Focal Cerebral Ischaemia in the Cat: Treatment with the Glutamate Antagonist MK-801 after Induction of Ischaemia

Park, C. K.; Nehls, Daniel G.; Graham, David I.; Teasdale, Graham M.; McCulloch, James

doi:10.1038/jcbfm.1988.124

Cited by 244 publications

(56 citation statements)

References 20 publications

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“…Glutamate receptor blockade of both NMDA (using MK-801 and AP5) and non-NMDA (using NBQX) subtypes have repeatedly been shown to protect neurons in different ischemia models, both in in vivo (focal ischemia: Park et al, 1988) and in in vitro models using dissociated neuronal cultures (Goldberg and Choi, 1993;Kaku et al, 1993), as well as in organotypic hippocampal cultures (Breder et al, 2000;Newell et al, 1995;Pringle et al, 1997;Vornov et al, 1994). Also, in a mouse model of global ischemia, MK-801 protected CA1 cells when given after the ischemic insult (M.-L. Smith, Ph.D., personal communication, 2002).…”

Section: Figmentioning

confidence: 99%

Mouse Hippocampal Organotypic Tissue Cultures Exposed to In Vitro “Ischemia” Show Selective and Delayed CA1 Damage that is Aggravated by Glucose

Rytter

Cronberg

Asztély

et al. 2003

J Cereb Blood Flow Metab

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Summary:Oxygen and glucose deprivation (OGD) in cell cultures is generally studied in a medium, such as artificial cerebrospinal fluid (CSF), with an ion composition similar to that of the extracellular fluid of the normal brain (2 to 4 mmol/L K + , 2 to 3 mmol/L Ca 2+ ; pH 7.4). Because the distribution of ions across cell membranes dramatically shifts during ischemia, the authors exposed mouse organotypic hippocampal tissue cultures to OGD in a medium, an ischemic cerebrospinal fluid, with an ion composition similar to the extracellular fluid of the brain during ischemia in vivo (70 mmol/L K + , 0.3 mmol/L Ca 2+ ; pH 6.8). In ischemic CSF, OGD induced a selective and delayed cell death in the CA1 region, as assessed by propidium iodide uptake. Cell death was glutamate receptor dependent since blockade of the N-methyl-D-aspartate and ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors mitigated cell damage. Hyperglycemia aggravates ischemic brain damage in vivo, whereas in vitro glucose in artificial CSF prevents oxygen deprivation-induced damage. The authors demonstrate that glucose in ischemic CSF significantly exacerbates cell damage after oxygen deprivation. This new model of in vitro "ischemia" can be useful in future studies of the mechanisms and treatment of ischemic cell death, including studies using genetically modified mice.

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Section: Figmentioning

confidence: 99%

Mouse Hippocampal Organotypic Tissue Cultures Exposed to In Vitro “Ischemia” Show Selective and Delayed CA1 Damage that is Aggravated by Glucose

Rytter

Cronberg

Asztély

et al. 2003

J Cereb Blood Flow Metab

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“…5 min after administration, the level in ischaemic tissue is 50% of that in the cerebellum) (Wallace et al, 1992). By virtue of its rapid brain uptake, MK-801 first administered 2 h after the onset of ischaemia is as effective as pretreatment in reducing the volume of ischaemic brain damage in the cat MCA occlusion model (Park et al, 1988b). In contrast for hydrophilic molecules such as D-CPPene (and almost all other competitive NMDA antagonists presently available) the rate at which equilibrium is achieved between plasma and CNS is extremely slow (half-time of CNS uptake of 60 min or more).…”

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confidence: 99%

Excitatory amino acid antagonists and their potential for the treatment of ischaemic brain damage in man.

McCulloch

1992

Brit J Clinical Pharma

142

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1 A wide range of therapeutic strategies has been explored in humans and experimental animals with the aim of improving outcome after brain ischaemia but few have shown convincing clinical benefit. 2 The massive increase in the extracellular concentration of glutamate which occurs in cerebral ischaemia is a key component in the sequence of neurochemical events which leads to neuronal death. Pharmacological blockade of the action of glutamate at the N-methyl-D-aspartate (NMDA) receptor, (the glutamate receptor subtype principally involved in the neurotoxic effects of the amino acid) provides a novel therapeutic approach to cerebral ischaemia. 3 The effects of NMDA receptor antagonists in animal models of focal cerebral ischaemia are uniquely consistent, viz, a marked reduction in the amount of irreversible ischaemic damage irrespective of the species, the model of cerebral ischaemia, when the animals are sacrificed after the ischaemic episode, whether ischaemia is permanent or temporary and followed by reperfusion and which particular NMDA antagonist was employed. 4 NMDA receptor antagonists have marked effects on brain function in normal animals.The balance between these potential adverse effects and the anti-ischaemic efficacy of these drugs will ultimately determine the clinical utility of this class of drugs. 5 The data which are reviewed provide the basis for the current clinical evaluation of NMDA receptor antagonists in stroke and head trauma.

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“…3 Others have produced similar results. 4 - 5 The mechanism of action is thought to be through inhibition of NMDA receptors. 6 Cerebral hypoxia or ischemia triggers release of excitatory amino acids in large quantities, 78 causing calcium entry into the cell 9 and, thus, exacerbating brain injury.…”

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confidence: 99%

MK-801 does not protect against hypoxic-ischemic brain injury in piglets.

LeBlanc

Vig

Smith

et al. 1991

Stroke

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Background and Purpose:The excitatory amino acid inhibitor MK-801 has been shown in many animals species to protect against hypoxic-ischemic brain injury. We sought to determine whether hypoxic-ischemic injury to the newborn pig's brain could be prevented by the use of MK-801.Methods: Hypoxic-ischemic injury to the brain was induced in forty 0-3-day-old piglets. They were randomized to receive either 3 mg/kg MK-801 (MK-801 group, n=20) or vehicle (control group, n=19) prior to insult At time 0, the carotid arteries were ligated and the blood pressure was reduced by one third by hemorrhage. At 15 minutes, inspired oxygen was reduced from 50% to 6%. At 30 minutes, inspired oxygen was changed to 100%, carotid ligatures were released, and the withdrawn blood was reinfused. An additional 14 piglets received 3 mg/kg MK-801 but not hypoxic-ischemic injury (drug-only group), and a final group of 11 piglets were subjected to only a sham operation (sham group).Results: Neurological examination scores at 24, 48, and 72 hours showed that MK-801 and drug-only piglets were significantly worse than the controls. Pathological examination of the brains at 72 hours showed significantly greater damage in the brains of the MK-801 and control pigs relative to the sham and drug-only groups. No differences were found between the control and the MK-801 groups. No differences were found between the sham and drug-only groups.Conclusions: MK-801, at a dose of 3 mg/kg, causes neurological dysfunction in piglets lasting at least 72 hours, but neither causes brain damage nor ameliorates the effects of hypoxicischemic injury to the brain of the newborn pig. (Stroke 1991^22:1270-1275)

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Focal Cerebral Ischaemia in the Cat: Treatment with the Glutamate Antagonist MK-801 after Induction of Ischaemia

Cited by 244 publications

References 20 publications

Mouse Hippocampal Organotypic Tissue Cultures Exposed to In Vitro “Ischemia” Show Selective and Delayed CA1 Damage that is Aggravated by Glucose

Mouse Hippocampal Organotypic Tissue Cultures Exposed to In Vitro “Ischemia” Show Selective and Delayed CA1 Damage that is Aggravated by Glucose

Excitatory amino acid antagonists and their potential for the treatment of ischaemic brain damage in man.

MK-801 does not protect against hypoxic-ischemic brain injury in piglets.

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