[A Multi-arm Placebo-controlled Study with Glutamic Acid Conducted in Rostock in 1953/1954]. / Eine Rostocker Placebo-kontrollierte mehrarmige Studie mit Glutaminsäure bei Kindern und Jugendlichen 1953/54.

A Multi-arm Placebo-controlled Study with Glutamic Acid Conducted in Rostock in 1953/1954 Glutamic acid was commonly used in the treatment of intellectually disabled children in the 50s. Koch reported first results of an observation of 140 children treated with glutamic acid in 1952. In this line is the multi-arm placebo-controlled study reported here. The original study protocols were available. 58 children with speech problems who attending a school of special needs received glutamic acid, or vitamin B, or St.-John's-wort. The effect of glutamic acid was in few cases an improvement of attention. On the other hand restlessness and stutter increased. The majority of all reported a weight loss. The treatment with vitamin B showed a positive effect concerning concentration. The treatment with St.-John's wort was stopped caused by headache and vomiting in eight of nine cases. The results of the study reported here are unpublished. The reason may be that until the 60s the effects of glutamic acid in the treatment of intellectually disabled children were in generally overestimated.

Twenty-five years of glutamate in schizophrenia: are we there yet?

At present, all medications for schizophrenia function primarily by blocking dopamine D2 receptors. Over 50 years ago, the first observations were made that subsequently led to development of alternative, glutamatergic conceptualizations. This special issue traces the historic development of the phencyclidine (PCP) model of schizophrenia from the initial description of the psychotomimetic effects of PCP in the early 1960s, through discovery of the link to N-methyl-D-aspartate-type glutamate receptors (NMDAR) in the 1980s, and finally to the development of NMDA-based treatment strategies starting in the 1990s. NMDAR antagonists uniquely reproduce both positive and negative symptoms of schizophrenia, and induce schizophrenia-like cognitive deficits and neurophysiological dysfunction. At present, there remain several hypotheses concerning mechanisms by which NMDAR dysfunction leads to symptoms/deficits, and several theories regarding ideal NMDAR-based treatment approaches as outlined in the issue. Several classes of agent, including metabotropic glutamate agonists, glycine transport inhibitors, and D-serine-based compounds are currently in late-stage clinical development and may provide long-sought treatments for persistent positive and negative symptoms and cognitive dysfunction in schizophrenia.

NMDA receptor and schizophrenia: a brief history.

Although glutamate was first hypothesized to be involved in the pathophysiology of schizophrenia in the 1980s, it was the demonstration that N-methyl-D-aspartate (NMDA) receptor antagonists, the dissociative anesthetics, could replicate the full range of psychotic, negative, cognitive, and physiologic features of schizophrenia in normal subjects that placed the "NMDA receptor hypofunction hypothesis" on firm footing. Additional support came from the demonstration that a variety of agents that enhanced NMDA receptor function at the glycine modulatory site significantly reduced negative symptoms and variably improved cognition in patients with schizophrenia receiving antipsychotic drugs. Finally, persistent blockade of NMDA receptors recreates in experimental animals the critical pathologic features of schizophrenia including downregulation of parvalbumin-positive cortical GABAergic neurons, pyramidal neuron dendritic dysgenesis, and reduced spine density.

Umami and the foods of classical antiquity.

Umami is the taste of foods that are rich in glutamic acid and 2 ribonucleotides, 5'-inosinate and 5'-guanylate. This distinctive taste of modern Eastern cuisine, which is finding a receptive audience in the Western hemisphere, characterized many dishes that ancient Romans consumed >2000 y ago. Romans enjoyed numerous foods that are identified today as containing significant amounts of natural umami substances and frequently used fish sauce as a condiment in their recipes. Fish sauce imparted to Roman dishes a moderately salty, slightly fishy taste that combines synergistically with other foods to create the umami flavor. Fish sauce derives from the hydrolysis of fish in the presence of salt primarily through endogenous enzymic proteolysis. Its simple production process, low cost, and ability to enhance the taste of many foods has made it the basic condiment for traditional dishes consumed in many Southeast Asian countries. Fish sauce also has important nutritional value, primarily in the form of amino acids. Because ancient Romans made fish sauce in the same way and with the same resources as modern fish sauce producers of Southeast Asia, the amino acid profiles of the 2 products are probably nearly identical. Archaeological sources indicate that fish-processing centers operated throughout the Mediterranean area, and processed fish was an important element in long-distance trade. A close study of the remains of the Roman city of Pompeii indicates that fish sauce was a thriving business that rendered the popular condiment accessible to people of all social classes.

Glutamate: from discovery as a food flavor to role as a basic taste (umami).

In 1908 Kikunae Ikeda identified the unique taste component of konbu (kelp) as the salt of glutamic acid and coined the term umami to describe this taste. After Ikeda's discovery, other umami taste substances, such as inosinate and guanylate, were identified. Over the past several decades, the properties of these umami substances have been characterized. Recently, umami has been shown to be the fifth basic taste, in addition to sweet, sour, salty, and bitter.

The glutamate story.

Glutamatergic synaptic transmission in the mammalian central nervous system was slowly established over a period of some 20 years, dating from the 1950s. Realisation that glutamate and like amino acids (collectively known as excitatory amino acids (EAA)) mediated their excitatory actions via multiple receptors preceded establishment of these receptors as synaptic transmitter receptors. EAA receptors were initially classified as N-methyl-D-aspartate (NMDA) and non-NMDA receptors, the latter subdivided into quisqualate (later AMPA) and kainate receptors after agonists that appeared to activate these receptors preferentially, and by their sensitivity to a range of differentially acting antagonists developed progressively during the 1970s. NMDA receptors were definitively shown to be synaptic receptors on spinal neurones by the sensitivity of certain excitatory pathways in the spinal cord to a range of specific NMDA receptor antagonists. Importantly, specific NMDA receptor antagonists appeared to be less effective at synapses in higher centres. In contrast, antagonists that also blocked non-NMDA as well as NMDA receptors were almost universally effective at blocking synaptic excitation within the brain and spinal cord, establishing both the existence and ubiquity of non-NMDA synaptic receptor systems throughout the CNS. In the early 1980s, NMDA receptors were shown to be involved in several central synaptic pathways, acting in concert with non-NMDA receptors under conditions where a protracted excitatory postsynaptic potential was effected in response to intense stimulation of presynaptic fibres. Such activation of NMDA receptors together with non-NMDA receptors led to the phenomenon of long-term potentiation (LTP), associated with lasting changes in synaptic efficacy (synaptic plasticity) and considered to be an important process in memory and learning. During the 1980s, it was shown that certain glutamate receptors in the brain mediated biochemical changes that were not susceptible to NMDA or non-NMDA receptor antagonists. This dichotomy was resolved in the early 1990s by the techniques of molecular biology, which identified two families of glutamate-binding receptor proteins (ionotropic (iGlu) and metabotropic (mGlu) receptors). Development of antagonists binding to specific protein subunits is currently enabling precise identification of discrete iGlu or mGlu receptor subtypes that participate in a range of central synaptic processes, including synaptic plasticity.

Reappraisal of the 20th-century version of amino acid metabolism.

In this article, we advocate the radical revision of the 20th-century version of amino acid metabolism as follows. (1) Classic studies on the incorporation of [15N]ammonia into glutamate, once considered to be an epoch-making event, are not distinctive proof of the ability of animals to utilize ammonia for the synthesis of alpha-amino nitrogen. (2) Mammalian glutamate dehydrogenase has been implicated to function as a glutamate-synthesizing enzyme albeit lack of convincing proof. This enzyme, in combination with aminotransferases, is now known to play an exclusive role in the metabolic removal of amino nitrogen and energy production from excess amino acids. (3) Dr. William C Rose's "nutritionally nonessential amino acids" are, of course, essential in cellular metabolism; the nutritional nonessentiality is related to their carbon skeletons, many of which are intermediates of glycolysis or the TCA cycle. Obviously, the prime importance of amino acid nutrition should be the means of obtaining amino nitrogen. (4) Because there is no evidence of the presence of any glutamate-synthesizing enzymes in mammalian tissues, animals must depend on plants and microorganisms for preformed alpha-amino nitrogen. This is analogous to the case of carbohydrates. (5) In contrast, individual essential amino acids, similar to vitamins and essential fatty acids, should be considered important nutrients that must be included regularly in sufficient amounts in the diet.

Umami and food palatability.

Umami is the term that identifies the taste of substances such as L-glutamate salts, which were discovered by Ikeda in 1908. Umami is an important taste element in natural foods; it is the main taste in the Japanese stock "dashi," and in bouillon and other stocks in the West. The umami taste has characteristic qualities that differentiate it from other tastes, including a taste-enhancing synergism between two umami compounds, L-glutamate and 5'-ribonucleotides, and a prolonged aftertaste. The key qualitative and quantitative features of umami are reviewed in this paper. The continued study of the umami taste will help to further our general understanding of the taste process and improve our knowledge of how the taste properties of foods contribute to appropriate food selection and good nutrition.