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Biomedical subjects

W Danysz

Publications and source records attributed to W Danysz.

At least 73 records · Page 4Linked to original sources
PubMed1998

GlycineB antagonists as potential therapeutic agents. Previous hopes and present reality.

It is not clear what therapeutic application is most likely for agents blocking glycine site of the NMDA receptors (glycineB). Majority of the studies to date used either glycineB antagonists with doubtful brain penetration or partial agonists. Following systemic administration to rats of our newly developed glycineB antagonists (MRZ 2/570; 2/571 and 2/576) and L-701,324 (MSD) as a reference agent the following behavioural effects were observed: weak (if any) antiparkinsonian-like effects, lack of anxiolytic activity, inhibition of physical and motivational aspects of morphine dependence and neuroprotective activity in global ischaemia. The side effects include: sedation, ataxia, and myorelaxation. We detected neither vacuolisation in the cingulate cortex nor impairment of pre-pulse inhibition indicating lack of psychotomimetic potential.

Animals↗
PubMed1998

Ethanol and N-methyl-D-aspartate receptor complex interactions: a detailed drug discrimination study in the rat.

The discriminative stimulus properties of compounds that interact with the NMDA receptor complex were investigated in rats trained to discriminate ethanol from saline. Male Wistar rats were trained in a two-lever operant drug discrimination paradigm to make differential responses [fixed ratio 10 (FR10)] for food after ethanol (1 g/kg i.p.; 12% v/v ethanol solution) and saline vehicle injections. Drug effects were assessed by means of generalization and antagonism tests. In the generalization tests, the noncompetitive NMDA antagonists acting at the ion channel dizocilpine, memantine, phencyclidine (PCP) and the sigma1 receptor agonists (+)-pentazocine and (+)-N-allyl-normetazocine (NANM) dose-dependently generalized for ethanol, whereas the alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) antagonist GYKI 52466, the glycine antagonists L-701,324 and MRZ 2/502, the polyamine site antagonist arcaine and the polyamine site ligand spermidine, did not. Our results show that the noncompetitive NMDA antagonists fully substitute dose-dependently for ethanol in a drug-discrimination task. The ethanol-like discriminative stimulus effects of PCP, pentazocine and NANM, which are also sigma receptor ligands, are likely to be attributed to their activity at NMDA receptors. We therefore assume that some of the acute effects of ethanol are mediated via NMDA receptor antagonism at the PCP binding site.

Animals↗
PubMed1998

Amantadine attenuates response alterations resulting from repetitive L-DOPA treatment in rats.

It has been shown that NMDA receptor antagonists can inhibit both the development and expression of a decrease in the duration of L-DOPA action in rats rotating after unilateral lesion of the nigro-striatal dopaminergic system. Using this model we found that the low affinity NMDA receptor antagonist amantadine (50 mg/kg b.i.d.) attenuated both the expression and development of the shortening of duration of L-DOPA (25 mg/kg b.i.d.) action. Amantadine was most efficient when given both during the induction and expression phase. However, an additional interaction experiment demonstrated that acutely given amantadine also prolongs the duration of L-DOPA-induced rotations. Hence, only the effect on development of shortening of L-DOPA action can be regarded as specific for repetitive treatment mode. The data suggest that treatment with amantadine might have beneficial effects on response fluctuations produced by chronic L-DOPA treatment.

Amantadine↗
PubMed1998

Inhibition of reinforcing effects of morphine and naloxone-precipitated opioid withdrawal by novel glycine site and uncompetitive NMDA receptor antagonists.

The glycine site (MRZ 2/570 and L-701,324), and uncompetitive (MRZ 2/579) NMDA receptor antagonists inhibited morphine-produced behaviors related to drug-abuse. The expression of morphine dependence was blocked by pretreatment with all three compounds (3-7.5 mg/kg); the effects of glycine/NMDA antagonists were not dose-dependent. Mice which were morphine-free for 3 days still displayed a significant severity of the withdrawal syndrome when challenged again with naloxone. This extinction of a residual morphine dependence was markedly diminished by treatment with similar doses of NMDA receptor antagonists at the test following the wash-out period. The rewarding impact of morphine was investigated in rats using the place preference (CPP) paradigm. All NMDA receptor antagonists (2.5-10 mg/kg) inhibited both the acquisition and expression of morphine-induced CPP. Once established, morphine-induced CPP was observed until 2 weeks after conditioning. NMDA receptor antagonists given for 3 days after the end of conditioning did not influence the extinction of morphine-induced CPP. Microdialysis studies revealed that the behaviorally effective doses of MRZ 2/579 resulted in a brain concentration close to its in vitro potency as an NMDA receptor antagonist. These data suggest that novel glycine site and uncompetitive NMDA receptor antagonists may have therapeutic potential in the treatment of opioid abuse.

Analgesics, Opioid↗
PubMed1998

Study on the role of glycine, strychnine-insensitive receptors (glycineB sites) in the discriminative stimulus effects of ethanol in the rat.

Several recent studies indicate that both competitive and noncompetitive NMDA receptor antagonists substitute for ethanol in a drug discrimination procedure. In the present study we examined compounds from another class of NMDA receptor antagonists--glycine, strychnine-insensitive, receptor (glycineB site) antagonists in rats trained to discriminate between i.p.-administered 1.0 g/kg ethanol (10% v/v) and saline. When the animals met the discriminative criteria, substitution tests were conducted with the noncompetitive NMDA receptor antagonist, memantine (3.0-12.0 mg/kg, i.p.) and selective, glycineB site antagonists--L-701,324 (0.3-3.0 mg/kg, i.p.) and MRZ 2/576 (0.1-10.0 mg/kg, i.p.). Memantine completely substituted for ethanol at the dose of 6.0 mg/kg, which significantly suppressed the rate of responding, L-701,324 substituted for ethanol at the dose of 3.0 mg/kg, which only tended to decrease the response rate. MRZ 2/576 produced maximal ethanol-appropriate responding (50%) at the dose of 5.0 mg/kg, which did not affect the rate of responding. Glycine (200-800 mg/kg, i.p.) did not antagonize the ethanol stimulus. These results indicate that glycine, strychnine-insensitive, site antagonists may induce some ethanol-like stimulus effects in the rat.

Animals↗
PubMed1998

Glutamate in CNS disorders as a target for drug development: an update.

The authors provide an extensive review of new data related to the role of glutamate in CNS disorders, describing new aspects in glutamate and glutamatergic receptors-NMDA receptors, NR2B-selective antagonists, non-NMDA ionotropic glutamate receptors, N-acetylaspartylglutamate, and glutamate and glycine transporters. New findings in animal models and in human diseases-stroke, traumatic brain injury, Alzheimer's, Parkinson's and Huntington's diseases, tardive dyskinesia, ALS, olivopontcerebellar degeneration, AIDS, allergic encephalomyelitis, epilepsy, anxiety, depression, schizophrenia, liver disease, aminoglycoside antibiotic-induced hearing loss, hemiplegia, chronic pain and drug tolerance and abuse-are presented. Finally, the authors cite the progress achieved in the development of agents that interact with the glutamatergic system: NMDA channel blockers, competitive NMDA receptor antagonists, NR2B-selective antagonists, glutamate release inhibitors, glycineB antagonists, AMPA and kainate receptor antagonists, AMPA receptor-positive modulators and agents that act by modifying endogenous kynurenic acid metabolism.

Journal Article↗
PubMed1997

Increased expression of cathepsin D in retrosplenial cortex of MK-801-treated rats.

Single administration of a high dose of an uncompetitive NMDA receptor antagonist-dizocilpine maleate (MK-801)-results in transient neuronal vacuolization and cell death in retrosplenial cortex in rodents. In this study expression of cathepsin D (CatD), a major lysosomal aspartic protease, was investigated in brains of female rats treated with 1, 5, or 10 mg/kg of MK-801. Northern blot analysis demonstrated that the CatD mRNA level was moderately increased in retrosplenial cortex 24 h-7 days after the treatment. Concomitantly, increased CatD immunoreactivity was observed, predominantly in the degenerating neurons in layer III of retrosplenial cortex. Neuronal response was spatially distinguished from glial reactivation marked by increased mRNA and protein levels of glial fibrillary acidic protein, as demonstrated by Northern blot and immunohistochemistry in retrosplenial cortex 24 h-7 days after MK-801 treatment. These data suggest that activation of the lysosomal proteolytic system of neurons may play a role in MK-801-evoked neurodegeneration.

Animals↗
PubMed1997

Protection against post-ischaemic neuronal loss in gerbil hippocampal CA1 by glycineB and AMPA antagonists. Short communication.

Novel antagonists of the glycineB site of the NMDA receptor (MRZ 2/570, MRZ 2/576), and an AMPA receptor antagonist, NBQX were tested in 3-min global ischaemia in gerbils. Untreated animals showed after 14 days a loss of almost 90% of pyramidal neurones in the CA1 region, which was prevented by NBQX, and reduced to 50% by both glycineB antagonists. NBQX produced a delayed, long lasting (up to 24 hr) hypothermia while hypothermia with both glycineB antagonists was transient.

Animals↗
PubMed1997

Uncompetitive NMDA receptor antagonists attenuate NMDA-induced impairment of passive avoidance learning and LTP.

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.

2-Amino-5-phosphonovalerate↗
PubMed1997

Anxiolytic activity of glycine-B antagonists and partial agonists--no relation to intrinsic activity in the patch clamp.

On the basis of animal models, anxiety was one of the first suggested clinical applications of partial agonists of the glycineB site coupled to the NMDA receptor. It is not certain, however, whether these findings can be extended to full glycineB antagonists and what is the relation between intrinsic activity (degree of NMDA receptor antagonism) and anxiolytic effect. In the present study several NMDA receptor antagonists, including several glycineB antagonists/partial agonists, were tested for anxiolytic activity in the Vogel conflict test and the elevated plus-maze. Additionally, the intrinsic activities of the glycineB partial agonists used [ACPC, (R,+)-HA-966 and D-cycloserine] were compared in patch-clamp experiments in cultured neurones. In the plus-maze the most striking increase in the time spent in open arms (index of anxiolytic effect) was seen after diazepam and D-cycloserine (at doses that did not change locomotion). Also reliable (dose-dependent), although weaker, anxiolytic activity was produced by the uncompetitive NMDA receptor antagonist (+)MK-801 and the competitive antagonist CGP 39551. Modest anxiolytic-like effect in the plus-maze was also observed after the glycineB antagonist L-701,324 and the partial agonist (+,R)-HA-966. Uncompetitive antagonists memantine and amantadine, the glycineB partial agonist ACPC (up to 600 mg/kg) or the full antagonists MRZ 2/570, MRZ 2/571 and MRZ 2/576 had no effect. In the Vogel conflict test neither memantine, nor any of the full glycineB antagonists tested (L-701,324 and MRZ 2/576), showed anxiolytic activity. Patch-clamp studies revealed that the intrinsic activity of (+,R)-HA-966, D-cycloserine and ACPC was 13, 57 and 92%, respectively, as compared to that of glycine itself (100%). In conclusion, for the agents tested there is no clear relation between the levels of intrinsic activity, i.e. degree of NMDA receptor inhibition, and anxiolytic activity. Moreover, L-701,324 and MRZ-type glycineB full antagonists do not exchibit anxiolytic activity in the elevated plus-maze and Vogel conflict test.

Animals↗
PubMed1997

Effects of D-cycloserine and aniracetam on spatial learning in rats with entorhinal cortex lesions.

A great body of behavioural and neurophysiological evidence suggests that excitatory amino acids are involved in mechanisms of learning and memory. Moreover, degeneration of glutamatergic pathways may underlie the cognitive deficits seen in various disorders such as Alzheimer's dementia. As direct stimulation of glutamatergic receptors with agonists may increase the risk of toxicity and accelerate neuropathological changes, a more valid approach seems to be positive modulation of glutamatergic receptors that may reverse the symptoms with a lower risk of excitotoxic effects. Such a possibility offered by partial agonists of the strychnine-insensitive glycine site of the NMDA receptor (Gly-B site) or positive modulators of AMPA receptors, such as aniracetam. In the present study, the effects of d-cycloserine and aniracetam were tested in two animal models of cognitive deficits (entorhinal cortex lesion-induced deficits evaluated in the radial maze and scopolamine-induced amnesia evaluated in passive avoidance test). D-cycloserine (6 mg/kg, for 10 days) had no effect on spatial working memory deficit induced by entorhinal cortex lesions. It did, however, reverse scopolamine-induced deficits in the passive avoidance test when given acutely at the same dose. In contrast, aniracetam (50 mg/kg, for 10 days) produced beneficial effects in the radial maze test in rats with entorhinal cortex lesions, but given at the same dose acutely did not influence scopolamine-induced amnesia. The positive effect of d-cycloserine against scopolamine-induced amnesia may be probably related to the cholinergic-glutamatergic interaction in the hippocampus. The negative data obtained with d-cycloserine in the model of entorhinal cortex lesions-induced cognitive deficits could be taken as a hint that it is probably not suitable for the symptomatological therapy of Alzheimer's disease. The mechanism of positive action of aniracetam cannot be explained on the basis of AMPA receptor modulation, as the dose used (50 mg/kg) is well below that required for the effect at AMPA receptors. Other actions such as peripheral effects or modulation of metabotropic receptors seem more likely.

Animals↗
PubMed1997

Aminoadamantanes as NMDA receptor antagonists and antiparkinsonian agents--preclinical studies.

Aminoadamantanes such as 1-aminoadamantane (amantadine) and 1-amino-3,5-dimethyladamantane (memantine) are N-methyl-D-aspartate (NMDA) receptor antagonists which show antiparkinsonian-like activity in animal models and in Parkinson's patients. The issue of whether NMDA antagonism plays a role in the symptomatological antiparkinsonian activity of amantadine and memantine is addressed by comparing: behaviourally effective doses, serum/brain levels, and their potency as NMDA receptor antagonists. In the case of memantine, blockade of NMDA receptors is probably the only mechanism responsible for antiparkinsonian activity, whereas for amantadine the situation is clearly far more complex. There are a number of differences between memantine and amantadine both in vitro and in vivo, and although NMDA receptor antagonism certainly participates in the antiparkinsonian activity of amantadine, other effects, some of which are elusive, also play a role. Moreover, it has been suggested that the pathomechanism of Parkinson's disease involves excitotoxic processes and that treatment with NMDA receptor antagonists might also slow the progression of neurodegeneration. If this claim is true, such an effect could be achieved with amantadine and memantine which show neuroprotective activity in animals at therapeutically relevant doses.

Amantadine↗
PubMed1997

Neuroprotection of acetylcholinergic basal forebrain neurons by memantine and neurokinin B.

The present study investigated whether chronic, low dose therapy with memantine could (1) prevent the loss of basal forebrain cholinergic cells induced by injection of N-methyl-D-aspartate (NMDA) into the nucleus basalis magnocellularis (NBM) of rats, and (2) attenuate impaired performance in the radial maze of rats with entorhinal cortex lesions. In addition, we investigated whether neuroprotection could be provided by neurokinin B (NKB). Following an injection of NMDA (0.015 M) into the NBM, rats were implanted with osmotic minipumps containing memantine (20 or 0.20 mg/kg/day for 2 weeks). Other rats were given unilateral NBM injections of 1.0 microliter of Solution A (0.5 microliter containing 8.26 mM NKB and 0.24 units of bacitracin and 0.5 microliter containing 0.03 M NMDA) or Solution B (0.5 microliter of PBS containing 0.24 U of bacitracin and 0.5 microliter containing 0.03 M NMDA). Two weeks later, the anterior cortex was analyzed for choline acetyltransferase (ChAT), a specific marker for the loss of acetylcholinergic neurons. Both chronic administration of memantine, and acute administration of NKB, prevented the decline in cortical ChAT activity associated with injection of NMDA into the NBM, and attenuated a reference memory deficit in the radial maze produced by entorhinal cortex lesions. Thus, memantine infusion at low doses leading to steady-state serum levels within a therapeutic range provides both neuroprotection and cognitive enhancement-an optimal combination for the treatment of neurodegenerative disorders.

Acetylcholine↗
PubMed1997

Inhibition of reinforcing effects of morphine and motivational aspects of naloxone-precipitated opioid withdrawal by N-methyl-D-aspartate receptor antagonist, memantine.

The present study focused on the effects of 1-amino-3,5-dimethyladamantane (memantine), a clinically used, low-affinity N-methyl-D-aspartate channel blocker, on the motivational impact of morphine and morphine withdrawal syndrome. Memantine (7.5 mg/kg) inhibited the acquisition as well as the expression of morphine-induced conditioned place preference. However, memantine did not affect significantly the acquisition or expression of conditioned place preference induced by food presentation. In addition, at the dose that blocked morphine-induced conditioned place preference, memantine by itself produced neither conditioned place preference nor conditioned place aversion. Memantine attenuated the negative motivational aspects of morphine withdrawal as assessed by conditioned place aversion produced by a low dose (0.1 mg/kg) of naloxone in morphine-dependent rats. Drug discrimination studies revealed that the inhibitory effects of memantine on morphine-induced conditioned place preference could not be attributed to the attenuation by memantine of the interoceptive cue produced by morphine. In addition, the inhibitory effects of memantine on the expression of morphine-induced conditioned place preference seemed not to be related to effects on memory retrieval, as revealed in the Morris water maze spatial task. These data suggest that memantine at a low, pharmacologically relevant dose of 7.5 mg/kg blocks the reinforcing effects of morphine and aversive effects of morphine withdrawal in rats, which suggests a new potential clinical indication for this agent in the treatment of opioid abuse.

Animals↗
PubMed1997

Novel systemically active antagonists of the glycine site of the N-methyl-D-aspartate receptor: electrophysiological, biochemical and behavioral characterization.

A series of novel tricyclic pyrido-phthalazine-dione derivatives was tested for antagonistic effects at the strychnine-insensitive modulatory site of the N-methyl-D-aspartate (NMDA) receptor (glycineB). All compounds displaced [3H]MDL-105,519 binding to rat cortical membranes with IC50 values of between 90 nM and 3.6 microM. In patch-clamp experiments, steady-state inward current responses of cultured hippocampal neurons to NMDA (200 microM, glycine 1 microM) were antagonized by these same compounds with IC50 values of 0.14 to 13.8 microM. The antagonism observed was typical for glycineB antagonists, i.e., they induced desensitization and their effects were not use or voltage dependent. Moreover, increasing concentrations of glycine were able to decrease their apparent potency. Much higher concentrations (>100 microM) were required to antagonize alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-induced currents. They were potent, systemically active NMDA receptor antagonists in vivo against responses of single neurons in the rat spinal cord to microelectrophoretic application of NMDA with ID50 values in the low milligram per kilogram i.v. range. They also inhibited pentylenetetrazol-, NMDA- and maximal electroshock-induced convulsions in mice with ED50 values ranging from 8 to 100 mg/kg i.p. The duration of anticonvulsive action was rather short but was prolonged by the organic acid transport inhibitor probenecid (200 mg/kg). The agents tested represent a novel class of systemically active glycineB antagonists with greatly improved bioavailability.

Animals↗
PubMed1996

Evidence for alcohol anti-craving properties of memantine.

Rats consuming alcohol voluntarily for a long time show increased alcohol consumption after a phase of alcohol deprivation and this might reflect increased craving for alcohol. Administration of memantine (1-amino-3,5-dimethyl-adamantane), a clinically used uncompetitive NDMA receptor antagonist, resulted in a significant reduction of the alcohol deprivation effect without any sedative, dysphoric or stimulant side-effects. The dose of memantine used (4.8 mg/day) resulted in serum levels close to the therapeutic range in humans. These results indicate that memantine may have therapeutical potential as an anti-craving drug for alcohol.

Alcoholism↗
PubMed1996

The effects of mitochondrial failure upon cholinergic toxicity in the nucleus basalis.

Increased glutamate or acetylcholine receptor stimulation may interact with mitochondrial failure to increase the vulnerability of cholinergic neurons within the nucleus basalis. Understanding of the mechanisms that underlie this vulnerability may lead to a therapy to prevent the degeneration of these neurons in Alzheimer's disease. In the presence of a mitochondrial energy deficit, excess stimulation of N-methyl-D-aspartate (NMDA) receptors was not required for cytotoxicity. Furthermore, stimulation of cholinergic receptors was cytotoxic to cholinergic neurons but this toxicity was not enhanced by NMDA stimulation. Chronic administration of NMDA antagonists, such as memantine, amantadine or MK-801, attenuated the effects of mitochondrial failure in the presence or absence of excessive cholinergic or NMDA receptor stimulation.

Acetylcholine↗