Search PubMed⌕ Search

Biomedical subjects

D W Choi

Publications and source records attributed to D W Choi.

At least 145 records · Page 8Linked to original sources
PubMed1993

Neuroprotective effects of glutamate antagonists and extracellular acidity.

Glutamate antagonists protect neurons from hypoxic injury both in vivo and in vitro, but in vitro studies have not been done under the acidic conditions typical of hypoxia-ischemia in vivo. Consistent with glutamate receptor antagonism, extracellular acidity reduced neuronal death in murine cortical cultures that were deprived of oxygen and glucose. Under these acid conditions, N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate-kainate antagonists further reduced neuronal death, such that some neurons tolerated prolonged oxygen and glucose deprivation almost as well as did astrocytes. Neuroprotection induced by this combination exceeded that induced by glutamate antagonists alone, suggesting that extracellular acidity has beneficial effects beyond the attenuation of ionotropic glutamate receptor activation.

Animals↗
PubMed1993

Glutamate receptor-mediated currents and toxicity in embryonal carcinoma cells.

While primary neuronal cell cultures have been used to investigate excitotoxicity, development of cell lines exhibiting glutamate receptor-mediated death is desirable. P19 mouse embryonal carcinoma cells, exposed to retinoic acid and plated onto a layer of cultured mouse cortical glial cells, differentiated into neuron-like elements immunoreactive for neurofilaments and neuron-specific enolase. Whole-cell recordings revealed inward currents in response to extracellular application of either NMDA or kainate. The NMDA-induced currents exhibited a voltage-dependent blockade by magnesium, required glycine for maximal activation, and were blocked by the NMDA antagonist dizocilpine. Kainate-induced currents were blocked by the AMPA/kainate receptor antagonist CNQX. Exposure to 500 microM NMDA for 24 h destroyed most P19 cells (EC50 approximately 70 microM); death was prevented by dizocilpine or D-APV. Exposure to 500 microM kainate also resulted in widespread death reduced by CNQX. Thus differentiated P19 cells exhibited both excitatory amino acid responses and vulnerability to excitotoxicity, characteristic of CNS neurons. These cells may provide a genetically open system useful for studying glutamate receptor-mediated phenomena at a molecular level.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1993

AMPA receptor activation potentiates zinc neurotoxicity.

Extracellular Zn2+ attenuates NMDA receptor-mediated neurotoxicity and increases AMPA receptor-mediated toxicity. Known electrophysiological effects of Zn2+ predict only the former. We considered the possibility that the latter rather reflects AMPA potentiation of Zn2+ toxicity, perhaps mediated by neuronal depolarization and Zn2+ entry through voltage-gated Ca2+ channels. High K+ or kainate also potentiated Zn2+ toxicity, and AMPA plus Zn2+ toxicity was attenuated by raising extracellular Ca2+, or by Ca2+ channel blockers. AMPA plus Zn2+ exposure induced an increase in fluorescence from neurons loaded with the Zn(2+)-sensitive dye TS-Q and increased subsequent 45Ca2+ accumulation. The ability of AMPA receptor activation to potentiate Zn2+ toxicity may be relevant to neuronal death associated with intense activation of glutamatergic pathways.

Animals↗
PubMed1993

Secobarbital attenuates excitotoxicity but potentiates oxygen-glucose deprivation neuronal injury in cortical cell culture.

We examined the effects of secobarbital and other sedative-hypnotic barbiturates on the neuronal death induced by exposure to excitatory amino acids or deprivation of oxygen or glucose in mouse cortical cell cultures. N-Methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4- isoxazolepropionate, and kainate toxicities were attenuated in a concentration-dependent fashion by high concentrations of secobarbital or thiopental. Antagonism of NMDA toxicity was not overcome by increasing NMDA concentration and not mimicked by gamma-aminobutyrate. Despite these antiexcitotoxic actions, secobarbital exacerbated the neuronal death induced by deprivation of either glucose alone or oxygen and glucose together; death induced by oxygen deprivation alone was little affected. Thiopental and methohexital also increased oxygen-glucose deprivation injury. A possible explanation for this injury potentiation was provided by the observation that secobarbital enhanced the cellular ATP depletion induced by combined oxygen-glucose deprivation. Deleterious effects on ATP production may counterbalance the protective effects of barbiturates under some conditions.

Adenosine Triphosphate↗
PubMed1993

Glial glycogen stores affect neuronal survival during glucose deprivation in vitro.

Glia perform several energy-dependent functions that may aid neuronal survival under pathological conditions. Glycogen is the major energy reserve in brain, and it is localized almost exclusively to astrocytes. Using murine cortical cell cultures containing both glia and neurons, we examined the effect of altered glial glycogen stores on neuronal survival following glucose deprivation. As previously reported, cultures exposed for several hours to media lacking glucose developed widespread neuronal degeneration without glial degeneration. If glial astrocyte glycogen content was increased to 2-3 times control levels by a 24-h pretreatment with 1 microM insulin or 0.5 mM methionine sulfoximine (MSO), glucose deprivation-induced neuronal degeneration was attenuated. These protective effects were blocked if glycogen levels were reduced back to control levels by a 30-min exposure to 1 mM dibutyryl cyclic AMP or 20 microM norepinephrine prior to glucose deprivation. Astrocyte glycogen stores may be an important factor influencing neuronal survival under conditions of energy substrate limitation.

Animals↗
PubMed1993

Glutamate receptor-induced 45Ca2+ accumulation in cortical cell culture correlates with subsequent neuronal degeneration.

Murine neuronal and glial cell cultures exposed briefly to glutamate accumulated large amounts of 45Ca2+ from the extracellular medium during the exposure. Most of the accumulation likely reflected influx into neurons, as little accumulation was observed in similarly treated glial cultures. When the concentration of glutamate was varied between 10 and 1000 microM, or exposure duration was varied between 0 and 10 min, the amount of 45Ca2+ accumulation correlated closely with the amount of neuronal death 24 hr later. Both 45Ca2+ accumulation and cell death could be attenuated in a dose-dependent manner by the competitive NMDA antagonist D-aminophosphonovalerate or the noncompetitive antagonist dextrorphan, with IC50 values of approximately 100 microM and 15 microM, respectively. In contrast, neither 45Ca2+ accumulation nor cell death was blocked by the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/kainate antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) in the presence of high glycine. With brief exposure, high concentrations of AMPA, kainate, or K+ produced much less death or 45Ca2+ accumulation than produced by glutamate, especially if 10 microM MK-801 was included in the exposure medium to block NMDA receptor activation. Kainate- or AMPA-induced 45Ca2+ accumulation or neuronal cell death was blocked with CNQX. However, high K(+)-triggered 45Ca2+ accumulation was only partially blocked with CNQX plus MK-801, consistent with mediation by voltage-gated Ca2+ channels. In addition to measuring the accumulation of 45Ca2+ occurring during agonist exposure, we also assessed accumulation during the 30 min immediately following completion of a 3-5 min exposure to 500 microM NMDA.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1993

Combined oxygen and glucose deprivation in cortical cell culture: calcium-dependent and calcium-independent mechanisms of neuronal injury.

Murine neocortical cell cultures were transiently deprived of both oxygen and glucose, producing widespread neuronal swelling in less than 60 min, followed by neuronal degeneration over the ensuing several hours, despite return to normal medium. Cultured glia (> 95% astrocytes) were irreversibly injured only by oxygen-glucose deprivation exposures exceeding 4-6 hr. Replacing either Na+ or Cl- with impermeant ions blocked acute neuronal swelling but did not prevent delayed neuronal degeneration. While neuronal swelling and death were increased by removing Ca2+ from the exposure medium, combined removal of extracellular Ca2+ together with Na+ or Cl- substitution blocked both acute and delayed injury. If acute swelling was limited by a hyperosmolar medium, then neuronal loss depended on extracellular [Ca2+]. Oxygen-glucose deprivation was associated with a large increase in extracellular glutamate concentration. Both early swelling and later neuronal degeneration were blocked by addition of NMDA receptor antagonists to the exposure medium but not by the AMPA/kainate receptor antagonist 6-cyano-7-dinitroquinoxaline-2,3-dione (CNQX), dihydropyridines nifedipine or nimodipine, or TTX. Oxygen-glucose deprivation induced substantial neuronal uptake of tracer 45Ca2+ from the exposure medium that was reduced by NMDA receptor antagonists and closely paralleled the degree of subsequent neuronal loss. These observations suggest the presence of two distinct components of hypoxic injury, each involving NMDA receptor activation and each capable of leading to neuronal death. Acute swelling is mediated by influx of Na+, Cl-, and water, and is enhanced by removal of extracellular Ca2+. Delayed neuronal degeneration depends on the presence of extracellular Ca2+ and correlates closely with cellular uptake of 45Ca2+.

Animals↗
PubMed1992

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↗
PubMed1992

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↗
PubMed1992

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↗
PubMed1992

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↗
PubMed1991

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↗