The neuroprotective action of dizocilpine (MK‐801) in the rat middle cerebral artery occlusion model of focal ischaemia

Abstract

1 An acute model of focal ischaemia, which involves permanent occlusion of the middle cerebral artery of the rat with 4 h survival, was used to find the minimum effective plasma concentration of dizocilpine (MK-801) and to determine its dose-effect relationship. 2 MK-801 was administered at the time of occlusion and was given as an i.v. bolus followed by an infusion for 4 h to maintain a steady state plasma concentration of the drug throughout the study.MK-801 was given at 3 dose levels; 0.04mgkg-1 i.v. bolus + 0.6 pgkg 1 min'-infusion; 0.12mgkg-I i.v.bolus + 1.8#ugkg-min-1 infusion; 0.4mgkg-' i.v. bolus + 6pgkg-min-1 infusion, which gave mean plasma levels over the 4 h of 8.0 ng ml -1, 18.9 ng ml-1 and 113.2 ng ml-1 respectively. 3 MK-801 at 8.Ongml-' gave 10% reduction in the volume of ischaemic brain damage in the cerebral cortex which just reached significance. The middle dose of MK-801 (18.9 ngml-1) gave a highly significant reduction in the volume of ischaemic brain damage in the cerebral cortex and hemisphere, volumes of ischaemic tissue being reduced by 60% and 50% compared to saline-treated animals, respectively. The highest plasma concentration of MK-801 (113.2ngml-1) resulted in a 35% reduction in the volume of hemispheric damage and a 40% reduction in the volume of cortical damage, which were significant. 4 The reduction in the amount of protection afforded by the highest dose of MK-801 may be due to the hypotensive effect of this dose. There was no protection against the volume of damage in the caudate nucleus for any of the doses of MK-801 tested. 5 Therefore the minimum effective plasma concentration of MK-801 was 8.0 ng ml1, although the greatest protection was seen with a plasma level of 18.9 ng ml-1. This correlates well with the concentration of MK-801 required to block N-methyl-D-aspartate (NMDA) receptors and prevent NMDA receptor mediated neurotoxicity in vitro.

Lack of effect of L‐687,414 ((+)‐cis‐4‐methyl‐HA‐966)5 an NMDA receptor antagonist acting at the glycine site, on cerebral glucose metabolism and cortical neuronal morphology

“…The present studies indicate that the doses of dizocilpine required for optimal neuroprotection (Gill et al, 1991b) are at the threshold of those for inducing changes in neuronal morphology since one of four rats showed a vacuolation response. Thus, there is little margin between wanted and unwanted effects with dizocilpine.…”

“…using fluorescence detection after solid phase extraction and pre-column derivatisation with FMOC chloride. Plasma dizocilpine levels resulting from the present dosing regimes have been reported previously (Gill et al, 1991b).…”

“…The objectives of the present studies were to examine the effects of neuroprotective dose regimes of L-687,414 on CMRg,c and neuronal morphology in comparison with the NMDA receptor channel blocker dizocilpine, the most potent neuroprotective agent yet described (Gill et al, 1991b). The study design mimicked that of experimental studies of focal ischaemia in rats and attempted to simulate some of the conditions that may occur in the clinic where neuroprotective agents might be given by bolus intravenous injection follow-ed by slow intravenous infusion to sustain plasma concentrations for prolonged periods of time.…”

Identification of Genes Regulated by Memantine and MK-801 in Adult Rat Brain by cDNA Microarray Analysis

“…It has been suggested that neuroprotective doses of MK-801 (0.3-0.8 mg/kg; i.p.) block NMDA receptors in the brain, and these doses produce plasma concentrations within the range of NMDA receptor affinity (Gill et al, 1991;Massieu et al, 1993).…”

Neuroprotective profile of lifarizine (RS‐87476) in rat cerebrocortical neurones in culture

“…The failure of nitrendipine to protect against glutamate neurotoxicity would suggest that L-type calcium channels are not involved in the evolution of this insult under the present experimental conditions, although a report by Weiss et al (1990) shown to reduce the neuronal damage produced by cerebral ischaemia in animal models. These agents include NMDA antagonists (Park et al, 1988;Gill et al, 1991), non-NMDA excitatory amino acid receptor antagonists (Sheardown et al, 1990;but see DeGraba et al, 1994), calcium and sodium channel inhibitors (Steen et al, 1985;Alps et al, 1988;Pauwels et al, 1991) and inhibitors of lipid peroxidation (Hall et al, 1988;Young et al, 1988 cultures. The anticonvulsant agent and sodium channel inhibitor, phenytoin, has been shown to enhance recovery of synaptic transmission in rat hippocampal slices under conditions of simulated ischaemia (Kenny & Sheridan, 1992).…”