Bench to bedside: the glutamate connection.
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Glutamates↗
Biomedical subjects
D W Choi
Publications and source records attributed to D W Choi.
Amyotrophic lateral sclerosis and glutamate--too much of a good thing?
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Amyotrophic Lateral Sclerosis↗
Do NMDA antagonists prevent neuronal injury? Yes.
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Animals↗
Excitotoxic cell death.
Excitotoxicity refers to the ability of glutamate or related excitatory amino acids to mediate the death of central neurons under certain conditions, for example, after intense exposure. Such excitotoxic neuronal death may contribute to the pathogenesis of brain or spinal cord injury associated with several human disease states. Excitotoxicity has substantial cellular specificity and, in most cases, is mediated by glutamate receptors. On average, NMDA receptors activation may be able to trigger lethal injury more rapidly than AMPA or kainate receptor activation, perhaps reflecting a greater ability to induce calcium influx and subsequent cellular calcium overload. It is possible that excitotoxic death may share some mechanisms with other forms of neuronal death.
Amino Acids↗
Oxygen or glucose deprivation-induced neuronal injury in cortical cell cultures is reduced by tetanus toxin.
We examined glutamate-mediated neurotoxicity in cortical cell cultures pretreated with 1-5 micrograms/ml tetanus toxin to attenuate the Ca(2+)-dependent release of neurotransmitters. Efficacy of the tetanus toxin pretreatment was suggested by blockade of electrical burst activity induced by Mg2+ removal and by reduction of glutamate efflux induced by high K+. Tetanus toxin reduced neuronal injury produced by brief exposure to elevated extracellular K+ or to glutamate, situations in which release of endogenous excitatory neurotransmitter is likely to play a role. Furthermore, although glutamate efflux evoked by anoxic conditions may occur largely via Ca(2+)-independent transport, tetanus toxin attenuated both glutamate efflux and neuronal injury following combined oxygen and glucose deprivation. With prolonged exposure periods, the neuroprotective efficacy of tetanus toxin was comparable to that of NMDA receptor antagonists. Presynaptic inhibition of Ca(2+)-dependent glutamate release may be a valuable approach to attenuating hypoxic-ischemic brain injury.
6-Cyano-7-nitroquinoxaline-2,3-dione↗
Comment: modeling for drug development in spinal cord injury.
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Animals↗
Extracellular alkalinity exacerbates injury of cultured cortical neurons.
BACKGROUND AND PURPOSE: We have previously shown that extracellular acidity protects cultured fetal murine neocortical neurons from glutamate toxicity and combined oxygen-glucose deprivation injury, an action at least in part mediated by reduction in N-methyl-D-aspartate receptor activation. We now investigate the effect of extracellular alkalinity on both glutamate neurotoxicity and injury due to combined oxygen-glucose deprivation. METHODS: The effects of extracellular alkalinity during injury induced by exposure of murine neocortical cultures to glutamate (0.5 mM for 5 minutes) or oxygen-glucose deprivation are characterized morphologically and quantitated by efflux of lactate dehydrogenase from both neurons and glia to the bathing medium. Calcium accumulation is measured with calcium-45. RESULTS: Moderate extracellular alkalinity is well tolerated by cortical cells but significantly potentiates both glutamate neuronal toxicity and oxygen-glucose deprivation neuronal injury. In contrast, glial viability in the face of combined oxygen-glucose deprivation is little affected by extracellular alkalinity. Increased accumulation of calcium-45 during oxygen-glucose deprivation in alkalotic medium and blockade of this increase by MK-801 is demonstrated. CONCLUSIONS: These observations suggest that alkaline pH can exacerbate excitotoxic neuronal injury, most likely because of increased N-methyl-D-aspartate receptor activation. Metabolic alkalosis of any etiology may sensitize neurons to ischemic injury and potentiate reperfusion injury.
Alkalies↗
Egg production of Clonorchis sinensis in different strains of inbred mice.
In order to compare the intraspecific variation in host-parasite relationship of Clonorchis sinensis, six strains of inbred mice, ICR, DDY, GPC, BALB/c, nude and DS, were infected orally with 20 metacercariae of C. sinensis. The biologic incubation period of C. sinensis was the shortest in DDY mice, 21.2 days in average, followed by GPC 21.4, BALB/c and DS 23.2, ICR and nude 23.4 days, respectively. The fertile period of the fluke was also the longest in the DDY strain, 164 days on average, followed by GPC 132, BALB/c 97, nude 37, DS 32 and ICR 28 days. The egg-laying capacity of the fluke in DDY and GPC was relatively high and stable compared with the other four strains of mice. It was found that there are intraspecific variations in biologic incubation period, fertile period, and fecundity of C. sinensis. The DDY mouse is likely to be the most suitable experimental animal among the six strains of the mice tested.
Animals↗
Antagonism of non-NMDA receptors augments the neuroprotective effect of NMDA receptor blockade in cortical cultures subjected to prolonged deprivation of oxygen and glucose.
A 30-60 min period of oxygen and glucose deprivation induced widespread degeneration of cultured murine neocortical neurons. Neuronal degeneration could be blocked by adding the selective NMDA antagonist MK-801 to the bathing medium; however, if the deprivation period was prolonged to 90-105 min, the neuroprotective effect of MK-801 was overcome. The non-NMDA antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) at 1-100 microM concentrations also failed to protect neurons against this prolonged insult, but the combination of CNQX with either MK-801 or D-APV produced marked neuroprotection. This synergistic action of CNQX was not due to enhanced blockade of NMDA receptors, as it was not mimicked by combining MK-801 with D-APV or 7-chlorokynurenate. These observations support the idea that combined NMDA and non-NMDA receptor blockade may have value in ameliorating the neuronal loss associated with prolonged ischemic insults in vivo.
2-Amino-5-phosphonovalerate↗
Selective blockade of non-NMDA receptors does not block rapidly triggered glutamate-induced neuronal death.
The quinoxalinedione, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), has been introduced as a relatively selective antagonist of non-N-methyl-D-aspartate (non-NMDA) glutamate receptors. We studied the ability of CNQX to block excitatory amino acid-induced neurotoxicity in murine cortical cell cultures. 100 microM CNQX blocked the acute neuronal swelling induced by 500 microM kainate, but it also attenuated the swelling and degeneration induced by 500 microM NMDA. Addition of 1 mM glycine to the CNQX eliminated antagonism of NMDA toxicity, while preserving antagonism of the neuronal degeneration induced by kainate or AMPA. This selective non-NMDA antagonist combination of CNQX plus glycine substantially attenuated the acute neuronal swelling induced by brief exposure to 500 microM glutamate, but had little effect on subsequent late degeneration, supporting the conclusion that rapidly triggered glutamate-induced cortical neuronal death is predominantly mediated by NMDA receptors.
6-Cyano-7-nitroquinoxaline-2,3-dione↗
Glutamate neurotoxicity in spinal cord cell culture.
The neurotoxicity of glutamate was investigated quantitatively in mixed neuronal and glial spinal cord cell cultures from fetal mice at 12-13 days of gestation. Five-minute exposure to 10-1000 microM glutamate produced widespread acute neuronal swelling, followed by neuronal degeneration over the next 24 h (EC50 for death about 100-200 microM); glia were not injured. Glutamate was neurotoxic in cultures as young as four days in vitro, although greater death was produced in older cultures. By 14-20 days in vitro, 80-90% of the neuronal population was destroyed by a 5-min exposure to 500 microM glutamate. Acute neuronal swelling following glutamate exposure was prevented by replacement of extracellular sodium with equimolar choline, with minimal reduction in late cell death. Removal of extracellular calcium enhanced acute neuronal swelling but attenuated late neuronal death. Both acute neuronal swelling and late degeneration were effectively blocked by the noncompetitive N-methyl-D-aspartate receptor antagonist dextrorphan and by the novel competitive antagonist CGP 37849. Ten micromolar 7-chlorokynurenate also inhibited glutamate neurotoxicity; protection was reversed by the addition of 1 mM glycine to the bathing medium. These observations suggest that glutamate is a potent and rapidly acting neurotoxin on cultured spinal cord neurons, and support involvement of excitotoxicity in acute spinal cord injury. Similar to telencephalic neurons, spinal neurons exposed briefly to glutamate degenerate in a manner dependent on extracellular Ca2+ and the activation of N-methyl-D-aspartate receptors.
Animals↗
Differential vulnerability to excitatory amino acid-induced toxicity and selective neuronal loss in neurodegenerative diseases.
Neurodegenerative diseases are characterized by selective degeneration of certain biochemically distinct subpopulations of central neurons. Studies of the intrinsic vulnerability of such neurons to injury by excitatory amino acids in vitro, as well as study of neurologic syndromes produced in animals or humans by ingestion of environmental excitatory amino acid neurotoxins may suggest a link between excitotoxicity, and the pathogenesis of certain neurodegenerative diseases.
Amino Acids↗
Safety and tolerance of oral dextromethorphan in patients at risk for brain ischemia.
Experimental ischemia models have shown the antitussive dextromethorphan to be an N-methyl-D-aspartate antagonist with neuroprotective properties. We treated 10 patients with a history of recent stroke or transient ischemic attack with oral dextromethorphan (60 mg q.i.d.) for 3 weeks in a placebo-controlled, double-blind, crossover tolerance study. We documented no clinical evidence of toxicity attributable to dextromethorphan in this preliminary study.
Administration, Oral↗
Epidemiological studies of digenetic trematodes in Yongyang County, Kyungpook Province.
The present study was undertaken to determine the endemicity of trematode infections in Yongyang County, Kyungpook Province, Korea. One hundred and seventy-seven out of 955 residents examined were found to be infected with one or more kinds of helminths. The prevalence rate was 18.5%. Among them, 70 were found to be infected with Clonorchis sinensis, 74 with Metagonimus sp. and 24 with both flukes. The eggs of Fasciolidae were demonstrated from two specimens. The prevalence rate of clonorchiasis in males was 12.6%, while that in females was 3.6% (p less than 0.05). The prevalence of metagonimiasis in males was 12.0% and was also significantly higher than 6.1% in females (p less than 0.05). The intensity of both infections was significantly heavier in males than in females. The prevalence of both flukes was higher in residents of over 30 years of age than in those below that age. No correlation was found between the intensity and the age group. Among eight species of the fresh-water fish collected at the Panbyon River, Zacco temmincki was found to be the most frequently and heavily infested with metacercariae of Metagonimus sp., and Gnathopogon atromaculatus alone was found to be infested with metacercariae of Clonorchis sinensis. The present results suggest that Yongyang area still remains endemic with Clonorchis sinensis and Metagonimus sp. infection.
Adolescent↗
Attempts to transfer immunity against Clonorchis sinensis in nude and DS mice.
The effects of peritoneal exudate cells (PEC) and sera of athymic nude and DS mice infected with Clonorchis sinensis metacercariae or sensitized by injection of metabolic products into footpad on transfer of immunity against the fluke to the syngeneic mice were studied. There was no significant difference in eggs per gram pattern between the sensitized and control groups, and between nude and DS mice. However, the worm burdens were slightly greater in nude mice than in DS mice. Also, a few plaque forming cells were found in only DS mice given PEC and serum from Group II DS mice. In the light of these results, it is likely that PEC and sera of nude or DS mice which are deficient, at least partially, in the cellular immune system are unable to transfer immunity against C. sinensis to syngeneic recipients.
Animals↗
Slow non-NMDA receptor mediated neurotoxicity and amyotrophic lateral sclerosis.
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Amino Acids↗
Selective vulnerability of cultured cortical glia to injury by extracellular acidosis.
Reduction of extracellular pH from 7.4 to 6.5 attenuated glutamate neurotoxicity in murine cortical neuronal and glial cultures, but if maintained for 24 h, resulted in morphological evidence of selective glial injury. Acid-induced gliotoxicity was examined quantitatively in cortical astrocyte cultures, using lactate dehydrogenase efflux as an index of cell damage. An exposure time of 9 h to pH 6.4 was sufficient to destroy about one third of the glia, whether or not 25 mM lactate was present. Furthermore, such acidosis increased the vulnerability of glia to injury by combined oxygen and glucose deprivation. These observations support the suggestion that the acidosis which accompanies ischemia in vivo may contribute to glial injury.
Acidosis↗