scholarly journals The Effects of Dizocilpine Maleate (MK-801), an Antagonist of the N-Methyl-D-Aspartate Receptor, on Neurologic Recovery and Histopathology following Complete Cerebral Ischemia in Primates

1990 ◽  
Vol 10 (2) ◽  
pp. 252-261 ◽  
Author(s):  
William L. Lanier ◽  
William J. Perkins ◽  
Bente R. Karlsson ◽  
James H. Milde ◽  
Bernd W. Scheithauer ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Excitatory Amino Acid ◽  
Neurologic Injury ◽  
Primate Model ◽  
Mk 801 ◽  
Neurologic Recovery ◽  
Aspartate Receptor ◽  
Significant Difference ◽  
Neurologic Function ◽  
Complete Cerebral Ischemia

The present study was designed to determine if the noncompetitive excitatory amino acid antagonist, dizocilpine maleate, when administered after a 17 min period of complete cerebral ischemia in primates, would improve postischemic neurologic function and hippocampal histopathologic outcome when compared to placebo-treated animals. Ten pigtail monkeys were anesthetized and subjected to complete cerebral ischemia using an established neck tourniquet model. Five minutes postischemia, five monkeys received dizocilpine 300 μg/kg i.v. over 5 min, followed by an infusion of 150 μg/kg/h for 10 h. This produced plasma levels of the drug in excess of 30 ng/ml for the duration of the infusion. An additional five monkeys were treated with an identical volume of saline placebo. All monkeys received intensive care for the initial 24 to 48 h postischemia. At 96 h postischemia, there was no significant difference in neurologic function between the two groups ( p = 0.53, with the placebo group having the numerically better outcome). There also was no significant difference between hippocampal histopathology scores between dizocilpine and placebo-treated monkeys. The authors conclude that dizocilpine is not an efficacious therapy in the treatment of neurologic injury that occurs following complete cerebral ischemia in this primate model.

EFFECT OF THE EXCITATORY AMINO ACID ANTAGONIST MK-801 ON NEUROLOGIC FUNCTION FOLLOWING COMPLETE CEREBRAL ISCHEMIA IN PRIMATES

1988 ◽  
Vol 69 (3A) ◽  
pp. A846-A846 ◽  
Author(s):  
W. L. Lanier ◽  
W. J. Perkins ◽  
B. Ruud ◽  
J. H. Milde ◽  
J. D. Michenfelder
Keyword(s):  
Amino Acid ◽  
Cerebral Ischemia ◽  
Excitatory Amino Acid ◽  
Mk 801 ◽  
Acid Antagonist ◽  
Neurologic Function ◽  
Complete Cerebral Ischemia

scholarly journals MK-801, an Excitatory Amino Acid Antagonist, Does Not Improve Neurologic Outcome following Cardiac Arrest in Cats

1989 ◽  
Vol 9 (6) ◽  
pp. 795-804 ◽  
Author(s):  
Jerry E. Fleischer ◽  
Akio Tateishi ◽  
John C. Drummond ◽  
Mark S. Scheller ◽  
Marjorie R. Grafe ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Cerebral Ischemia ◽  
Care Setting ◽  
Excitatory Amino Acid ◽  
Occipital Cortex ◽  
Intensive Care Setting ◽  
Relevant Model ◽  
Mk 801 ◽  
Treatment Groups ◽  
Complete Cerebral Ischemia

The excitatory amino antagonist MK-801 was administered to cats following resuscitation from cardiac arrest to evaluate its effect on neurologic and neuropathology outcome in a clinically relevant model of complete cerebral ischemia. In 29 cats studied, cardiac arrest (ventricular fibrillation) was maintained for 18 min and resuscitation was successfully performed in 21 cats. Four animals underwent a sham arrest. MK-801 or placebo was administered in a blinded, randomized manner. Beginning at 5 min post resuscitation (PR), MK-801 330 μg/kg over 2 min followed by 73 μg/kg/h for 10 h or the same volume of placebo was administered. Resuscitated animals remained paralyzed and sedated in an intensive care setting for 24–30 h PR. Neurologic examinations were performed at 2, 4, and 7 days PR by observers blinded to the treatment groups. Seventeen cats were entered into data analysis (nine MK-801-treated and eight placebo-treated). MK-801-treated animals had a significantly greater neurologic deficit score (NDS) rank (0 = normal, 100 = brain death) 2 days PR (mean rank 12.1 vs. 5.6; p = 0.008). This difference is most likely due to ongoing sedative actions of MK-801. There were no significant differences in NDS rank at 4 (10.3, MK-801 vs. 7.5, placebo) and 7 (9.6, MK-801 vs. 8.3, placebo) days PR. There were no significant differences in frontal cortex, hippocampus, occipital cortex, or cerebellar neuropathology between groups. Sham-arrested cats had normal neurologic and neuropathologic evaluations. In the circumstance of complete cerebral ischemia as employed in the current study, MK-801 had no beneficial effect upon neurologic or neuropathologic outcome.

Temperature Changes of greater or equal to 1 degree Celsius Alter Functional Neurologic Outcome and Histopathology in a Canine Model of Complete Cerebral Ischemia

1995 ◽  
Vol 83 (2) ◽  
pp. 325-335. ◽  
Author(s):  
C. Thomas Wass ◽  
William L. Lanier ◽  
Roger E. Hofer ◽  
Bernd W. Scheithauer ◽  
Amy G. Andrews
Keyword(s):  
Cerebral Ischemia ◽  
Reference Group ◽  
Canine Model ◽  
Neurologic Outcome ◽  
Right Atrial ◽  
Neurologic Injury ◽  
Temperature Changes ◽  
Neurologic Function ◽  
Treat All ◽  
Complete Cerebral Ischemia

Background Changes in basal temperature of > or = 1 degree C (e.g., fever-induced hyperthermia or anesthesia-related hypothermia) are a common occurrence in neurologically impaired patients. The current study tested the hypothesis that temperature changes as small as 1 degree C or 2 degrees C would significantly alter post-ischemic functional neurologic outcome and cerebral histopathology. The hypothesis was tested in a canine model of transient, complete cerebral ischemia. Methods After institutional approval, 21 dogs were randomly assigned to one of three temperature-specific groups: (1) a reference group maintained at 37.0 +/- 0.3 degree C (target temperature +/- range); (2) a 38.0 +/- 0.3 degree C group; or (3) a 39.0 +/- 0.3 degree C group (n = 7 per group). Complete cerebral ischemia 12.5 min in duration was produced using an established model of arterial hypotension plus intracranial hypertension. Right atrial and cranial (beneath the temporalis muscles) temperatures were maintained at the target value, beginning 20 min before ischemia and ceasing 1 h postischemia. Thereafter, temperatures were returned to 37.0 +/- 0.3 degree C in all dogs. After discharge from the intensive care environment, all dogs were placed in a temperature-controlled recovery area. Neurologic assessment was performed by a blinded observer at 24, 48, and 72 h postischemia using a 100-point scoring scale. After the 72 h examination (with the dogs anesthetized) or at the time of ischemia-related death, the brains were excised and preserved. The brains subsequently were histologically scored by a neuropathologist who was unaware of the treatment groups. All 21 dogs were included in the analysis of neurologic function; however, only dogs that survived for > or = 24 h postischemia were included in the histopathology analysis. Results Dogs were well matched for systemic physiologic variables throughout the study, with the exception of temperature. During the 72 h postischemic examination, dogs maintained at 37 degrees C were either normal or near normal. In contrast, dogs maintained at 39 degrees C were either comatose or died from ischemia-related causes. Dogs maintained at 38 degrees C were intermediate between 37 degrees C and 39 degrees C dogs. When compared with the reference group, both 38 degrees C and 39 degrees C dogs had significantly worse neurologic function scores (P < 0.01 and < 0.001, respectively) and histopathology scores (P < 0.01 for both). There also was a significant correlation between neurologic function and histopathology rank scores (rs = 0.96; P < 0.001). Conclusions Small, clinically relevant changes in temperature (1 degree C or 2 degrees C) resulted in significant alterations in both postischemic neurologic function and cerebral histopathology. Assuming that our results are transferable to humans, the results suggest that, in patients at imminent risk for ischemic neurologic injury, body temperature should be closely monitored. Further, the clinician should aggressively treat all episodes of hyperthermia until the patient is no longer at risk for ischemic neurologic injury.

Evaluation of the glutamate antagonist dizocilipine maleate (MK-801) on neurologic outcome in a canine model of complete cerebral ischemia: correlation with hippocampal histopathology

1989 ◽  
Vol 481 (2) ◽  
pp. 228-234 ◽  
Author(s):  
John D. Michenfelder ◽  
William L. Lanier ◽  
Bernd W. Scheithauer ◽  
William J. Perkins ◽  
Gary T. Shearman ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Canine Model ◽  
Neurologic Outcome ◽  
Mk 801 ◽  
Glutamate Antagonist ◽  
Complete Cerebral Ischemia

Effects of the N-Methyl-d-Aspartate Receptor Blocker MK-801 on Neurologic Function After Experimental Brain Injury

1989 ◽  
Vol 6 (4) ◽  
pp. 247-259 ◽  
Author(s):  
TRACY K. MCINTOSH ◽  
ROBERT VINK ◽  
HOLLY SOARES ◽  
RONALD HAYES ◽  
ROGER SIMON
Keyword(s):  
Brain Injury ◽  
Receptor Blocker ◽  
Mk 801 ◽  
Aspartate Receptor ◽  
Neurologic Function

scholarly journals Nimodipine Improves Cerebral Blood Flow and Neurologic Recovery after Complete Cerebral Ischemia in the Dog

1983 ◽  
Vol 3 (1) ◽  
pp. 38-43 ◽  
Author(s):  
Petter A. Steen ◽  
Leslie A. Newberg ◽  
James H. Milde ◽  
John D. Michenfelder
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Cerebral Ischemia ◽  
Protective Effect ◽  
Calcium Entry ◽  
Calcium Entry Blocker ◽  
Neurologic Recovery ◽  
Entry Blocker ◽  
Ischemic Episode ◽  
Complete Cerebral Ischemia

Ten minutes of complete ischemia was produced in 11 dogs by temporary ligation of the aorta. Immediately before the ischemic episode, the dogs received nimodipine, a new calcium entry blocker, 10 μg kg−1, i.v., followed by an infusion of 1 μg kg−1 min−1 for 2 h. Post-ischemic cerebral blood flow and metabolism were measured for 120 min in six dogs. Neurologic recovery was evaluated 48 h post-ischemia in five dogs. The results were compared to previously determined controls. Nimodipine nearly doubled cerebral blood flow in the delayed post-ischemic hypoperfusion period, compared to untreated dogs (approximately 45% versus 25% of pre-ischemic control values), but had no significant effect on metabolism. Nimodipine also improved neurologic recovery. Four of five treated dogs were normal and one was moderately damaged, whereas six of seven controls were either severely damaged or dead. This suggests that the delayed hypoperfusion state occurring after complete cerebral ischemia probably does contribute to the ultimate neurologic damage, and that nimodipine offers a potential protective effect.

Alterations in the N-Methyl-D-Aspartate Receptor Complex following Focal Cerebral Ischemia

1989 ◽  
Vol 9 (5) ◽  
pp. 709-712 ◽  
Author(s):  
D. Dewar ◽  
M. C. Wallace ◽  
A. Kurumaji ◽  
J. McCulloch
Keyword(s):  
Cerebral Cortex ◽  
Cerebral Ischemia ◽  
Focal Cerebral Ischemia ◽  
Artery Occlusion ◽  
Receptor Complex ◽  
Ischemic Insult ◽  
Mk 801 ◽  
Aspartate Receptor ◽  
Cerebral Artery Occlusion ◽  
The Brain

The functional integrity of the N-methyl-d-aspartate receptor complex following focal cerebral ischemia in the rat has been examined at a time when brain tissue is irreversibly damaged. Twelve hours after unilateral permanent middle cerebral artery occlusion, [3H]-MK-801 binding was not significantly altered in the ischemic cerebral cortex compared to sham-operated animals. Moreover, the enhancement of [3H]MK-801 binding by exogenous glutamate was preserved in an area of the brain that was permanently damaged by the ischemic insult.

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