Neuroprotective Properties of the Uncompetitive NMDA Receptor Antagonist Remacemide Hydrochloride

Palmer, Gene C.; Cregan, Edward F.; Borrelli, A. R.; Willett, F.

doi:10.1111/j.1749-6632.1995.tb16580.x

Cited by 25 publications

(12 citation statements)

References 31 publications

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“…Mechanisms of glutamate mediated toxicity include excessive activation of N-methyl-D-aspartate (NMDA) receptor causing massive calcium influx and subsequent necrosis and apoptotic cell death (McCulloch, 1992; Owens et al , 1997). Experimental studies indicate that the early inhibition of glutamate receptors prevents aSAH associated blood-brain barrier leakage (Palmer et al , 1995) and development of delayed vasospasm (Zuccarello et al , 1994). A number of investigators have used magnesium to block NMDA receptor activity in attempt to prevent the development of delayed vasospasm and DINDs in aSAH patients (Dorhout Mees et al , 2010; Wong et al , 2006).…”

Section: Early Events After Asahmentioning

confidence: 99%

The importance of early brain injury after subarachnoid hemorrhage

Sehba

Hou

Pluta

et al. 2012

Progress in Neurobiology

502

392

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Aneurysmal subarachnoid hemorrhage (aSAH) is a medical emergency that accounts for 5% of all stroke cases. Individuals affected are typically in the prime of their lives (mean age 50 years). Approximately 12% of patients die before receiving medical attention, 33% within 48 hours and 50% within 30 days of aSAH. Of the survivors 50% suffer from permanent disability with an estimated lifetime cost more than double that of an ischemic stroke. Traditionally, spasm that develops in large cerebral arteries 3-7 days after aneurysm rupture is considered the most important determinant of brain injury and outcome after aSAH. However, recent studies show that prevention of delayed vasospasm does not improve outcome in aSAH patients. This finding has finally brought in focus the influence of early brain injury on outcome of aSAH. A substantial amount of evidence indicates that brain injury begins at the aneurysm rupture, evolves with time and plays an important role in patients’ outcome. In this manuscript we review early brain injury after aSAH. Due to the early nature, most of the information on this injury comes from animals and few only from autopsy of patients who died within days after aSAH. Consequently, we began with a review of animal models of early brain injury, next we review the mechanisms of brain injury according to the sequence of their temporal appearance and finally we discuss the failure of clinical translation of therapies successful in animal models of aSAH.

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Section: Early Events After Asahmentioning

confidence: 99%

The importance of early brain injury after subarachnoid hemorrhage

Sehba

Hou

Pluta

et al. 2012

Progress in Neurobiology

502

392

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“…co-administered with a subthreshold dose of L-Dopa methylester dosedependently increased motor activity. Remacemide is also an uncompetitive NMDA antagonist with neuroprotective properties (Palmer et al, 1995). In parkinsonian rhesus monkeys, remacemide (10mg/kg, p.o.)…”

Section: Mptp Salinementioning

confidence: 99%

Co-administration of memantine and amantadine with sub/suprathreshold doses of L-Dopa restores motor behaviour of MPTP-treated mice

et al. 2001

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The antiparkinsonian effects of the uncompetitive NMDA antagonists, memantine, amantadine and MK-801, in combination with an acute subthreshold dose of L-Dopa (5 mg/kg) in drug-naive MPTP-treated mice or a suprathreshold dose (20 mg/kg) in L-Dopa tolerant MPTP-treated mice were investigated. In the former case, memantine (locomotion: 3 mg/kg; rearing: 1 mg/kg) and amantadine (locomotion and rearing: 10 mg/kg) injected 60 min before the subthreshold dose of L-Dopa (5 mg/kg), each induced an antiparkinsonian action in hypokinesic MPTP-treated mice that consisted of dose-specific, as opposed to dose-related, elevations of locomotion and rearing behaviour. At the same time, higher doses of memantine reduced further the rearing (10 and 30 mg/kg) and locomotor (30mg/kg) behaviour of the MPTP-treated mice. MK-801 plus L-Dopa elevated locomotion (0.1 mg/kg) but reduced rearing at the 0.3 mg/kg dose. In control, saline-treated mice, memantine (3, 10 and 30 mg/kg) and MK-801 (0.1 and 0.3 mg/kg) increased locomotor behaviour but decreased rearing behaviour, while amantadine produced no effects. Memantine increased locomotor (1 and 3 mg/kg, s.c.; 1 mg/kg dose restored activity) and rearing (0.3 and 3 mg/kg) activity in the L-Dopa tolerant MPTP-treated mice, whereas amantadine (3 and 10 mg/kg) restored both locomotor (30 mg/kg significantly increased locomotion but did not restore the activity level) and rearing (3 mg/kg only) activity. MK-801 (0.1 and 0.3 mg/kg, s.c.) also increased significantly locomotor activity of L-Dopa-tolerant MPTP mice although the antikinetic action was not reversed, thereby precluding a restorative effect of the compound. These results, demonstrating both a synergistic and a restorative effect of the NMDA antagonists in coadministration with L-Dopa, demonstrate a putative antiparkinson action by these compounds in a functional animal model that incorporates the "wearing-off" complications of L-Dopa administration in the disorder.

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“…Most recent efforts at developing NMDA receptor channel blockers have focused on low affinity antagonists which appear to have a better therapeutic index (ROGAWSKI 1993). Specifically, ketamine, dextromethorphan, memantine, remacemide, the remacemide analog FPL12495, and ADCI (5-aminocarbonyl- 1O,1l-dihydro-5-H-dibenzo-(a,d)cyclohepten,5,l0-imine) are low affinity channel blockers with generally more acceptable side effects (PALMER et al 1995). The low affinity antagonists are associated with faster on kinetics (due to the higher concentrations necessary for binding) and faster off kinetics.…”

Section: Channel Blocker Pharmacologymentioning

confidence: 99%

Glutamate Receptor Ion Channels: Activators and Inhibitors

Jane¹,

Tse²,

Skifter³

et al. 2000

Pharmacology of Ionic Channel Function: Activators and Inhibitors

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The classification of excitatory amino acid (EAA) receptors into N-methyl-oaspartic acid (NMDA) and non-NMDA receptors was based mainly on the discovery of selective agonists and antagonists (for a review see WATKINS and EVANS 1981). Thus the selective NMDA receptor antagonist, o-aaminoadipate blocked responses due to NMDA but not those due to quisqualate or kainate in the frog and rat spinal cord. Evidence for more than one type of non-NMDA receptor came from the observation that responses due to quisqualate but not those due to kainate are depressed by L-glutamic acid diethyl ester (GDEE) (McLENNAN and LOOGE 1979; while responses to kainate can be selectively antagonized by y"oglutamylglycine (rDGG) . In addition, receptors present on dorsal root fibers were shown to be sensitive to kainate but not quisqualate ). These observations resulted in the classification of EAA receptors into NMDA, quisqualate and kainate receptors. Such receptors are linked to ionic fluxes and are now known as ionotropic glutamate receptors (iGluRs) as distinct from the more recently discovered metabotropic glutamate receptors (mGluRs) linked to G-protein coupled metabolic changes (CONN and PIN 1997). The isoxazole analogue, (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) was reported to be more selective for the quisqualate type of iGluR than quisqualate itself (KROGSGAARO-LARSEN et al. 1980 and this led to this ionotropic receptor being renamed the AMPA receptor to avoid confusion with quisqualate-activated mGluRs (MONAGHAN et al. 1989;). Molecular biology has identified a large number of subtypes of both iGluRs and mGluRs.Progress in defining the role of EAA receptors in CNS function has also followed the development of receptor-selective antagonists. With the availability of NMDA receptor antagonists, it was possible to demonstrate a role of NMDA receptors in polysynaptic responses in the vertebrate spinal cord EVANS et al. 1979) and in hippocampal long term potentiation (COLLINGRIDGE et al. 1983;HARRIS et al. 1984

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Neuroprotective Properties of the Uncompetitive NMDA Receptor Antagonist Remacemide Hydrochloride

Cited by 25 publications

References 31 publications

The importance of early brain injury after subarachnoid hemorrhage

The importance of early brain injury after subarachnoid hemorrhage

Co-administration of memantine and amantadine with sub/suprathreshold doses of L-Dopa restores motor behaviour of MPTP-treated mice

Glutamate Receptor Ion Channels: Activators and Inhibitors

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