Evidence for an N-methyl-D-aspartate (NMDA) receptor in the GI tract of guinea pigs: Studies with diethylhomospermine (DEHSPM)

Sninsky, C.A.; Brooderson, Richard J.; Broome, T.A.; Bergeron, Richard

doi:10.1016/0016-5085(94)90290-9

Cited by 7 publications

(6 citation statements)

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“…Table 1 summarizes the distribution of the GluRs in peripheral tissues demonstrated by using various methodologies such as: RT-PCR, PCR, northern blots, western blots, immunohistochemistry and in situ hybridization. These tissues include adrenal medulla (85,90), peripheral nervesmyelinated and unmyelinated (1,15), bone (14,26), bone marrow (26), bronchial smooth muscle, endocrine pancreas (4-6, 30, 32, 37, 45, 49, 54, 87), gut (8,58,77,81,86), esophagus (this study), hepatocytes (27,78), heart (27,28,55,69,87), taste buds (12,35), keratinocytes (55), lungs (29,34,70,77), pituitary (41,86), pineal gland (52), ileal longitudinal muscle (56,74,75), autonomic and sensory ganglia (85), rat glaborous skin (10), kidney, spleens, ovaries, (26, 28, this study), vagus and other cholinergic nerves (1), tachykinincontaining sensory nerves and vestibular tissues (18). In our studies, we have conducted a thorough analysis on the distribution of the GluRs in peripheral tissues of the rat where the antibodies and the methodology used have been previously described (27,28,29).…”

Section: Metabotropic Glutamate Receptorsmentioning

confidence: 78%

“…Experimental evidence from several labs and from this laboratory (Figure 7) have shown the GluRs to be present in the stomach, duodenum and descending colon (8,56,74,75,83). Immunohistochemical analysis showed that GluRs antibodies had poor af nity for the esophagus with the exception of anti-NMDAR 1, which preferentially stained the less mature cells within the basal layer of the strati ed squamous epithelium (Figure 7).…”

Section: Glutamate Receptors In the Gastro-intestinal (Gi) Tractmentioning

confidence: 92%

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Review Article: Glutamate Receptors in Peripheral Tissues: Current Knowledge, Future Research, and Implications for Toxicology

2001

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We illustrate the speci c cellular distribution of different subtypes of glutamate receptors (GluRs) in peripheral neural and non-neura l tissues. Some of the noteworthy locations are the heart, kidney, lungs, ovary, testis and endocrine cells. In these tissues the GluRs may be important in mediating cardiorespiratory, endocrine and reproductive functions which include hormone regulation, heart rhythm, blood pressure, circulation and reproduction . Since excitotoxicity of excitatory amino acids (EAAs) in the CNS is intimately associated with the GluRs, the toxic effects may be more generalized than initially assumed. Currently there is not enough evidence to suggest the reassessment of the regulated safety levels for these products in food since little is known on how these receptors work in each of these organs. More research is required to assess the extent that these receptors participate in normal functions and/or in the development of diseases and how they mediate the toxic effects of EAAs. Non-neural GluRs may be involved in normal cellular functions such as excitability and cell to cell communication. This is supported by the wide distribution in plants and animals from invertebrates to primates. The important tasks for the future will be to clarify the multiple biological roles of the GluRs in neural and non-neura l tissues and identify the conditions under in which these are up-or down-regulated. Then this could provide new therapeutic strategies to target GluRs outside the CNS.Keywords. Glutamate receptors; peripheral tissues; general injury mechanism; excitotoxicity PERSPECTIVE Food toxicology is the science of evaluating the safety of chemicals that enter the human food chain either as natural compounds, contaminants and/or during processing. To assess chemical safety, tissues and organs are examined for structural, chemical, or functional alterations. These investigations help to establish the safety margins of such compounds for consumption by humans and animals as either food or therapeutic products. Therefore, product safety requires continual reassessment as new information becomes available with advances in technology.Glutamate (Glu) and aspartate (Asp) are naturally occurring amino acids found in the central nervous system (CNS) where they act as major excitatory neurotransmitters (20,21,25,36) by stimulating or exciting the postsynaptic neurons. These excitatory amino acids (EAAs) and their various analogues can be neurotoxic, particularly when they excessively stimulate the same excitatory receptors-a phenomenon known as excitotoxicity (13,20,21,25,36,63). This creates the potential to "over excite" neurons and cause possible neuronal damage. EAAs access the brain tissue of the Address correspondenc e to: Santokh S. Gill, Health Canada, Banting Bldg., Tunney's Pasture, Ottawa, Ontario K1A 0L2, Canada; email: santokh gill@hc-sc.gc.ca. circumventricular organs that are located outside the blood brain barrier (BBB) (7,67). Despite the BBB protective mechanisms, the local or circulating ...

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Section: Metabotropic Glutamate Receptorsmentioning

confidence: 78%

Section: Glutamate Receptors In the Gastro-intestinal (Gi) Tractmentioning

confidence: 92%

Review Article: Glutamate Receptors in Peripheral Tissues: Current Knowledge, Future Research, and Implications for Toxicology

2001

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“…To our knowledge, this is the first report of the existence of NMDA receptors in the lung, and of NMDA receptor activation as a possible mechanism of tissue injury outside the CNS. Since this investigation was begun (39), we have become aware of several reports of the expression of functional NMDA receptors in peripheral tissues, including the myenteric plexus (40), sensory and autonomic ganglion neurons (41), adrenal medulla (42), pancreatic islet cells (43), and the gastrointestinal tract (44).…”

Section: Discussionmentioning

confidence: 99%

Excitotoxicity in the lung: N-methyl-D-aspartate-induced, nitric oxide-dependent, pulmonary edema is attenuated by vasoactive intestinal peptide and by inhibitors of poly(ADP-ribose) polymerase.

Said

Berisha

Pakbaz

1996

Proc. Natl. Acad. Sci. U.S.A.

144

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Excitatory amino acid toxicity, resulting from overactivation of N-methyl-D-aspartate (NMDA) glutamate receptors, is a major mechanism of neuronal cell death in acute and chronic neurological diseases. We have investigated whether excitotoxicity may occur in peripheral organs, causing tissue injury, and report that NMDA receptor activation in perfused, ventilated rat lungs triggered acute injury, marked by increased pressures needed to ventilate and perfuse the lung, and by high-permeability edema. The The amino acid glutamate, abundantly present in the mammalian central nervous system (CNS), is the major excitatory neurotransmitter, and plays an important role in many functions, including learning, memory, development, and other forms of synaptic plasticity (1-5). Among the classes of glutamate receptors that have been identified, cloned, and characterized (4, 6), the ionotropic N-methyl-D-aspartate (NMDA) receptor has been the focus of much attention because of its implication in neuronal cell injury and death in such acute conditions as head injury, strokes, and epileptic seizures, and in chronic neurodegenerative diseases including Alzheimer disease, Huntington disease, Parkinson disease, amyotrophic lateral sclerosis (7-10), and AIDS dementia (11).Evidence linking NMDA receptor activation to neurotoxicity is based on glutamate toxicity to neuronal cells in culture and upon systemic administration in vivo (12)(13)(14), and the neuroprotective effect of NMDA receptor antagonists in a variety of settings (9, 13). The view that neuronal injury induced by glutamate or related excitatory amino acids resulted from overexcitation suggested the term "excitotoxicity" (7). An important insight into the mechanisms underlying this phenomenon was the observation that NMDA neurotoxicity was Ca2+-dependent (15,16). The influx of Ca2+ into the cell may lead to cell death by several mechanisms, including the activation of protein kinases, phospholipases, proteases, and nitric oxide synthase (NOS), and the generation of reactive oxygen species (9). Evidence has been presented for a key mediator role for NO in glutamate-stimulated neurotoxicity in primary cultures of rat fetal cortical, striatal, and hippocampal neurons (11,(17)(18)(19), although others could not confirm an essential role for NO in NMDA-induced neurotoxicity (20,21).The generation of reactive oxygen species, including superoxide and hydroxyl radicals and singlet oxygen, together with NO or as a result of its formation, may contribute importantly to NMDA toxicity (22)(23)(24)(25). NO itself, produced in high concentrations, can injure neurons and other cells through a variety of toxic actions, including the inhibition of the mitochondrial electron-transport chain and of mitochondrial enzymes, and DNA damage, which in turn triggers the activation of poly-(ADP-ribose) polymerase (PARP), also known as poly(ADPribose) synthetase (PARS) (26,27).Using the isolated perfused and ventilated rat lung as a model, we have investigated the possible occurrence and ...

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“…In addition, glutamate agonists induce various cellular responses in peripheral tissues, such as a rise in intracellular cal-cium concentration in the rat pituitary cell and the stimulation of growth hormone. They also induce the release of insulin and glucagon from the rat endocrine pancreas and the contraction of the myenteric plexus-longitudinal muscle of the guinea pig ileum (14,32,35,(37)(38)(39). Current evidence indicates that the GluRs are present in the following tissues: lungs (29,30), sensory ganglia (37), adrenal and pineal glands (20,37), tongue (3), pancreas (11,14,38), pituitary (36), vestibular system (6), bone (4), gut (1, 31), and heart (9, 10,21,22,28).…”

Section: Introductionmentioning

confidence: 99%

Potential Target Sites in Peripheral Tissues for Excitatory Neurotransmission and Excitotoxicity

et al. 2000

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Glutamate receptors (GluRs) are ubiquitously present in the central nervous system (CNS) as the major mediators of excitatory neurotransmission and excitotoxicity. Neural injury associated with trauma, stroke, epilepsy, and many neurodegenerative diseases such as Alzheimer's, Huntington's, and Parkinson's diseases and amyotrophic lateral sclerosis may be mediated by excessive activation of GluRs. Neurotoxicity associated with excitatory amino acids encountered in food, such as domoic acid and monosodium glutamate, has also been linked to GluRs. Less is known about GluRs outside the CNS. Recent observations suggest that several subtypes of GluRs are widely distributed in peripheral tissues. Using immunochemical and molecular techniques, the presence of GluR subtypes was demonstrated in the rat and monkey heart, with preferential distribution within the conducting system, nerve terminals, and cardiac ganglia. GluR subtypes NMDAR 1, GluR 2/3, and mGluR 2/3 are also present in kidney, liver, lung, spleen, and testis. Further investigations are needed to assess the role of these receptors in peripheral tissues and their importance in the toxicity of excitatory compounds. Therefore, food safety assessment and neurobiotechnology focusing on drugs designed to interact with GluRs should consider these tissues as potential target/effector sites.

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Evidence for an N-methyl-D-aspartate (NMDA) receptor in the GI tract of guinea pigs: Studies with diethylhomospermine (DEHSPM)

Cited by 7 publications

References 0 publications

Review Article: Glutamate Receptors in Peripheral Tissues: Current Knowledge, Future Research, and Implications for Toxicology

Review Article: Glutamate Receptors in Peripheral Tissues: Current Knowledge, Future Research, and Implications for Toxicology

Excitotoxicity in the lung: N-methyl-D-aspartate-induced, nitric oxide-dependent, pulmonary edema is attenuated by vasoactive intestinal peptide and by inhibitors of poly(ADP-ribose) polymerase.

Potential Target Sites in Peripheral Tissues for Excitatory Neurotransmission and Excitotoxicity

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