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.

scholarly journals Isoflurane and Propofol Block Neurotoxicity Caused by MK-801 in the Rat Posterior Cingulate/Retrosplenial Cortex

1997 ◽  
Vol 17 (2) ◽  
pp. 168-174 ◽  
Author(s):  
Vesna Jevtović-Todorović ◽  
Charity O. Kirby ◽  
John W. Olney
Keyword(s):  
Brain Injury ◽  
Neuronal Degeneration ◽  
Nmda Antagonist ◽  
Retrosplenial Cortex ◽  
Acute Brain Injury ◽  
Nmda Antagonists ◽  
General Anesthetics ◽  
General Anesthetic ◽  
Mk 801 ◽  
Anesthetic Agents

In acute brain injury syndromes, the potent N-methyl-D-aspartate (NMDA) antagonist, MK-801, can prevent neuronal degeneration, and the general anesthetics, isoflurane and propofol, may also provide neuroprotective benefits. An obstacle to the use of NMDA antagonists for neuroprotective purposes is that they can cause a neurotoxic vacuole reaction in cerebrocortical neurons. This study demonstrates the ability of isoflurane and propofol to prevent the neurotoxic vacuole reaction induced by MK-801. Low sedative doses of inhaled isoflurane (1%) or intravenous (i.v.) propofol (7.5 mg/kg/h) were as effective as higher general anesthetic doses. Thus, in the clinical management of acute brain injury conditions such as stroke and brain trauma, administration of one of these anesthetic agents together with an NMDA antagonist may be an excellent formula for obtaining optimal neuroprotection while eliminating serious side effects.

scholarly journals Integrative review of the use of NMDA antagonists for TBI treatment

2021 ◽  
Author(s):  
Fernanda Cristina Poscai Ribeiro ◽  
Everton Lopes Rodrigues
Keyword(s):  
Adverse Effects ◽  
Clinical Studies ◽  
Adverse Reactions ◽  
Glutamate Release ◽  
Nmda Antagonist ◽  
Mechanical Deformation ◽  
Literature Analysis ◽  
Nmda Antagonists ◽  
Ionotropic Receptors ◽  
Animal Tests

Introduction: The kinetic energy of TBI generates mechanical deformation, which causes release of glutamate, activating ionotropic receptors, principally NMDA receptors, favoring the flow of Ca++ and Na+ into the cell, producing edema. Then, the neurotoxicity generated by glutamate release can be avoided by NMDA antagonists. Objectives: To define if NMDA antagonists are promising for the treatment of TBI by literature analysis and to verify if there are reports of adverse reactions. Methodology: The review utilized the Scielo and Pubmed databases and the keywords used were: NMDA antagonist, Brain edema and Brain injury. The review contains 5 animal tests and 5 clinical studies. Results: Animal tests: CP-98,133 minimized edema, motor damage and is promising in the treatment of memory dysfunction after TBI. The NPS 1506 reduced edema in 24h, without altering the necrosis significantly. Ketamine decreased the volume of necrosis without altering the edema. HU-211 reduced the edema slightly. Clinical studies: NPS 1506 showed a neuroprotective profile and no serius effects. Traxoprodil decreased the mortality rate by 7%. CP-101.606 improved the patient’s condition, without adverse effects. Conclusion: Although NMDA antagonists demonstrate effectiveness in TBI treatment, more studies about adverse effects and efficiency are still needed. Among those analyzed, traxoprodil, NPS-1506 and CP-101.606 still don’t present serious adverse effects and demonstrate effectiveness, proving promising for new studies.

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.

N-methyl-D-aspartate (NMDA) and non-NMDA receptor antagonists block the hyperexcitability of dorsal horn neurons during development of acute arthritis in rat's knee joint

1993 ◽  
Vol 70 (4) ◽  
pp. 1365-1377 ◽  
Author(s):  
V. Neugebauer ◽  
T. Lucke ◽  
H. G. Schaible
Keyword(s):  
Dorsal Horn ◽  
Time Course ◽  
Receptive Fields ◽  
Nmda Antagonist ◽  
Mechanical Stimuli ◽  
Nmda Antagonists ◽  
Spinal Cord Neurons ◽  
Intravenous Injections ◽  
Mechanical Threshold ◽  
Before And After

1. In 22 anesthetized rats we studied the involvement of N-methyl-D-aspartate (NMDA) and non-NMDA receptors in the generation and maintenance of hyperexcitability in spinal cord neurons with knee input that develops in the course of an acute inflammation in the knee. In all experiments one neuron with knee input was identified, and the responses to mechanical stimuli and the receptive fields were monitored before and after induction of inflammation by the intra-articular injections of kaolin and carrageenan into the joint cavity. In most experiments multibarrel electrodes were used to administer specific NMDA and non-NMDA antagonists ionophoretically close to the neuron to test their effects on the inflammation-evoked changes. 2. Six neurons in the deep dorsal horn in six rats were used to establish the time course of the development of hyperexcitability in the untreated animal. In control periods of up to 3 h, the responses to mechanical stimuli and the receptive fields were stable. After induction of inflammation, the neurons developed increased responsiveness to mechanical stimuli applied to the injected knee but also to mechanical stimuli applied to the ipsilateral ankle and paw (including a reduction in the mechanical threshold in nociceptive specific neurons). The receptive fields expanded in five out of six neurons. The changes of responsiveness occurred mainly in the 2nd to 3rd h after the injection of kaolin. 3. In four rats three to four intravenous injections of the NMDA antagonist ketamine (2 mg/kg) were given during the injections of kaolin and carrageenan and in the following periods (up to 101 min postkaolin). During this treatment none of the four neurons exhibited the changes of responsiveness that were usually seen in control animals, although swelling of the knee developed in the same fashion as in control rats. Similarly, the generation of hyperexcitability was prevented when the NMDA antagonists ketamine and DL-2-amino-5-phosphonovalerate (AP5) were administered ionophoretically (ketamine in 4, AP5 in 2 rats) during the injections of kaolin and carrageenan and up to 100 min postkaolin. The doses of ketamine and AP5 were sufficient to reduce the responses to NMDA, whereas the responses to the non-NMDA agonist alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) were not influenced. 4. The ionophoretic application of the non-NMDA antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) during the injections of the kaolin and carrageenan and up to 103 min postkaolin also prevented the generation of hyperexcitability in six neurons in six rats.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Pre- and Post-Ischemic Administration of Dizocilpine (MK-801) Reduces Cerebral Necrosis in the Rat

1989 ◽  
Vol 16 (3) ◽  
pp. 340-344 ◽  
Author(s):  
M.R. Rod ◽  
R.N. Auer
Keyword(s):  
Nmda Antagonist ◽  
Therapeutic Window ◽  
Neuronal Necrosis ◽  
Mk 801 ◽  
Aspartate Receptor ◽  
Bilateral Carotid ◽  
Intravenous Saline ◽  
Ischemic Period ◽  
Cerebral Necrosis ◽  
The Brain

ABSTRACT:The purpose of this study was to determine the effectiveness of the non-competitive N-methyl-D-aspartate receptor antagonist dizocilpine, or (+)-5-methyl-10,l l-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine (MK-801) in mitigating ischemic neuronal necrosis in the rat. Ten minutes of transient forebrain ischemia was induced by a combination of bilateral carotid clamping and hypotension to 50 mm Hg. Control animals received intravenous saline, whereas treated animals received dizocilpine, either 1 mg/kg iv 20 min. pre ischemia, 1 mg/kg iv 20 min. post ischemia, 10 mg/kg iv 20 min. post ischemia, 10 mg/kg ip 2 hrs. post ischemia, 10 mg/kg ip 24 hrs. post ischemia. The groups receiving dizocilpine before or up to 20 min. after ischemia all showed a significant reduction in the number of dead neurons as assessed by quantitative histopathology in hippocampus, caudate nucleus and cerebral cortex after one week of recovery. However, dizocilpine administered either 2 or 24 hrs. after ischemia afforded no protection. These results suggest that the potent non-competitive NMDA antagonist dizocilpine may have some value in protecting the brain from hippocampal and cortical neuronal necrosis after a short insult consisting of dense transient cerebral ischemia. Noteworthy is the fact that pharmacologic intervention in the post-ischemic period was successful in preventing neuronal death, provided that drug administration occurred within dizocilpine's “therapeutic window”.

scholarly journals Extended therapeutic window for caspase inhibition and synergy with MK-801 in the treatment of cerebral histotoxic hypoxia

1998 ◽  
Vol 5 (10) ◽  
pp. 847-857 ◽  
Author(s):  
Jörg B Schulz ◽  
Michael Weller ◽  
Russell T Matthews ◽  
Michael T Heneka ◽  
Peter Groscurth ◽  
...  
Keyword(s):  
Therapeutic Window ◽  
Mk 801 ◽  
Caspase Inhibition ◽  
Histotoxic Hypoxia

Attenuation of febrile seizures in epileptic chicks by N-methyl-D-aspartate receptor antagonists

1990 ◽  
Vol 68 (1) ◽  
pp. 84-88 ◽  
Author(s):  
Simon C. J. Pedder ◽  
Robert I. Wilcox ◽  
John M. Tuchek ◽  
Dennis D. Johnson ◽  
R. D. Crawford
Keyword(s):  
Nmda Receptor ◽  
Nmda Antagonist ◽  
Febrile Seizures ◽  
Diaminopimelic Acid ◽  
Nmda Antagonists ◽  
Binding Assays ◽  
Receptor Antagonists ◽  
Mk 801 ◽  
Vitro Binding

Experimental febrile seizures can be evoked in epileptic chicks by elevation of their body temperature. Both competitive N-methyl-D-aspartate (NMDA) receptor antagonists [(3-(±)2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), DL-2-amino-7-phosphosphonoheptanoic acid (APH), DL-2-amino-5-phosphonovaleric acid (APV), D-α-aminoadipic acid (AAA), and DL-α,ε-diaminopimelic acid (DAP)] and the noncompetitive NMDA antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate (MK-801) produced dose-dependent increases in latency to the onset of seizures. Of the drugs tested, MK-801 had the highest potency followed in order by CPP = APH > APV [Formula: see text] AAA > DAP. There was a high correlation (r = 0.995) between the dose capable of doubling seizure latency and the affinity of the competitive NMDA antagonists for the NMDA receptor as determined by in vitro binding assays. These data suggest that NMDA receptor mediated mechanisms may be involved in the production of seizures in response to hyperthermia.Key words: seizures, NMDA antagonists, epileptic chickens, anticonvulsant activity, receptors.

Paired-pulse facilitation in the dentate gyrus: a patch-clamp study in rat hippocampus in vitro

1994 ◽  
Vol 72 (1) ◽  
pp. 326-336 ◽  
Author(s):  
M. Andreasen ◽  
J. J. Hablitz
Keyword(s):  
Patch Clamp ◽  
Dentate Gyrus ◽  
Time Constant ◽  
Rise Time ◽  
Time Course ◽  
Nmda Antagonist ◽  
Paired Pulse ◽  
Stimulation Intensity ◽  
Paired Pulse Facilitation ◽  
Epsc Amplitude

1. Whole-cell patch-clamp recordings were used to study paired-pulse facilitation (PPF) of the lateral perforant path input to the dentate gyrus in thin hippocampal slices. 2. Orthodromic stimulation of the lateral perforant pathway evoked a excitatory postsynaptic current (EPSC) with a latency of 3.3 +/- 0.1 ms (mean +/- SE) that fluctuated in amplitude. The EPSC had a rise time (10-90%) of 2.79 +/- 0.06 ms (n = 35) and decayed with a single exponential time course with a time-constant of 9.14 +/- 0.24 ms (n = 35). No correlation was found between the amplitude of the EPSC and the rise time or decay time-constant. The non-N-methyl-D-aspartate (NMDA) antagonist 6-cyano-7-nitroquinoxaline-2,3-dione completely blocked the EPSC whereas the NMDA antagonist D-aminophosphonovaleric acid (APV) had modest effects. 3. When a test (T-)EPSC was preceded at an interval of 100 ms by a conditioning (C-)EPSC, a significant increase in the amplitude of the T-EPSC was seen in 38 out of 44 trials analyzed from a total of 27 granule cells. The average amount of PPF was 35.7 +/- 2.1%. There was no apparent correlation between the amount of PPF and the stimulation intensity or mean amplitude of the C-EPSC. The time course of the facilitated T-EPSC was not significantly different from that of the C-EPSC. 4. No correlation was found between the amplitude of the C-EPSC and that of the T-EPSC. Estimates of quantal content (mcv) were determined by calculating the ratio of the squared averaged EPSC amplitude (from 48 responses) to the variance of these responses (M2/sigma 2) whereas quantal amplitudes (qcv) were estimated by calculating the ratio of the response variance to average EPSC amplitude (sigma 2/M). PPF was found to be associated with an average increase in mcv of 64.8 +/- 7.2% (n = 38) whereas qcv was decreased by 12.1 +/- 3.8%. 5. The time course of PPF was studied by varying the interval between the C- and T-pulse from 10 to 400 ms while keeping the stimulation intensity constant. Maximal facilitation of the T-EPSC was obtained with interpulse intervals < or = 25 ms where the average facilitation amounted to approximately 70% (n = 6). The decline of facilitation was nearly exponential and was no longer evident with intervals > 350 ms.(ABSTRACT TRUNCATED AT 400 WORDS

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