Oral creatine supplementation attenuates L-DOPA-induced dyskinesia in 6-hydroxydopamine-lesioned rats.

L-DOPA-induced dyskinesia (LID) is among the motor complications that arise in Parkinson patients after a prolonged treatment with levodopa (L-DOPA). Since previous transcriptome and proteomic studies performed in the rat model of LID suggested important changes in striatal energy-related components, we hypothesize that oral creatine supplementation could prevent or attenuate the occurrence of LID. In this study, 6-hydroxydopamine-lesioned rats received a 2% creatine-supplemented diet for 1 month prior to L-DOPA therapy.

Proteomic analysis of striatal proteins in the rat model of L-DOPA-induced dyskinesia.

L-DOPA-induced dyskinesia (LID) is among the motor complications that arise in Parkinson's disease (PD) patients after a prolonged treatment with L-DOPA. To this day, transcriptome analysis has been performed in a rat model of LID [Neurobiol. Dis.

Neuroprotective and symptomatological action of memantine relevant for Alzheimer's disease--a unified glutamatergic hypothesis on the mechanism of action.

The involvement of glutamate mediated neurotoxicity in the pathogenesis of Alzheimer's disease is finding increasingly more acceptance in the scientific community. Central to this hypothesis is the assumption that in particular glutamate receptors of the N-methyl-D-aspartate (NMDA) type are overactivated in a tonic rather than a phasic manner. Such continuous mild activation leads under chronic conditions to neuronal damage.

NMDA-NR2B subtype selectivity of stereoisomeric 2-(1,2,3,4-tetrahydro-1-isoquinolyl)ethanol derivatives.

Enantiopure 2-(1,2,3,4-tetrahydro-1-isoquinolyl)ethanol derivatives were tested for their affinity to the ifenprodil binding site of the NMDA receptor, their potency to inhibit [3H]MK801 binding and their NMDA-NR2B subtype selectivity. The (1S,1'S)-configurated series displayed the highest affinity to the ifenprodil binding site. A reasonable potency and NMDA-NR2B subtype selectivity was found for (1S,1'S)-4c (R1=Me, R2=OMe).

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.

Behavioural evaluation of long-term neurotoxic effects of NMDA receptor antagonists.

High doses of NMDA antagonists e.g. (+)MK-801 evoke neurodegeneration in retrosplenial cortex in rodents.

Neuroprotective effects of NS-7, voltage-gated Na+/Ca2+ channel blocker in a rodent model of transient focal ischaemia.

The aim of the present study was to characterize neuroprotective activity of NS- 7, a mixed voltage-gated sodium and calcium channel blocker in a model of transient focal ischaemia in rats. Ischaemia was induced by a 75 min reversible occlusion of middle cerebral artery (MCAo) using a nylon filament. NS-7 (0.

Neuroprotection by memantine against neurodegeneration induced by beta-amyloid(1-40).

Progressive neuronal loss and cognitive decline in Alzheimer's disease (AD) might be aggravated by beta-amyloid-enhanced excitotoxicity. Memantine is an uncompetitive NMDA receptor antagonist under clinical development for the treatment of AD. Memantine has neuroprotective actions in several in vitro and in vivo models.

PET studies of 18F-memantine in healthy volunteers.

Previous studies in mice and PET investigations in a Rhesus monkey showed that the regional uptake of 18F-memantine could be blocked by pharmacological doses of memantine and (+)-MK-801. In the present study, the binding characteristics of 18F-memantine was examined in five healthy volunteers. In humans, 18F-memantine was homogeneously distributed in gray matter i.

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

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.

In vitro and in vivo activities of aminoadamantane and aminoalkylcyclohexane derivatives against Trypanosoma brucei.

We reported recently that the bloodstream form of the African trypanosome, Trypanosoma brucei, is sensitive to the anti-influenza virus drug rimantadine. In the present report we describe the trypanocidal properties of a further 62 aminoadamantane and aminoalkylcyclohexane derivatives. Seventeen of the compounds were found to be more active than rimantadine, with four inhibiting growth in vitro of T.

Extracellular concentrations of taurine, glutamate, and aspartate in the cerebral cortex of rats at the asymptomatic stage of thioacetamide-induced hepatic failure: modulation by ketamine anesthesia.

Subclinical hepatic encephalopathy (SHE) was produced in rats by two intraperitoneal injections of TAA at 24 h intervals and the animals were examined 21 days later. Concentrations of the neuroactive amino acids taurine (Tau), glutamate (Glu) and aspartate (Asp), were measured in the cerebral cortical microdialysates of thioacetamide (TAA)-treated and untreated control rats. During microdialysis some animals were awake while others were anesthetized with ketamine plus xylazine.

NMDA channel blockers: memantine and amino-aklylcyclohexanes--in vivo characterization.

The previous overviews provided the basis for better therapeutic efficacy/tolerability of low to moderate affinity NMDA channel blockers. This prediction finds support in in vitro studies comparing protective and plasticity impairing effects (therapeutic vs. side-effect) of memantine and (+)MK-801.

Memantine and the amino-alkyl-cyclohexane MRZ 2/579 are moderate affinity uncompetitive NMDA receptor antagonists--in vitro characterisation.

There is general agreement that moderate affinity uncompetitive NMDA receptor antagonists combine good efficacy and tolerability in animal models of disturbances in glutamatergic transmission. There are several theories on which properties are important for this profile including 1, rapid access to the channel at the start of pathological overactivity 2, rapid, voltage-dependent relief of blockade during physiological synaptic activation and 3, partial untrapping. Merz has developed a series of novel uncompetitive NMDA receptor antagonists based on the cyclohexane structure.

Synthesis and structure-affinity relationships of 1,3, 5-alkylsubstituted cyclohexylamines binding at NMDA receptor PCP site.

A series of 1,3,5-alkylsubstituted cyclohexylamines 2 were synthesized as ligands for the N-methyl-D-aspartate (NMDA) receptor phencyclidine (PCP) binding site. Pure diastereomers with defined configuration of amino group 2-ax and 2-eq were obtained. The optimal size of 1,3,5-substituents was determined for cyclohexylamines 2 with an equatorial amino group in the lowest energy conformation using Hansch analysis.

No interaction of memantine with acetylcholinesterase inhibitors approved for clinical use.

The loss of cholinergic neurons within the basal forebrain of patients with Alzheimer's disease (AD) may underlie aspects of the dementia. Excessive activation of N-methyl-D-aspartate (NMDA) receptors may underlie the degeneration of cholinergic cells. New drug therapies have been designed to either enhance cholinergic function by inhibition acetylcholinesterase (AChE), e.

Increase of the duration of the anticonvulsive activity of a novel NMDA receptor antagonist using poly(butylcyanoacrylate) nanoparticles as a parenteral controlled release system.

A novel non-competitive NMDA receptor antagonist MRZ 2/576 is a potent but rather short-acting (5-15 min) anticonvulsant following intravenous administration to mice as estimated by the prevention of maximal electroshock induced convulsions. This is most probably due to a rapid elimination of the drug from the central nervous system by transport processes that are sensitive to probenecid. Intravenous administration of the drug bound to poly(butylcyanoacrylate) nanoparticles coated with polysorbate 80 prolongs the duration of the anticonvulsive activity in mice up to 210 min and after probenecid pre-treatment up to 270 min compared to 150 min with probenecid and MRZ 2/576 alone.

Memantine is a clinically well tolerated N-methyl-D-aspartate (NMDA) receptor antagonist--a review of preclinical data.

N-methyl-D-aspartate (NMDA) receptor antagonists have therapeutic potential in numerous CNS disorders ranging from acute neurodegeneration (e.g. stroke and trauma), chronic neurodegeneration (e.

L-ornithine-L-aspartate lowers plasma and cerebrospinal fluid ammonia and prevents brain edema in rats with acute liver failure.

Brain edema sufficient to cause intracranial hypertension and brain herniation remains a major cause of mortality in acute liver failure (ALF). Studies in experimental animal models of ALF suggest a role for ammonia in the pathogenesis of both encephalopathy and brain edema in this condition. As part of a series of studies to evaluate the therapeutic efficacy of ammonia-lowering agents, groups of rats with ALF caused by hepatic devascularization were treated with L-ornithine-L-aspartate (OA), an agent shown previously to be effective in reducing blood ammonia concentrations in both experimental and human chronic liver failure.

Amino-alkyl-cyclohexanes are novel uncompetitive NMDA receptor antagonists with strong voltage-dependency and fast blocking kinetics: in vitro and in vivo characterization.

The present study characterized the in vitro NMDA receptor antagonistic properties of novel amino-alkyl-cyclohexane derivatives and compared these effects with their ability to block excitotoxicity in vitro and MES-induced convulsions in vivo. The 36 amino-alkyl-cyclohexanes tested displaced [3H]-(+)-MK-801 binding to rat cortical membranes with K(i)s between 1.5 and 143 microM.

Fluorine-18 radiolabelling, biodistribution studies and preliminary PET evaluation of a new memantine derivative for imaging the NMDA receptor.

A synthetic method has been established for preparing [18F]1-amino-3-fluoromethyl-5-methyl-adamantane ([18F]AFA). Biodistribution of the radiotracer in mice showed high brain uptake. The peak uptake (3.

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.

Effect of the antioxidant Nicanartine on the proliferative and inflammatory response after experimental balloon angioplasty.

Background: Antioxidant treatment seems to reduce the development of restenosis after percutaneous transluminal angioplasty. In this study, the effect of Nicanartine, a new antioxidant drug with both antiproliferative and lipid-lowering properties, on the proliferative and inflammatory response after balloon angioplasty was investigated in a rabbit model of restenosis.

Methods: To induce pre-interventional plaques in the common carotid artery of 48 New Zealand White rabbits, electrostimulation was carried out for 28 days.

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.