Methionine sulfoximine shows excitotoxic actions in rat cortical slices

1999 ◽  
Vol 77 (11) ◽  
pp. 871-877 ◽  
Author(s):  
C A Shaw ◽  
J S Bains ◽  
B A Pasqualotto ◽  
K Curry
Keyword(s):  
Lactate Dehydrogenase ◽  
Neurological Disorders ◽  
Time Course ◽  
Glutamate Release ◽  
Field Potential ◽  
Nmda Antagonist ◽  
The United States ◽  
Methionine Sulfoximine ◽  
Contributing Factors

Methionine sulfoximine (MSO) is a rare amino acid. It occurs in nature or as a by-product of some forms of food processing. A notable example of the latter was a former method for bleaching wheat flour, using nitrogen trichloride, the "agene process," in use for most of the first 50 years of this century. "Agenized" flour was found to be responsible for various neurological disorders in animals, and MSO was identified as the toxic factor. The agene process was subsequently discontinued in the United States and the United Kingdom circa 1950. MSO inhibits the synthesis of both glutathione and glutamine, and it is possible that its actions on the nervous system arise from alterations in the amount or distribution of these molecules. Structurally, MSO resembles glutamate, an observation that has also raised the possibility that it might have more direct glutamate-like actions on neurons. In the present investigation, we report excitatory and toxic actions of MSO in an in vitro preparation of adult rat cortex. Field potential recordings in this preparation show that MSO application evokes a sustained depolarization, which can be blocked by the N-methyl-D-aspartate (NMDA) antagonist L-(+)-2-amino-5-phosphonovalerate (AP5). However, competition assays using MSO on [3H]CGP-39653 (DL-(E)-2-amino-4-propyl-1-phosphono-3-pentenoate) binding in rat cortical homogenates show only 20% displacement of total binding, suggesting that MSO is acting indirectly, perhaps by releasing glutamate. To investigate this possibility, we measured glutamate release during MSO application. Time course and dose-response experiments with MSO showed significant [3H]glutamate release, which was partially attenuated by AP5. To assess cellular toxicity, we measured lactate dehydrogenase (LDH) release from cortical sections exposed to MSO. MSO treatment led to a rapid increase in LDH activity, which could be blocked by AP5. These data suggest that MSO acts by increasing glutamate release, which then activates NMDA receptors, leading to excitotoxic cell death. These data suggest the possibility that MSO in processed flour had excitotoxic actions that may have been contributing factors to some human neuronal disorders.Key words: agene process, glutamate release, lactate dehydrogenase, methionine sulfoximine, N-methyl-D-aspartate (NMDA) receptor, neurological disorders.

scholarly journals DL-3-n-butylphthalide enhances synaptic plasticity in mouse model of brain impairments

STEMedicine ◽  
2022 ◽  
Vol 3 (1) ◽  
pp. e113
Author(s):  
Qian Ding ◽  
Qian Yu ◽  
Lei Tao ◽  
Yifei Guo ◽  
Juan Zhao ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Nmda Receptor ◽  
Glutamate Release ◽  
Field Potential ◽  
Nmda Receptor Subunits ◽  
Glutamate Level ◽  
Regulatory Effects ◽  
Glutaminase Activity

Synaptic impairment results in cognitive dysfunction of Alzheimer’s disease (AD). As a plant extract, it is found that DL-3-n-butylphthalide (L-NBP) rescues abnormal cognitive behaviors in AD animals. However, the regulatory effects of L-NBP on synaptic plasticity remains unclear. APP/PS1 mice at 12 months old received oral L-NBP treatment for 12 weeks. A water maze test assessed cognitive performances. In vitro patch-clamp recordings and in vivo field potential recordings were performed to evaluate synaptic plasticity. The protein expression of AMPA receptor subunits (GluR1 and GluR2) and NMDA receptor subunits (NR1, NR2A, and NR2B) was examined by Western blot. In addition, glutaminase activity and glutamate level in the hippocampus were measured by colorimetry to evaluate presynaptic glutamate release. L-NBP treatment could significantly improve learning and memory ability, upregulate NR2A and NR2B protein expressions, increase glutaminase activity and glutamate level in the hippocampus, and attenuate synaptic impairment transmission in the AD mice. L-NPB plays a beneficial role in AD mice by regulating NMDA receptor subunits’ expression and regulating presynaptic glutamate release.

Dopaminergic neuromodulation of synaptic transmission between mitral and granule cells in the teleost olfactory bulb

2012 ◽  
Vol 107 (5) ◽  
pp. 1313-1324 ◽  
Author(s):  
Takafumi Kawai ◽  
Hideki Abe ◽  
Yoshitaka Oka
Keyword(s):  
Olfactory Bulb ◽  
Synaptic Transmission ◽  
Granule Cells ◽  
Glutamate Release ◽  
Field Potential ◽  
Olfactory Nerve ◽  
Oscillatory Activity ◽  
Cellular Mechanisms ◽  
Olfactory Information

A growing body of evidence suggests that teleosts are important models for the study of neural processing of olfactory information, and the functional role of dopamine (DA), which is a potent neuromodulator endogenous to the mammalian olfactory bulb, has been one of the strongest focuses in this field. However, the cellular mechanisms of dopaminergic neuromodulation in olfactory bulbar neural circuits have not been fully understood. We investigated such mechanisms by using the goldfish, which offers several advantages for analyzing olfactory information processing by electrophysiological methods. First, we found in the olfactory bulb that numerous cell bodies of the dopaminergic neurons are mainly distributed in the mitral cell layer and extend fine processes to the glomerular layer. Next, we made in vitro field potential recordings and showed that synaptic transmissions from mitral to granule cells were suppressed by DA application. DA also increased the paired-pulse ratio, suggesting that the suppression of synaptic transmission is caused by a decrease in presynaptic glutamate release from the mitral cells. Furthermore, DA significantly suppressed the oscillatory activity of the olfactory bulb in response to olfactory stimuli. Although DA suppresses the synaptic inputs from the olfactory nerve to the olfactory bulbar neurons in mammals, this phenomenon was not observed in the goldfish. These findings indicate that suppression of the mitral to granule cell synaptic transmission in the reciprocal synapses plays an important role in the negative regulation of olfactory responsiveness in the goldfish olfactory bulb.

scholarly journals Synapse Elimination in the Corticospinal Projection During the Early Postnatal Period

2006 ◽  
Vol 95 (4) ◽  
pp. 2304-2313 ◽  
Author(s):  
Tsutomu Kamiyama ◽  
Noboru Yoshioka ◽  
Masaki Sakurai
Keyword(s):  
Gray Matter ◽  
Time Course ◽  
Field Potential ◽  
Ventral Side ◽  
Postnatal Period ◽  
Cervical Cord ◽  
Synapse Elimination ◽  
Medullary Pyramid

In corticospinal synapses reconstructed in vitro by slice co-culture, we previously showed that the synapses were distributed across the gray matter at 6–7 days in vitro (DIV). Thereafter, they began to be eliminated from the ventral side, and dorsal-dominant distribution was nearly complete at 11–12 DIV. The synapse elimination is associated with retraction of the corticospinal (CS) terminals. We studied whether this specific type of synapse elimination is a physiological phenomenon rather than in vitro artifact. The rat corticospinal tract was stimulated at the medullary pyramid, and field potentials were recorded at the cervical cord along an 200-μm interval lattice on the axial plane. Clearly defined negative field potential were identified as field excitatory postsynaptic potentials (fEPSPs) generated by corticospinal synapses. They were recorded from the entire spinal gray matter at postnatal day 7 (P7). These negative fEPSPs reversed to positive in the most ventrolateral part at P8. Reversal extended to the more mediodorsal area at P10, indicative of progressive synapse elimination in the ventrolateral area. To verify that regression of the axons in vivo paralleled the changes in spatial distribution of fEPSPs as observed in vitro, corticospinal axons were anterogradely labeled. Redistribution of the labeled terminals closely paralleled the fEPSP distribution, being present in the ventrolateral spinal cord at P7, decreased at P8, further deceased at P10, but unchanged at P11. Furthermore, double immunostaining for labeled terminals and synaptophysin observed under a confocal microscope suggests that corticospinal fibers at P7 possess presynaptic structures in the ventrolateral area as well as the dorsomedial area. These findings suggest that corticospinal synapses are widely formed in the spinal gray matter at P7, are rapidly eliminated from the ventrolateral side from P8 to P10, a time-course very similar to that observed in vitro, and are associated with axonal regression.

The Resusciatative Fluid You Chose May Potentiate Bleeding.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1029-1029
Author(s):  
Kathleen E. Brummel-Ziedins ◽  
Matthew F. Whelihan ◽  
Eduards G. Ziedins ◽  
Kenneth G. Mann
Keyword(s):  
Hemorrhagic Shock ◽  
Tissue Factor ◽  
Thrombin Generation ◽  
Time Course ◽  
In Vitro Study ◽  
The United States ◽  
Fibrin Clot ◽  
Blood Dilution ◽  
Lactated Ringer's Solution

Abstract Trauma is the leading cause of death in the younger population in the United States, frequently from the development of hemorrhagic shock. Controversy exists over the type of volume resuscitation to be used (dilutions ranging up to 66%) in hemorrhagic shock for restoring hemodynamic stability. Trauma results in massive exposure of tissue factor to the circulation and explosive amounts of thrombin being generated. We studied the effect of various resuscitative formulas to blood coagulation, specifically thrombin generation and fibrin formation, in a controlled setting using corn trypsin inhibited whole blood initiated with a 5pM stimulus of tissue factor. Thrombin generation measured as its complex with antithrombin III (TAT) was evaluated periodically over a time course of 20 min. Fibrin clots were collected and weighed. We investigated four diluents (0.9% NaCl (NS), lactated Ringer’s solution (LR), 6% hydroxyethyl starch (HES) and 3% NaCl (HS)) each at a 0,10, 20, 30, 40, 50 and 60% blood dilution. At a 10% dilution TAT generation was in the order of LR (−4%) < HES (−8%)< NS and HS (−12%). Diluting by 20% resulted in further decreases of TAT formation. The fibrin clot mass decreased dramatically with a 20% dilution for NS (−42%) and HES (−30%). Conversely, HS produced no change in fibrin mass but effected the largest change in thrombin generation rate (−56%). At a 50% dilution, comparable thrombin generation profiles were obtained for LR, HES and NS (~35% decrease). However, the fibrin masses decreased by 27% with LR, 46% with NS and 74% with HES. No clot formation or thrombin generation was seen with HS at > 20% dilution. This in vitro study shows that: 1) LR has the least effect on thrombin generation and gave higher than anticipated clot weights; 2) HES reduced the fibrin clot mass at higher dilutions; 3) HS abolishes coagulation after a 20% dilution. Overall, both the extent and nature of hemodilution cause profound alterations in the hemostatic mechanism.

Evidence for Postsynaptic Induction and Expression of NMDA Receptor Independent LTP

1998 ◽  
Vol 79 (3) ◽  
pp. 1167-1182 ◽  
Author(s):  
Lawrence M. Grover
Keyword(s):  
Nmda Receptor ◽  
Receptor Antagonist ◽  
Ampa Receptor ◽  
Metabotropic Glutamate Receptor ◽  
Glutamate Release ◽  
Field Potential ◽  
Long Term Potentiation ◽  
Separate Experiment ◽  
Tetanic Stimulation

Grover, Lawrence M. Evidence for postsynaptic induction and expression of NMDA receptor independent LTP. J. Neurophysiol. 79: 1167–1182, 1998. Whole cell/patch-clamp and extracellular field potential recordings were used to study the induction and expression of N-methyl-d-aspartate (NMDA) receptor independent long-term potentiation (LTP) in area CA1 of the in vitro rat hippocampus. Induction of NMDA receptor independent LTP was prevented by manipulations that inhibited postsynaptic depolarization during tetanic stimulation: direct hyperpolarization of postsynaptic neurons and bath application of an α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and kainate receptor antagonist. NMDA receptor independent LTP also was blocked by intracellular application of the lidocaine derivative, N-(2,6-dimethylphenylcarbamoylmethyl)triethylammonium bromide (QX-314), to CA1 pyramidal neurons. These results complement the previous findings that NMDA receptor independent LTP was inhibited by postsynaptic injections of the calcium chelator 1,2-bis(2-aminophenoxy)ethane- N,N,N′,N′-tetraacetic acid and also was inhibited by a L-type voltage-dependent calcium channel antagonist (nifedipine). Collectively, these data make a strong case for the postsynaptic induction of this form of LTP. This paper also provides evidence for postsynaptic expression of NMDA receptor independent LTP. In an experiment where AMPA- and NMDA-receptor–mediated excitatory postsynaptic potentials (EPSPs) were isolated pharmacologically, LTP was found for only the AMPA-receptor–mediated EPSPs. In a separate experiment, paired-pulse facilitation (PPF) was measured during NMDA receptor independent LTP. Although there was an initial decrease in PPF, suggesting a posttetanic increase in the probability of glutamate release, the change in PPF decayed within 30–40 min of the tetanic stimulation, whereas the magnitude of the LTP was constant over this same time period. In addition, the LTP, but not the corresponding change in PPF, was blocked by the metabotropic glutamate receptor antagonist (±)-α-methyl-4-carboxyphenylglycine. These results are accounted for most easily by a selective increase in postsynaptic AMPA receptor function, but one type of presynaptic modification—an increase in the number of release sites without an overall change in the probability of release—also could account for these results (assuming that the level of glutamate release before LTP induction fully saturated NMDA, but not AMPA, receptors). One possible presynaptic modification, an increase in axon excitability, was ruled out by analysis of the presynaptic fiber volley, which was not increased at any time after LTP induction.

scholarly journals Improved Therapeutic Window for Treatment of Histotoxic Hypoxia with a Free Radical Spin Trap

1995 ◽  
Vol 15 (6) ◽  
pp. 948-952 ◽  
Author(s):  
Jörg B. Schulz ◽  
Russell T. Matthews ◽  
Bruce G. Jenkins ◽  
Preetinder Brar ◽  
M. Flint Beal
Keyword(s):  
Free Radical ◽  
Time Course ◽  
Spin Trap ◽  
Glutamate Release ◽  
Lactate Production ◽  
Nmda Antagonist ◽  
Therapeutic Window ◽  
Nmda Antagonists ◽  
Mk 801 ◽  
Histotoxic Hypoxia

The therapeutic time window for N-methyl-d-aspartate (NMDA) antagonists, non-NMDA antagonists, and glutamate release inhibitors in focal models of ischemia appears to be about 1–2 h. In contrast, a free radical spin trap was found to have an improved therapeutic window. We compared the therapeutic time windows of the NMDA antagonist dizolcilpine maleate (MK-801), the glutamate release inhibitor lamotrigine, and the free radical spin trap n-tert-butyl-α-(2-sulfophenyl)-nitrone (S-PBN) against striatal lesions produced by the mitochondrial toxin malonate, which produces histotoxic hypoxia. Lamotrigine exerted neuroprotective effects when administered at 1 h before malonate injections. MK-801 protected at 1 h before and 1 h after malonate injections, whereas S-PBN showed efficacy when administered up to 6 h after malonate injections. Striatal injections of malonate produced a rapid increase in lactate production and early changes in diffusion-weighted imaging as assessed by magnetic resonance imaging. Therefore, the time course to evolve a lesion in our model of histotoxic hypoxia is comparable with that of other models of focal ischemia. These findings provide direct evidence that a free radical spin trap has an improved therapeutic window compared to an NMDA antagonist and a glutamate release inhibitor. This could be a therapeutic advantage in the treatment of clinical stroke patients.

Neuromodulatory Effect of GnRH on the Synaptic Transmission of the Olfactory Bulbar Neural Circuit in Goldfish, Carassius auratus

2010 ◽  
Vol 104 (6) ◽  
pp. 3540-3550 ◽  
Author(s):  
Takafumi Kawai ◽  
Hideki Abe ◽  
Yasuhisa Akazome ◽  
Yoshitaka Oka
Keyword(s):  
Carassius Auratus ◽  
Neural Circuits ◽  
Neural Circuit ◽  
Granule Cells ◽  
Glutamate Release ◽  
Sensory Information ◽  
Field Potential ◽  
Field Potentials ◽  
Goldfish Carassius Auratus

Gonadotropin-releasing hormone (GnRH) is well known as a hypophysiotropic hormone that is produced in the hypothalamus and facilitates the release of gonadotropins from the pituitary gonadotropes. On the other hand, the functions of extrahypothalamic GnRH systems still remain elusive. Here we examined whether the activity of the olfactory bulbar neural circuits is modulated by GnRH that originates mainly from the terminal nerve (TN) GnRH system in goldfish ( Carassius auratus). As the morphological basis, we first observed that goldfish TNs mainly express salmon GnRH (sGnRH) mRNA and that sGnRH-immunoreactive fibers are distributed in both the mitral and the granule cell layers. We then examined by extracellular recordings the effect of GnRH on the electrically evoked in vitro field potentials that arise from synaptic activities from mitral to granule cells. We found that GnRH enhances the amplitude of the field potentials. Furthermore, these effects were observed in both cases when the field potentials were evoked by stimulating either the lateral or the medial olfactory tract, conveying functionally different sensory information, separately, and suggesting that GnRH may modulate the responsiveness to wide categories of odorants in the olfactory bulb. Because GnRH also changed the paired-pulse ratio, it is suggested that the increased amplitude of the field potential results from changes in the presynaptic glutamate release of mitral cells rather than the increase in the glutamate receptor sensitivity of granule cells. These results suggest that TN regulates the olfactory responsiveness of animals appropriately by releasing sGnRH peptides in the olfactory bulbar neural circuits.

Effects of Xenon on In Vitro  and In Vivo  Models of Neuronal Injury

2002 ◽  
Vol 96 (6) ◽  
pp. 1485-1491 ◽  
Author(s):  
Stefan Wilhelm ◽  
Daqing Ma ◽  
Mervyn Maze ◽  
Nicholas P. Franks
Keyword(s):  
Lactate Dehydrogenase ◽  
Neuronal Degeneration ◽  
Neuroprotective Effect ◽  
Nmda Antagonist ◽  
Neuronal Injury ◽  
Oxygen Deprivation ◽  
In Vivo Models ◽  
Lactate Dehydrogenase Release

Background Xenon, the "inert" gaseous anesthetic, is an antagonist at the N-methyl-D-aspartate (NMDA)-type glutamate receptor. Because of the pivotal role that NMDA receptors play in neuronal injury, the authors investigated the efficacy of xenon as a neuroprotectant in both in vitro and in vivo paradigms. Methods In a mouse neuronal-glial cell coculture, injury was provoked either by NMDA, glutamate, or oxygen deprivation and assessed by the release of lactate dehydrogenase into the culture medium. Increasing concentrations of either xenon or nitrogen (10-75% of an atmosphere) were coadministered and maintained until injury was assessed. In separate in vivo experiments, rats were administered N-methyl-dl-aspartate and killed 3 h later. Injury was quantified by histologic assessment of neuronal degeneration in the arcuate nucleus of the hypothalamus. Results Xenon exerted a concentration-dependent protection against neuronal injury provoked by NMDA (IC(50) = 19 +/- 6% atm), glutamate (IC(50) = 28 +/- 8% atm), and oxygen deprivation (IC(50) = 10 +/- 4% atm). Xenon (60% atm) reduced lactate dehydrogenase release to baseline concentrations with oxygen deprivation, whereas xenon (75% atm) reduced lactate dehydrogenase release by 80% with either NMDA- or glutamate-induced injury. In an in vivo brain injury model in rats, xenon exerted a concentration-dependent protective effect (IC(50) = 78 +/- 8% atm) and reduced the injury by 45% at the highest xenon concentration tested (75% atm). Conclusions Xenon, when coadministered with the injurious agent, exerts a concentration-dependent neuroprotective effect at concentrations below which anesthesia is produced in rodents. Unlike either nitrous oxide or ketamine (other anesthetics with NMDA antagonist properties), xenon is devoid of both neurotoxicity and clinically significant adverse hemodynamic properties. Studies are proposed to determine whether xenon can be used as a neuroprotectant in certain clinical settings.

scholarly journals Bioprospecting for Trichothecene 3-O-Acetyltransferases in the Fungal GenusFusariumYields Functional Enzymes with Different Abilities To Modify the Mycotoxin Deoxynivalenol

2010 ◽  
Vol 77 (4) ◽  
pp. 1162-1170 ◽  
Author(s):  
Piyum A. Khatibi ◽  
Sean A. Newmister ◽  
Ivan Rayment ◽  
Susan P. McCormick ◽  
Nancy J. Alexander ◽  
...  
Keyword(s):  
United States ◽  
Time Course ◽  
The United States ◽  
Trichothecene Mycotoxin ◽  
Steady State Kinetic ◽  
Extended Sequence ◽  
Small Grains ◽  
State Kinetic ◽  
New Strategies

ABSTRACTThe trichothecene mycotoxin deoxynivalenol (DON) is a common contaminant of small grains, such as wheat and barley, in the United States. New strategies to mitigate the threat of DON need to be developed and implemented. TRI101 and TRI201 are trichothecene 3-O-acetyltransferases that are able to modify DON and reduce its toxicity. Recent work has highlighted differences in the activities of TRI101 from two different species ofFusarium(F. graminearumandF. sporotrichioides), but little is known about the relative activities of TRI101/TRI201 enzymes produced by other species ofFusarium. We clonedTRI101orTRI201genes from seven different species ofFusariumand found genetic identity between sequences ranging from 66% to 98%.In vitrofeeding studies using transformed yeast showed that all of the TRI101/TRI201 enzymes tested were able to acetylate DON; conversion of DON to 3-acetyl-deoxynivalenol (3ADON) ranged from 50.5% to 100.0%, depending on theFusariumspecies from which the gene originated. A time course assay showed that the rate of acetylation varied from species to species, with the gene fromF. sporotrichioideshaving the lowest rate. Steady-state kinetic assays using seven purified enzymes produced catalytic efficiencies for DON acetylation ranging from 6.8 × 104M−1·s−1to 4.7 × 106M−1·s−1. Thermostability measurements for the seven orthologs ranged from 37.1°C to 43.2°C. Extended sequence analysis of portions ofTRI101/TRI201from 31 species ofFusarium(including known trichothecene producers and nonproducers) suggested that other members of the genus may contain functionalTRI101/TRI201genes, some with the potential to outperform those evaluated in the present study.

Correlative microscopy in distrubuted (client/server) computing environments: tools for catalyzing the rapid dissemination of information about the cell biology of the human prostate

1995 ◽  
Vol 53 ◽  
pp. 682-683
Author(s):  
A. Hakam ◽  
J.T. Gau ◽  
M.L. Grove ◽  
B.A. Evans ◽  
M. Shuman ◽  
...  
Keyword(s):  
United States ◽  
Cell Biology ◽  
Tissue Bank ◽  
The United States ◽  
Prostate Adenocarcinoma ◽  
Correlative Microscopy ◽  
Client Server ◽  
Critical Elements ◽  
Transplant Organ

Prostate adenocarcinoma is the most common malignant tumor of men in the United States and is the third leading cause of death in men. Despite attempts at early detection, there will be 244,000 new cases and 44,000 deaths from the disease in the United States in 1995. Therapeutic progress against this disease is hindered by an incomplete understanding of prostate epithelial cell biology, the availability of human tissues for in vitro experimentation, slow dissemination of information between prostate cancer research teams and the increasing pressure to “ stretch” research dollars at the same time staff reductions are occurring.To meet these challenges, we have used the correlative microscopy (CM) and client/server (C/S) computing to increase productivity while decreasing costs. Critical elements of our program are as follows:1) Establishing the Western Pennsylvania Genitourinary (GU) Tissue Bank which includes >100 prostates from patients with prostate adenocarcinoma as well as >20 normal prostates from transplant organ donors.

Sign in / Sign up

Export Citation Format

Share Document