(+)-MK 801 Maleate

(+)-MK 801 is a potent antagonist of NMDA with Ki value of 30.5nM [1].

MK 801 is a potent anticonvulsant exhibits both anxiolytic and sympathomimetic properties. It is found to be a noncompetitive antagonist of NMDA. MK 801 can penetrate into the central nervous system. In the in vitro assay, MK 801 binds to rat cerebral cortical membrane with high affinity in a saturable manner. This binding is reversible even when the concentration of MK 801 is up to 100μM. It is also found that the binding shows a regional specificity. Most of these binding sites are located in the hippocampus. In rat cortical-slice preparations, MK 801 causes a potent blockade of depolarizing responses to NMDA with a high selectivity. This effect is persistent. The blockade can also cause a suppression of the epileptiform activity induced by tetrodotoxin or other neurotoxin [1].

References:
[1] Wong EH, Kemp JA, Priestley T, Knight AR, Woodruff GN, Iversen LL . The anticonvulsant MK-801 is a potent N-methyl-D-aspartate antagonist. Proc Natl Acad Sci U S A. 1986 Sep;83(18):7104-8.

Systemic administration of dizocilpine maleate (MK-801) or L-dopa reverses the increases in GAD65 and GAD67 mRNA expression in the globus pallidus in a rat hemiparkinsonian model.[Pubmed:12373737]

Synapse. 2002 Dec 15;46(4):224-34.

This study examined the consequences of systemic treatment with either L-dopa or MK-801 on the levels of mRNAs encoding the 65 and 67 kDa isoforms of glutamate decarboxylase (GAD65 and GAD67) in the striatum and globus pallidus (GP) of rats rendered hemiparkinsonian by intranigral 6-hydroxydopamine injection. GADs mRNA levels were assessed by means of in situ hybridization histochemistry. In the striatum, dopamine denervation resulted in increased GAD67 mRNA levels at the rostral and caudal levels, whereas GAD65 showed selective increase at the caudal level. L-dopa and MK-801 treatments showed differential effects on the two GAD isoform levels in rats with 6-hydroxydopamine lesion. The lesion-induced increases in GAD67 transcripts were potentiated by L-dopa but unaffected by MK-801, whereas the increases in GAD65 were suppressed by MK-801 but unaffected by L-dopa. These data suggest a heterogeneity of glutamate-dopamine interaction in the anteroposterior extent of the striatum and show that NMDA-mediated mechanisms are involved in the 6-hydroxydopamine lesion-induced transcriptional changes in striatal GAD65 but not GAD67. In GP, the 6-OHDA lesion elicited increases in both GAD65 and GAD67 mRNA levels. L-dopa or MK-801 treatment suppressed the lesion-induced augmentations in the two GADs mRNA levels. These results indicate that dopamine denervation-induced changes in the functional activity of GP neurons involve both dopamine and glutamate NMDA receptor-mediated mechanisms. Comparison between the effects of L-dopa and MK-801 treatments on markers of the activity of striatal and pallidal GABA neurons further suggest that the impact of these treatments at the GP level do not depend solely on the striatopallidal input.

Pre- and postischemic effects of the NMDA receptor antagonist dizocilpine maleate (MK-801) on collateral cerebral blood flow.[Pubmed:9384406]

J Neurosurg. 1997 Dec;87(6):927-33.

The authors studied the effects of pre- and postischemic administration of dizocilpine maleate (MK-801) on collateral and regional cerebral blood flow (CBF). The ischemic penumbra appears to benefit most from the neuroprotective effects of MK-801. The precise mechanism by which MK-801 provides this neuroprotection remains controversial. Alterations in CBF have been demonstrated with MK-801 administration, but whether the response is an increase or decrease in flow has remained unclear. A left-sided craniectomy was performed in 20 dogs. A branch of the middle cerebral artery (MCA) was cannulated and collateral blood supply-dependent tissue (CDT) was identified using the "shadow flow" technique. Regional CBF was measured using radiolabeled microspheres. Six dogs received MK-801 (1 mg/kg administered intravenously) before they underwent MCA branch occlusion; the remaining 14 dogs received MK-801 after they underwent MCA occlusion. Cerebral blood flow and vascular pressures were measured 30 and 60 minutes after MK-801 administration. In animals that received MK-801 before MCA occlusion, CBF did not change significantly from baseline values before or after occlusion. In contrast, in animals that received MK-801 after MCA occlusion, CBF was significantly reduced in all regions of the brain, including the CDT. Collateral blood supply-dependent tissue showed a 51.7% reduction in flow, whereas normal CBF was reduced by 29.7%. The MK-801 induced cerebral vasoconstriction in both groups. The neuroprotective effects of MK-801 do not appear to be caused by the augmentation of collateral or global cerebral circulation and, in fact, may block the glutamate-mediated vasodilation that occurs during ischemia.

Repeated injections of dizocilpine maleate (MK-801) do not suppress the effects of nigrostriatal dopamine deafferentation on glutamate decarboxylase (GAD67) mRNA expression in the adult rat striatum.[Pubmed:9037536]

Brain Res Mol Brain Res. 1996 Dec 31;43(1-2):219-24.

The present study examined the effects of glutamate transmission blockade through N-methyl-D-aspartate (NMDA) receptor subtype by repeated administration of dizocilpine maleate (0.2 mg/kg. i.p., twice a day for eight days) alone or in combination with unilateral 6-hydroxydopamine-induced lesion of the nigrostriatal dopaminergic pathway on GABAergic neurons in the adult rat striatum. For this purpose, the expression of the messenger RNA encoding for the 67 kDa isoform of the GABA synthesizing enzyme, glutamate decarboxylase (GAD67 mRNA), was studied in the various conditions by quantitative in situ hybridization. The dizocilpine maleate treatment alone did not induce significant change of GAD67 mRNA levels in the striatum, indicating that NMDA receptors may not have a major role in the transcriptional regulation of GAD67 in the adult rat striatum. As reported previously, the unilateral dopaminergic lesion resulted in marked increases in GAD67 mRNA levels in the ipsilateral striatum. This up-regulation was not significantly affected by the treatment with dizocilpine maleate started 12 days after the unilateral intranigral 6-hydroxydopamine injection. Therefore, NMDA receptors are unlikely to contribute to the dopamine lesion-induced GAD67 mRNA up-regulation in striatal projection neurons. This result is of major interest in comparison with our previous finding that NMDA receptor activation is necessary to maintain the up-regulation of enkephalin expression in the striatum after dopamine lesion.

Dizocilpine maleate, MK-801, but not 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline, NBQX, prevents transneuronal degeneration of nigral neurons after neurotoxic striatal-pallidal lesion.[Pubmed:10188935]

Neuroscience. 1999 Apr;90(1):79-85.

Unilateral neurotoxin lesion of rat caudate-putamen and globus pallidus resulted in delayed, transneuronal degeneration of GABAergic substantia nigra pars reticulata neurons. To explore whether the disinhibition of endogenous glutamate excitatory input played a role in the degeneration of substantia nigra pars reticulata neurons, animals with unilateral striatal-pallidal lesions received three daily intraperitoneal injections of either dizocilpine maleate (MK-801, 1 or 10 mg/kg), an N-methyl-D-aspartate glutamate receptor blocker, or 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX, 30 mg/kg), an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor blocker, that began 24 h after the striatal-pallidal neurotoxin lesion. Drug treatment affected neither the volume of the initial lesion nor the volume of striatal-pallidal glial fibrillary acidic protein immunoreactivity. Neuron number in the substantia nigra pars reticulata ipsilateral to the lesioned striatopallidum was reduced on average by 37% in untreated control rats, in low dose MK-801, and NBQX-treated rats (P<0.0001). However, in animals treated with high doses of MK-801 there was no difference in the number of neurons in the substantia nigra pars reticulata ipsilateral or contralateral to the neurotoxin lesion. These data demonstrate that dose-related treatment with N-methyl-D-aspartate glutamate receptor blockers protects substantia nigra pars reticulata neurons, and suggests that glutamatergic mechanisms play a role in delayed transneuronal degeneration.

Uncompetitive NMDA receptor antagonists attenuate NMDA-induced impairment of passive avoidance learning and LTP.[Pubmed:9257940]

Neuropharmacology. 1997 Jul;36(7):961-71.

In general, N-methyl-D-aspartate (NMDA) receptor antagonists inhibit learning and long term potentiation (LTP). However, it has been suggested that direct tonic, i.e. non-temporal, activation of NMDA receptors, in contrast to learning, may lead to an increase in synaptic "noise" and, in turn, to a loss of association detection. In the present study, a two-choice passive avoidance task and LTP in vitro (CA1 hippocampal region) were used to address this issue. Dark avoidance learning was impaired by systemic NMDA administration (starting at 25 mg/kg) that was not related to either toxic effects or state-dependent learning. NMDA-induced amnesia was antagonized by ((+)-5-methyl-10,11-dihydro-5H-dibenzocyclohepten-5,10-imine maleate (MK-801) and 1-amino-3,5-dimethyladamantane (memantine), starting at low doses of 0.05 and 2.5 mg/kg, respectively, in a bell-shaped dose-response relationship. A competitive NMDA receptor antagonist CGP-39551 failed to reverse NMDA-induced amnesia. In hippocampal slices, NMDA (10 microM) depressed (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolproprionic acid (AMPA) receptor-mediated field potentials in CA1 and also caused a moderate reduction of LTP induction/expression. It was this latter effect that was antagonized by memantine (1 microM). Thus, under conditions of tonic activation of NMDA receptors, uncompetitive NMDA receptor antagonists can paradoxically reverse deficits in learning and synaptic plasticity.

The dose-response relationship and therapeutic window for dizocilpine (MK-801) in a rat focal ischaemia model.[Pubmed:1526248]

Eur J Pharmacol. 1992 May 27;216(1):1-7.

The purpose of the present study was to examine the dose-response relationship and the maximum time for which effective therapy could be delayed for the N-methyl-D-aspartate antagonist dizocilpine (MK-801) as a neuroprotective agent in a permanent focal ischaemia model in the rat. The ED50 for dizocilpine in the amelioration of cortical damage in this model was found to be approximately 0.3 mg/kg (single i.p. dose, 30 min post onset of ischaemia) and significant protection was only obtained when therapy (3 mg/kg i.p.) was delayed for one hour or less after the onset of ischaemia. In a further experiment, dizocilpine 3 mg/kg i.p., produced a peak plasma level of 44 ng/ml and had a t1/2 elimination of 1.65 h.

The neuroprotective action of dizocilpine (MK-801) in the rat middle cerebral artery occlusion model of focal ischaemia.[Pubmed:1912992]

Br J Pharmacol. 1991 Aug;103(4):2030-6.

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; 0.04 mg kg-1 i.v. bolus + 0.6 micrograms kg-1 min-1 infusion; 0.12 mg kg-1 i.v. bolus + 1.8 micrograms kg-1 min-1 infusion; 0.4 mg kg-1 i.v. bolus + 6 micrograms kg-1 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 8.0 ng ml-1 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 ng ml-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 (113.2 ng ml-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 ngml1, 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.

The anticonvulsant MK-801 is a potent N-methyl-D-aspartate antagonist.[Pubmed:3529096]

Proc Natl Acad Sci U S A. 1986 Sep;83(18):7104-8.

The compound MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine maleate)] is a potent anticonvulsant that is active after oral administration and whose mechanism of action is unknown. We have detected high-affinity (Kd = 37.2 +/- 2.7 nM) binding sites for [3H]MK-801 in rat brain membranes. These sites are heat-labile, stereoselective, and regionally specific, with the hippocampus showing the highest density of sites, followed by cerebral cortex, corpus striatum, and medulla-pons. There was no detectable binding in the cerebellum. MK-801 binding sites exhibited a novel pharmacological profile, since none of the major neurotransmitter candidates were active at these sites. The only compounds that were able to compete for [3H]MK-801 binding sites were substances known to block the responses of excitatory amino acids mediated by the N-methyl-D-aspartate (N-Me-D-Asp) receptor subtype. These comprised the dissociative anesthetics phencyclidine and ketamine and the sigma-type opioid N-allylnormetazocine (SKF 10,047). Neurophysiological studies in vitro, using a rat cortical-slice preparation, demonstrated a potent, selective, and noncompetitive antagonistic action of MK-801 on depolarizing responses to N-Me-D-Asp but not to kainate or quisqualate. The potencies of phencyclidine, ketamine, SKF 10,047, and the enantiomers of MK-801 as N-Me-D-Asp antagonists correlated closely (r = 0.99) with their potencies as inhibitors of [3H]MK-801 binding. This suggests that the MK-801 binding sites are associated with N-Me-D-Asp receptors and provides an explanation for the mechanism of action of MK-801 as an anticonvulsant.

Dizocilpine maleate (MK-801 maleate) is a potent, selective and non-competitive NMDA receptor antagonist with Kd of 37.2 nM in rat brain membranes.

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