitive species) that the minimal active oral dose is 0.7 g/kg MSG (as a 10% solution), whereas in adult mice, a dose of 1.2 g/kg is required. In general, although there is little disagreement that MSG can be neurotoxic at high doses in animals, there is substantial disagreement about the significance of this observation for human nutrition and health.

One important point concerns the relationship of the plasma GA concentrations achieved when a neurotoxic dose of MSG is administered to animals to those attained when MSG is ingested by humans as a component of food. Infant and adult rodents experience 8- to 12-fold increments in plasma GA levels when gavaged with neurotoxic doses of MSG (Airoldi et al. 1979). Peak plasma GA concentrations reach 0.8–1 mmol/L. These levels are many times higher (10- to 40-fold, depending on the experimental conditions employed) than those occurring in humans under normal conditions of MSG use, or even after the administration of maximum palatable doses. A detailed analysis of these results has been made elsewhere (Airoldi et al. 1979, Garattini 1979, Ghezzi et al. 1980, Salmona et al. 1980).

Another important point concerns the manner of MSG use. To be effective as a neurotoxin in animals, the amino acid must be ingested (or administered) in relatively high concentrations in a very short time. In contrast, as a food flavoring agent consumed by humans, it is presented in low concentrations over the relatively long periods associated with the ingestion of a meal. It should be emphasized that when MSG is given to animals as a component of food, even at final ingested doses exceeding those that induce neurotoxicity when given as a single dose (by injection or gavage), plasma GA concentrations rise only modestly, and no neurotoxicity results (Heywood et al. 1977, Heywood and Worden 1979, Takasaki 1978, Takasaki et al. 1979).

Even if GA neurotoxicity is unlikely to occur in humans consuming MSG, it is of interest to analyze the relationship in animals between plasma and brain GA levels at neurotoxic MSG doses. As shown in Table 3, whole brain GA levels do not change in infant or adult animals administered neurotoxic doses of MSG, even though plasma GA levels may increase 10-fold or more. Infant rodents, which are born with incomplete myelinization, do not differ in this respect from guinea pigs, which are born with a more mature brain (Folch-Pi 1955), as shown in Table 3.


Plasma and brain levels of glutamic acid before and after monosodium glutamate (MSG)1

Species Basal levels Increase (fold) after 1 g/kg (gavage)
Plasma Brain Plasma Brain
μmol/(L · mL) μmol/(L · g)
Mouse Infant 0.15 ± 0.01 4.42 ± 0.18 13 NS2
Adult 0.17 ± 0.01 8.21 ± 0.21 12 NS
Rat Infant 0.20 ± 0.01 4.83 ± 0.14 18 NS
Adult 0.15 ± 0.02 8.05 ± 0.25 10 NS
Guinea pig Infant 0.17 ± 0.01 8.04 ± 0.15 12 NS
Adult 0.20 ± 0.01 7.56 ± 0.15 12 NS
Rabbit Adult 0.12 ± 0.01 10.65 ± 0.40
Dog Adult 0.05 ± 0.003 5.80 ± 0.02 36 NS
Monkey (rhesus) Adult 0.13 ± 0.01 9.14 ± 1.97 4 NS
1 Modified from Garattini (1979) and Airoldi et al. (1979).
2 NS, not significant.

The concept that brain levels of GA depend on the equilibrium between its influx and efflux offers a possible explanation why, despite high plasma GA levels and a saturable transport system [as well as a nonsaturable mechanism operating at very high plasma GA concentrations (Pardridge 1979)], whole-brain GA levels do not change after MSG administration (in adult or newborn rodents, dogs or monkeys). Most likely, the export of GA from the brain functions as a “buffering” mechanism, dampening changes in brain GA levels. This mechanism is so powerful that even intraventricular injection to rats of a dose of GA equal to one third of the GA content of the whole brain causes no measurable changes in brain GA levels, although it elicits clear biochemical effects, e.g., an increase in cerebellar cyclic GMP (Mao et al. 1974).

The experimental findings shown in Table 3 contradict the concept that newborn animals have an “immature” blood-brain barrier for GA. According to Saunders (1977) the blood-brain barrier begins to function at an early stage of life; brain endothelial tight junctions are established in the first trimester of human fetal life (Møllgard and Saunders 1975) and in wk 2 of rat fetal life (Olsson et al. 1968). This would explain why high doses of MSG do not lead to changes in the level of GA in the cerebrospinal fluid (CSF) of animals (Kamin and Handler 1951, McLaughlan et al. 1970, Reynolds et al. 1979, Schwerin et al. 1950) or humans (Perry et al. 1975). Quite possibly, the rates of GA influx and efflux differ characteristically in various brain regions; this, together with other factors, might explain the uneven distribution of GA in discrete brain regions.

The fact that GA even at high doses does not induce changes in whole-brain GA levels does not mean that discrete areas of the brain are impermeable to circulating GA. Indeed, the pattern of lesions induced by MSG in the rodent CNS suggests that GA penetrates and accumulates only in specific brain regions. The circumventricular organs (CVO) and contiguous areas are the regions most affected by MSG treatment, in both adult and newborn animals. This focus may reflect the fact that the blood-brain barrier within the CVO has unusual properties (Weindl 1973). That is, capillaries in the CVO have large interendothelial pores (and show active pinocytosis) rather than tight junctions, as is commonly found in other brain areas (Brightman 1977, Pardridge 1979). Possibly, therefore, GA increases that are communicated to the CVO from the plasma can diffuse into contiguous brain areas, or be accumulated via retrograde axoplasmic flow of GA from CVO nerve endings (Pardridge 1979). In this regard, Perez et al. (1976) reported about a twofold rise in hypothalamic arcuate nucleus (NAH) GA concentrations after MSG administration at high doses; plasma GA levels were not reported. However, work from our laboratories (Airoldi et al. 1979) indicated that oral doses of 4 g MSG/kg to adult rats or 3 g/kg to 4-d-old rats did not change GA levels in the NAH or in the lateral thalamus, even when measured at several time points after dosing. In infant (but not adult) mice, 2 g/kg oral MSG did produce a small increase (25%) in NAH GA concentrations. However, this effect could be explained by the increase found in serum osmolality (in infants but not adults; see Airoldi et al. 1980), suggesting that locally high concentrations of GA (0.1–1.0 mmol/L) might have disrupted the blood-brain barrier mechanically, possibly in relation to a nitric oxide–dependent mechanism (Mayhan and Didion 1996). No changes in GA in the NAH of infant or adult guinea pigs were observed after neurotoxic doses of glutamic acid (Airoldi and Garattini 1979). Together, these data cast doubt on the theory that the selective vulnerability of the NAH to MSG-induced neurotoxicity in sensitive animal species results from accumulation of GA in this brain region.

Subsequent studies excluded the possibility that pyroGA, a metabolite of GA, is neurotoxic in infant mice. An oral dose of 0.5 g/kg pyroGA, which raises plasma and brain pyroGA ∼70- and 5-fold (respectively) did not induce lesions in the NAH (Caccia et al. 1983). However, local brain injections of very high concentrations of pyroGA did induce neurotoxic lesions that appeared to be similar to those produced by kainic acid (Borg et al. 1986).

Despite the difficulties in obtaining effects, the possible actions of pyroGA should be investigated further in brain (Moret and Briley 1988), particularly considering that this metabolite is normally present in CSF (Lam et al. 1978) and brain (Caccia et al. 1982), competitively inhibits the high affinity uptake of GA into rat striatal synaptosomes (Dusticier et al. 1985) and is metabolized to glutamate via 5-oxoprolinase (van der Werf and Meister 1975) (Fig. 2).

The existence of a large metabolic pool of GA in the brain (between 4 and 8 mmol/L; 40 times basal plasma levels; see Table 3) may mask subtle but physiologically important changes in the extracellular disposition of this amino acid. In fact, studies using the microdialysis technique, which allows the measurement of the extracellular levels of neurochemical mediators in freely moving animals, show that the extracellular concentration of GA is 2.0 ± 0.2 μmol/L in dorsal hippocampus (Benveniste et al. 1984) and 1–5 μmol/L in striatum (Rawls and McGinty 1998). These levels probably derive from glutamine, as suggested by the marked decrease in glutamine concentrations that accompanies the substantial increase in extracellular GA observed during brain ischemia (Benveniste et al. 1984). Microdialysis studies from our laboratory show that in the hypothalamus, extracellular GA is increased about ninefold when rats receive 4 g/kg of MSG by oral gavage. This increase is comparable to that resulting from KCl-induced neuronal depolarization (Monno et al. 1995). It should be noted, however, that the increase of extracellular brain GA concentrations induced by such high oral doses of MSG is nonetheless one order of magnitude or more below the GA concentration employed in vitro (30 μmol/L–2 mmol/L) (Du et al. 1997, Sohn et al. 1998) to induce neurotoxicity. It remains to be determined whether these results also apply to infant rodents (because of the technical problems in using microdialysis in such small animals). It is also noteworthy that no increase in extracellular GA in hypothalamus (Monno et al. 1995) or striatum (Bogdanov and Wurtman 1994) occurred when MSG was administered as a component of food.

Glutamic acid as a source of new drugs

The neurotoxic effect that can result from overstimulating GA receptors, as well as their postulated roles in the etiology of neurodegenerative diseases, has aroused interest in the development of drugs to block GA receptors. This approach has had the additional appeal that because of the variety of GA receptor subtypes, drugs that act selectively in retarding the progression of neurodegenerative diseases might be found, producing few side effects.

Two main approaches to the blockade of GA action in brain have been followed by industrial and academic laboratories: 1) the inhibition of GA receptors, and 2) the blockade of neuronal GA release. Table 4shows some of the antagonists currently available that selectively block GA glutamate receptor subtypes. The NMDA-sensitive receptor consists of several interacting domains (Young and Fagg 1990), including an agonist recognition site with a coupled ion channel and a strychnine-insensitive glycine site that allosterically modulates the other two components. Many antagonists have been developed that act either competitively at the GA recognition site or noncompetitively at the ion channel site. However, therapeutic application of these agents has been hampered by their poor penetration into the CNS and unwanted psychotomimetic effects (Farooqui and Horrocks 1991, McDonald and Johnston 1990). An interesting example has been the noncompetitive NMDA antagonist MK801 ((+)-S-methyl-10,11 dihydro-SH-dibenzo[a,d]cyclopenten 5,10 imine hydrogen maleate) (Linders et al. 1993). Like diphenyliodonium (Nakamura et al. 1997), MK801 protects against the neurodegeneration induced by GA under a variety of experimental conditions (Auer et al. 1996, Gill et al. 1996). 4(R)-(3 Phenylpropyl) 2(S) glutamic acid (19) is another inhibitor of NMDA receptors. Competitive antagonists of NMDA receptors are also potentially interesting in the treatment of neurodegenerative and convulsive diseases (Schwarcz and Meldrum 1985) and appear to have fewer psychotomimetic effects. DL-(E)-2-Amino-4-methyl-5-phosphono-3-pentenoic carboxyethylester (CGP 39551) is one such compound, having potent and long-lasting anticonvulsive and antineurotoxic properties after oral administration to rodents (Fagg et al. 1990, Schmutz et al. 1990). Such actions, coupled with its relatively high therapeutic index, make it an interesting candidate for potential therapeutic application in humans. Compounds that act as antagonists (or partial agonists) at the strychnine-insensitive glycine binding sites of NMDA receptors also afford neuroprotection in animal models of acute ischemia (Gill et al. 1995, Newell et al. 1995, Smith et al. 1993, Warner et al. 1995). Such agents are therefore being sought, with an eye toward their potential therapeutic use as neuroprotective agents that lack the side effects of competitive or noncompetitive NMDA receptor antagonists (Chiamulera et al. 1990, Hargreaves et al. 1993, Koek and Colpaert 1990). Other drugs, such as ifenprodil, act indirectly by other mechanisms to prevent NMDA receptor stimulation. This agent blocks the enhancement of NMDA agonist activation that occurs with polyamines (Dogan et al. 1997).


Some antagonists of glutamate receptors

Compound Antagonism on glutamate receptors
CGP39653 NMDA, competitive
5,7-diCl-kynuremic acid NMDA, glycine site
Dizolcipine NMDA, ion channel
GAMS1 Kainate
Phenylglycine analogs Metabotropic
1 γ-D-glutamylamino-methylsulfonate; see Table 2 for other abbreviations.

Work that focuses on the other GA receptors is also ongoing. For example, GA neurotoxicity can be inhibited by NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo (F) quinoxaline), a known antagonist of AMPA receptors (Sheardown et al. 1990). There is also interest in phenylglycines, antagonists of glutamate metabotropic receptors (Ferraguti et al. 1994).

The pharmacologic inhibition of GA release from presynaptic terminals was first described for 2-aminophosphobutyric acid (Cheramy et al. 1992Hubert et al. 1994Martin et al. 1993), and subsequently for lamotrigine (Leach et al. 1986Meldrum et al. 1992). These and other compounds are candidate therapeutic agents for such neurodegenerative diseases as stroke, Alzheimer’s disease, neurolathyrism, amyotrophic lateral sclerosis (ALS), Parkinson’s disease and Huntington’s disease. Of interest is the recent approval of riluzole by the European regulatory authority for the treatment of ALS. Riluzole reduces the release of GA, an effect that may be secondary to the blockade of Na+ channels (Obrenovitch 1998). Blockade of GA release may be important for avoiding excessive synaptic GA accumulation in diseases such as ALS in which GA uptake by the glial GLT-1 GA transporter is below normal (Rothstein et al. 1995).

As a new target of pharmacologic research, recent findings indicate that excessive activation of GA circuits in brain, particularly in frontal cortex, may contribute to the appearance of addictive behavior. If so, then drugs that block GA release or GA receptors may ultimately be found to be of value in diminishing addictive habits (Wickelgren 1998). An additional focus of interest may also develop from recent observations that several kainate receptor antagonists appear to reduce chronic inflammatory pain.

Concluding remarks

Twenty years have elapsed since the last symposium. Since then, there is no doubt that substantial progress has been made in understanding the functions of GA in mammals. Not only is there a broader current knowledge of the amino acid’s participation in intermediary metabolism, both inside and outside the brain, but also of its role as a CNS neurotransmitter. Considerable information has also accumulated regarding mechanisms of neuronal GA release and uptake. Furthermore, GA transporter proteins have been identified, and at least three families of receptors (with >20 subtypes) have been characterized. The mechanism of the flavor-promoting actions of MSG has also evolved into a specific taste receptor, leading to the definition of “umami” as the fifth basic taste. The basis for using MSG in food has thus acquired a more robust scientific foundation. At the same time, the safety of dietary MSG has been more fully established, through the careful clarification of the nonphysiologic conditions under which exogenous (and endogenous) GA can become neurotoxic in brain. This latter avenue of investigation has had a further, unanticipated benefit, i.e., it has led to an exploration for drugs that diminish GA release and receptor function, hence a potential new means of identifying treatments for neurodegenerative diseases.

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amyotrophic lateral sclerosis

α-amino-3-hydroxy-5-methyl-4-isoxazole propionate

α-amino-3-hydroxy-5-tert-butyl-4-isoxazole propionate

central nervous system

cerebrospinal fluid

circumventricular organs

glutamic acid

γ-amino acid

L-amino-4 phosphobutyrate

lateral hypothalamic area


sodium salt of glutamic acid

nucleus arcuatus of the hypothalamus





ventromedial hypothalamus

© 2000 The American Society for Nutritional Sciences

S. Garattini – The Journal of Nutrition, Volume 130, Issue 4, 1 April 2000, Pages 901S–909S,

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