dizocilpine-maleate and Nervous-System-Diseases

Ischemic stroke complicating with arrhythmia is one of the main causes of sudden death. To investigate the association between ischemic stroke-induced arrhythmia and the activity of paraventricular nucleus (PVN), we used Fos protein as an objective indicator to illustrate the functional state of PVN neurons in middle cerebral artery occlusion (MCAO) rats, in single intracerebroventricular injection of l-glutamate rats and in application of MK-801 before l-glutamate injection and MCAO rats.. The standard limb II electrocardiography was continuously recorded by a biological signal collecting and processing system. The experimental cerebral ischemic animal model was established by occluding the right middle cerebral artery. The Fos protein expression was detected by immunohistochemistry and Western blot.. The incidence of arrhythmia was significantly higher than that of controls (75.89% versus 0%), and Fos protein expression in the PVN also increased significantly in MCAO rats; both of them could be blocked by prior application of MK-801. Intracerebroventricular injection of l-glutamate induced changes in Fos protein expression and arrhythmia similar to that in the stroke, which could also be blocked by prior application of MK-801.. It was concluded that activation of the PVN in MCAO rats is likely mediated by glutamate via activation of N-methyl-D-aspartic acid (NMDA) receptors, which causes arrhythmias.

Topics: Animals; Arrhythmias, Cardiac; Disease Models, Animal; Dizocilpine Maleate; Electrocardiography; Gene Expression Regulation; Glutamic Acid; Heart Rate; Infarction, Middle Cerebral Artery; Injections, Intraventricular; Male; Nervous System Diseases; Neuroprotective Agents; Paraventricular Hypothalamic Nucleus; Proto-Oncogene Proteins c-fos; Rats; Rats, Wistar; Time Factors

N-methyl-D-aspartate (NMDA) glutamate receptors are regulators of fast neurotransmission and synaptic plasticity in the brain. Disruption of NMDA-mediated glutamate signaling has been linked to behavioral deficits displayed in psychiatric disorders such as schizophrenia. Recently, noncoding RNA molecules such as microRNAs (miRNAs) have emerged as critical regulators of neuronal functions. Here we show that pharmacological (dizocilpine) or genetic (NR1 hypomorphism) disruption of NMDA receptor signaling reduces levels of a brain-specific miRNA, miR-219, in the prefrontal cortex (PFC) of mice. Consistent with a role for miR-219 in NMDA receptor signaling, we identify calcium/calmodulin-dependent protein kinase II gamma subunit (CaMKIIgamma), a component of the NMDA receptor signaling cascade, as a target of miR-219. In vivo inhibition of miR-219 by specific antimiR in the murine brain significantly modulated behavioral responses associated with disrupted NMDA receptor transmission. Furthermore, pretreatment with the antipsychotic drugs haloperidol and clozapine prevented dizocilpine-induced effects on miR-219. Taken together, these data support an integral role for miR-219 in the expression of behavioral aberrations associated with NMDA receptor hypofunction.

Topics: Animals; Behavior, Animal; Biological Transport; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cell Line, Tumor; Dizocilpine Maleate; Gene Expression Regulation; Genetic Therapy; Male; Mice; Mice, Inbred C57BL; MicroRNAs; Nervous System Diseases; Protein Subunits; Receptors, N-Methyl-D-Aspartate; RNA, Messenger; Signal Transduction

Several studies involving postnatal administration of the N-methyl-D-aspartate (NMDA) antagonists, dizocilpine (MK-801; 3 x 0.5 mg/kg, at 08.00, 16.00 and 24.00 h) on Postnatal day 11, or Ketamine (1 x 50 mg/kg) or Ethanol (1 x 2.5 g/kg, Ethanol-Low, or 2 x 2.5 g/kg, 2-h interval, Ethanol-High) on Postnatal day 10, are described. Some mice from each treatment/vehicle group were sacrificed 24 h after NMDA antagonist treatment and brain regions were taken for fluoro-jade staining analysis. Functional analysis was initiated at 60 days of age. All three treatments inducing an antagonistic action at NMDA receptors, MK-801, Ketamine and Ethanol-High induced a similar pattern of initial hypoactivity followed by marked and lasting hyperactivity in the motor activity test chambers. In each case, the basal hyperactivity level was abolished by acute treatment with a low dose of D-amphetamine (0.25 mg/kg). All three treatments, MK-801, Ketamine and Ethanol-High, induced a deficit in acquisitive performance in the radial arm maze test of instrumental learning. The deficit induced by postnatal MK-801 was abolished by acute treatment with the low dose of D-amphetamine. All three treatments, MK-801, Ketamine and Ethanol-High, resulted in normal acquisitive performance during the first three test days in the circular swim with the submerged platform maintained in a constant position, but on the fourth test day, with the platform position shifted to a different "quadrant", induced marked deficits. Fluoro-jade staining analyses indicated a devastating cell degeneration in several brain regions of mice administered NMDA antagonists postnatally, including the hippocampus, frontal cortex, parietal cortex, and cerebellum. Severe cell degeneration in the laterodorsal thalamus due to Ethanol or diazepam (5 mg/kg) appeared not to affect the different aspects of function. The pattern of dysfunctional outcome and apoptotic cell loss following postnatal NMDA antagonist treatment offers a plausible similarity to the major aspects of 'syndromatic continuity' in ADHD, hyperactivity, inattention and impulsivity, thereby providing an interesting animal model of the disorder.

Topics: Animals; Animals, Newborn; Apoptosis; Attention Deficit Disorder with Hyperactivity; Central Nervous System Depressants; Central Nervous System Stimulants; Dextroamphetamine; Diazepam; Dizocilpine Maleate; Ethanol; Excitatory Amino Acid Antagonists; Female; Fluoresceins; Fluorescent Dyes; Hypnotics and Sedatives; Ketamine; Maze Learning; Mental Disorders; Mice; Motor Activity; Nerve Degeneration; Nervous System Diseases; Organic Chemicals; Pregnancy; Receptors, N-Methyl-D-Aspartate; Swimming; Weight Gain

The etiology of various age-related neurological diseases remains unknown. Sporadic forms ofAlzheimer's, Parkinson's and Lou Gehrig's disease have been linked to environmental factors that cause neuronal cell death either by excitotoxicity or by inducing oxidative stress. Our recent studies have demonstrated that various compounds not previously associated with these diseases, i.e. methionine sulfoximine (MSO), originally isolated from 'agenized' flour, and sitosterol glucoside (BSSG), isolated from the seed of the cycad, appear to be neurotoxins, likely acting by excitotoxic mechanisms. For these compounds, the primary excitotoxic effect appears to involve glutamate release followed by NMDA receptor activation. Lactate dehydrogenase assays demonstrate that both compounds cause rapid cell death in vitro. In addition, both compounds appear to alter antioxidant defense mechanisms, acting particularly on levels of reduced glutathione (GSH). In vivo application of MSO has historically been linked to behavioral abnormalities, including seizures, in various species. Our recent experiments have demonstrated that mice fed cycad flour containing sitosterol glucoside have severe behavioral abnormalities of motor and cognitive function, as well as significant levels of neurodegeneration in cortex, hippocampus, spinal cord and other CNS regions measured post mortem. The combined weight of excitotoxic action, in concert to a decline in antioxidant defenses, induced by molecules such as methionine sulfoximine and sitosterol glucoside is hypothesized to be causal to neuronal degeneration in various neurological diseases. Understanding the mechanisms of action of these and functionally related molecules may serve to focus attention on potential neurotoxins present in the human environment. Only once such molecules have been identified, can we begin to design appropriate pharmaceutical strategies to prevent or halt the progression of the age-related neurological diseases.

Topics: Animals; Behavior, Animal; Cerebral Cortex; Dizocilpine Maleate; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Flour; Glutamic Acid; Glutathione; Kynurenic Acid; L-Lactate Dehydrogenase; Male; Methionine Sulfoximine; Mice; Mice, Inbred Strains; N-Methylaspartate; Nervous System Diseases; Oxidative Stress; Plants, Toxic; Rats; Rats, Sprague-Dawley; Sitosterols

NMDA receptors, an ionotropic subtype of glutamate receptors (GluRs) forming high Ca(2+)-permeable cation channels, are composed by assembly of the GluRzeta subunit (NR1) with any one of four GluRepsilon subunits (GluRepsilon1-4; NR2A-D). In the present study, we investigated neuronal functions in mice lacking the GluRepsilon1 subunit. GluRepsilon1 mutant mice exhibited a malfunction of NMDA receptors, as evidenced by alterations of [(3)H]MK-801 binding as well as (45)Ca(2+) uptake through the NMDA receptors. A postmortem brain analysis revealed that both dopamine and serotonin metabolism were increased in the frontal cortex and striatum of GluRepsilon1 mutant mice. The NMDA-stimulated [(3)H]dopamine release from the striatum was increased, whereas [(3)H]GABA release was markedly diminished in GluRepsilon1 mutant mice. When (+)bicuculline, a GABA(A) receptor antagonist, was added to the superfusion buffer, NMDA-stimulated [(3)H]dopamine release was significantly increased in wild-type, but not in the mutant mice. GluRepsilon1 mutant mice exhibited an increased spontaneous locomotor activity in a novel environment and an impairment of latent learning in a water-finding task. Hyperlocomotion in GluRepsilon1 mutant mice was attenuated by treatment with haloperidol and risperidone, both of which are clinically used antipsychotic drugs, at doses that had no effect in wild-type mice. These findings provide evidence that NMDA receptors are involved in the regulation of behavior through the modulation of dopaminergic and serotonergic neuronal systems. In addition, our findings suggest that GluRepsilon1 mutant mice are useful as an animal model of psychosis that is associated with NMDA receptor malfunction and hyperfunction of dopaminergic and serotonergic neuronal systems.

Topics: Animals; Antipsychotic Agents; Biogenic Monoamines; Calcium; Corpus Striatum; Dizocilpine Maleate; Dopamine; Excitatory Amino Acid Antagonists; Frontal Lobe; GABA Antagonists; gamma-Aminobutyric Acid; Hippocampus; Learning; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Motor Activity; N-Methylaspartate; Nervous System Diseases; Neurons; Protein Subunits; Receptors, N-Methyl-D-Aspartate; Serotonin; Thalamus

In this study, we examined the effect of post-treatment with clozapine on the neuropathological changes in the rat retrosplenial cortex induced by the administration of non-competitive NMDA receptor antagonist dizocilpine ((+)-MK-801). The maximal increase in vacuolized neurons, which are representative of neuropathology, was observed 4 hours after a single injection of dizocilpine (0.5 mg/kg s.c.), with a complete reversal of the neuropathology after 16-24 hours. The administration of clozapine (10 mg/kg, i.p.,) 4 hours after the administration of dizocilpine significantly decreased the number of vacuolized neurons in the retrosplenial cortex 6, 8 or 10 hours after administration of dizocilpine, compared to vehicle-treated animals. Furthermore, the administration of clozapine (5, 10 or 20 mg/kg i.p.) 4 hours after the administration of dizocilpine produced a significant decrease in the number of vacuolized neurons in the retrosplenial cortex in a dose-dependent manner when measure 6 hours post-dizocilpine. These results show that neuropathological changes in the rat retrosplenial cortex produced by dizocilpine can be attenuated by post-treatment with clozapine.

Topics: Animals; Antipsychotic Agents; Cerebral Cortex; Clozapine; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Female; Limbic System; Nervous System Diseases; Neurons; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Vacuoles

Segmental ligation of spinal nerves in the rat induces a long-lasting hyperalgesia and allodynia that mimicks neuropathic conditions in humans. In the present study we attempted to determine whether supraspinal NMDA receptors contribute to the induction of the long-lasting hypersensitivity to noxious and innocuous mechanical stimulation following segmental ligation of spinal nerves in the rat. MK-801, an NMDA receptor antagonist, was microinjected into the rostroventromedial medulla (RVM) 15 min before or 25 min after the ligation of spinal nerves and mechanical hypersensitivity was assessed at various time points following surgery by determining the hindlimb withdrawal threshold to noxious and innocuous mechanical stimulation. A single dose of MK-801 administered prior to nerve ligation into the RVM significantly attenuated the development of mechanical hypersensitivity throughout the 2 week postoperative observation period, whereas corresponding administration of MK-801 immediately after the nerve ligation attenuated the development of mechanical hypersensitivity only during the first postoperative day but not later. The results indicate that NMDA receptors in the RVM are involved in triggering the enhanced sensitivity to mechanical stimulation induced by a nerve injury.

Topics: Animals; Dizocilpine Maleate; Hyperalgesia; Hypnotics and Sedatives; Ligation; Male; Medulla Oblongata; Microinjections; Motor Activity; Nervous System Diseases; Neuroprotective Agents; Pain Measurement; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Spinal Nerves

3-Nitropropionic acid (NPA), an inhibitor of succinate dehydrogenase, is dietary neurotoxin. It is not known if neurons and astrocytes differ in their vulnerability to NPA, therefore, we investigated its toxicity in primary cultures of cerebellar granule cells and astrocytes. NPA inhibited succinate dehydrogenase and tricarboxylic acid cycle activity to the same degree in neurons and astrocytes. Even so NPA acid was 16 times more toxic to neurons than to astrocytes (LC50: 0.7 and 11 mM, respectively). The neurotoxicity of NPA was mediated by NMDA-receptor activation, calcium influx, and formation of reactive oxygen species, as revealed by the protective effect of NMDA-receptor blockade, the accumulation of 45Ca, and the protective effect of N-t-butyl-alpha-phenylnitron (PBN), a scavenger of reactive oxygen species. Cytotoxic concentrations of NPA caused a reduction in the intracellular level of glutathione, which probably contributed to the oxidative damage in both neurons and astrocytes. The relative resistance of astrocytes to NPA appeared to be related to their low tricarboxylic acid cycle activity (5%-10% of that in neurons) and to the inability of NPA to cause astrocytic calcium overload. We conclude that NPA acid predominantly is an astrocyte-sparing neurotoxin.

Topics: Amino Acids; Animals; Astrocytes; Calcium; Cell Survival; Citric Acid Cycle; Cyclic N-Oxides; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Free Radical Scavengers; Glucose; Male; Nervous System Diseases; Neurons; Neurotoxins; Nitro Compounds; Nitrogen Oxides; Propionates; Rats; Rats, Wistar; Succinate Dehydrogenase

Neuronal death in neurodegenerative diseases may involve energy impairment leading to secondary excitotoxicity, and free radical generation. Potential therapies for the treatment of neurodegenerative diseases therefore include glutamate release blockers, excitatory amino acid receptor antagonists, agents that improve mitochondrial function, and free radical scavengers. In the present study we examined whether these strategies either alone or in combination had neuroprotective effects against striatal lesions produced by mitochondrial toxins. The glutamate release blockers lamotrigine and BW1003C87 significantly attenuated lesions produced by intrastriatal administration of 1-methyl-4-phenylpyridinium. Lamotrigine significantly attenuated lesions produced by systemic administration of 3-nitropropionic acid. Memantine, an N-methyl-D-aspartate antagonist, protected against malonate induced striatal lesions. We previously found that coenzyme Q10 and nicotinamide, and the free radical spin trap n-tert-butyl-alpha-(2-sulfophenyl)-nitrone (S-PBN) dose-dependently protect against lesions produced by intrastriatal injection of malonate. In the present study we found that the combination of MK-801 (dizocipiline) with coenzyme Q10 exerted additive neuroprotective effects against malonate. Lamotrigine with coenzyme Q10 was more effective than coenzyme Q10 alone. The combination of nicotinamide with S-PBN was more effective than nicotinamide alone. These results provide further evidence that glutamate release inhibitors and N-acetyl-D-aspartate antagonists can protect against secondary excitotoxic lesions in vivo. Furthermore, they show that combinations of agents which act at sequential steps in the neurodegenerative process can produce additive neuroprotective effects. These findings suggest that combinations of therapies to improve mitochondrial function, to block excitotoxicity and to scavenge free radicals may be useful in treating neurodegenerative diseases.

Topics: 1-Methyl-4-phenylpyridinium; Animals; Anticonvulsants; Coenzymes; Cyclic N-Oxides; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Free Radicals; Lamotrigine; Male; Malonates; Memantine; Mitochondria; Nervous System Diseases; Neuroprotective Agents; Neurotoxins; Niacinamide; Nitro Compounds; Nitrogen Oxides; Propionates; Pyrimidines; Rats; Rats, Sprague-Dawley; Spin Labels; Thallium; Triazines; Ubiquinone

Amino acid esters containing tertiary or quaternary nitrogen heterocycles were synthesized for dexanabinol (1) and evaluated as water-soluble prodrugs or congeners.. Syntheses were performed by conventional methods; stability studies in water, blood (rat, dog, human) and assay-media were performed by HPLC; NMDA receptor binding was determined by [3H] MK-801 displacement; neuroprotection and neurotoxicity studies were performed in cortical cell cultures.. 7-morpholino and N-methylpiperazino acetates and butyrates and the respective N-methylmorpholinium and piperazinium iodides as well as a 3'-N-methyl morpholino butyrate and the corresponding N-methyl quaternary type derivative were synthesized. All compounds were relatively soluble in water or 10% aqueous ethanol. The examined derivatives were stable in water and generally less stable in blood and assay media. Quaternary derivatives of dexanabinol were found to hydrolyze faster. All examined compounds inhibited NMDA receptor and protected neurons against NMDA induced toxicity. Neuroprotection (with one exception) is however attributed to the parent 1 released by hydrolysis during the assay.. Some of the examined derivatives could be further evaluated as prodrugs on congeners of 1.

Topics: Animals; Binding, Competitive; Cells, Cultured; Dizocilpine Maleate; Dogs; Dronabinol; Drug Stability; Excitatory Amino Acid Antagonists; Humans; Hydrolysis; Morpholines; Nervous System Diseases; Neurons; Neuroprotective Agents; Piperazines; Prodrugs; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Solubility; Structure-Activity Relationship; Tritium; Water

Antagonists of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor are of considerable interest for various neurotherapeutic purposes, including preventing neuronal degeneration in stroke and CNS trauma, suppressing neuropathic pain and preventing the development of tolerance to opiate analgesics. Unfortunately, NMDA antagonists can cause potentially serious side effects, including acute neurodegenerative changes in corticolimbic regions of the adult rat brain and psychotic reactions in adult humans. We have been investigating the mechanisms underlying the neuropathological changes in rat brain and exploring methods of suppressing or preventing such changes. Here we report that alpha 2 adrenergic agonists can prevent NMDA antagonist neurotoxicity. Therefore, administering alpha 2 adrenergic agonists together with NMDA antagonists may be a valuable strategy for preventing adverse side effects of NMDA antagonists and making these agents safer for various neurotherapeutic purposes.

Topics: Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists; Animals; Dizocilpine Maleate; Female; Nervous System Diseases; Rats; Receptors, N-Methyl-D-Aspartate; Yohimbine

The activation of glutamate receptors by endogenuous glutamate has been implicated in the processes that underlie cell loss associated with ischemia and trauma and in the development of some neurodegenerative diseases. The antagonism of NMDA-sensitive glutamate receptors may therefore have therapeutic applications. The present study compared the side effects and neuroprotective potency of 1-aminoadamantane hydrochloride (amantadine), 1-amino-3,5-dimethyladamantane hydrochloride (memantine), and (+)-5-methyl-10,11-dihydro-5H-debenzocyclhepten-5,10-imine maleate ((+)-MK-801) against NMDA injected directly into the nucleus basalis magnocellularis of rats. Each drug significantly attenuated the loss of nucleus basalis magnocellularis cholinergic cells. The ED50s were respectively 0.077, 2.81 and 43.5 mg/kg for (+)-MK-801, memantine and amantadine, giving a relative potency ratio of 1:36:565. The ratio of the ED50 for the side effects observed, including ataxia, myorelaxation and stereotypy, and the ED50 for neuroprotective ability, was highest for memantine and the lowest for (+)-MK-801. The results suggest that a potential neuroprotective action of NMDA receptor antagonists, memantine and amantadine in particular, can be seen at low doses lacking side effects.

Topics: Amantadine; Animals; Basal Ganglia; Cerebral Cortex; Choline O-Acetyltransferase; Dizocilpine Maleate; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Male; Memantine; N-Methylaspartate; Nervous System Diseases; Neuroprotective Agents; Rats; Receptors, N-Methyl-D-Aspartate

In the rat, loose ligation of the sciatic nerve results in behavioural signs of hyperalgesia reminiscent of neuropathy in man. A further rat model, of chronic inflammatory hyperalgesia, is produced by intraplantar administration of Freund's complete adjuvant (FCA). We report here that preemptive administration of a non-competitive antagonist of the glutamate N-methyl-D-aspartate (NMDA) receptor, MK-801 (0.3 mg kg-1, s.c.) 30 min prior to and twice daily for a further 8 days following loose ligation of the sciatic nerve, blocks the development of mechanical hyperalgesia measured 27 days later. In contrast, MK-801 administration using the same dosing regimen did not significantly inhibit the hyperalgesia apparent 15 days following i.pl. administration of FCA. Our results suggest that the mechanisms responsible for the development of mechanical hyperalgesia associated with chronic nerve injury and chronic inflammation differ.

Topics: Animals; Chronic Disease; Dizocilpine Maleate; Freund's Adjuvant; Hyperalgesia; Inflammation; Male; N-Methylaspartate; Nervous System Diseases; Nociceptors; Physical Stimulation; Rats; Receptors, N-Methyl-D-Aspartate; Sciatic Nerve

Protective effects of NMDA antagonists on dopaminergic and serotonergic neurotoxicity produced by methamphetamine (MA) were examined. Four injections of MA (7.5 mg/kg, s.c., at 2 h intervals) caused significant decrements (40-60% of control values) in levels of dopamine (DA) and its metabolites in the rat striatum and levels of serotonin (5-HT) and its metabolite in the medial prefrontal cortex, nucleus accumbens, striatum, anterior hypothalamus, amygdala and hippocampus. These decreases in DA, 5-HT and their metabolites were prevented by pretreatment with MK-801, a noncompetitive N-methyl-D-aspartate (NMDA) antagonist, or D-CPP-ene (SDZ EAA 494), a competitive NMDA antagonist. The results suggest that NMDA receptors play a role for MA-induced serotonergic damage in various brain regions as well as dopaminergic damage in the striatum.

Topics: Animals; Brain Chemistry; Chromatography, High Pressure Liquid; Dizocilpine Maleate; Dopamine; Hydroxyindoleacetic Acid; Male; Methamphetamine; N-Methylaspartate; Nervous System Diseases; Piperazines; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Serotonin

LY274614, 3SR,4aRS,6SR,8aRS-6-[phosphonomethyl]decahydr oisoquinoline-3- carboxylic acid, has been described as a potent antagonist of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor. Here its ability to antagonize the prolonged depletion of dopamine in the striatum by amphetamine in iprindole-treated rats is reported. A single 18.4 mg/kg (i.p.) dose of (+/-)-amphetamine hemisulfate, given to rats pretreated with iprindole, resulted in persistent depletion of dopamine in the striatum 1 week later. This prolonged depletion of dopamine in the striatum was antagonized by dizocilpine (MK-801, a non-competitive antagonist of NMDA receptors) or by LY274614 (a competitive antagonist of NMDA receptors). The protective effect of LY274614 was dose-dependent, being maximum at 10-40 mgkg (i.p.). A 10 mg/kg dose of LY274614 was effective in antagonizing the depletion of dopamine in the striatum, when given as long as 8 hr prior to amphetamine but not when given 24 hr prior to amphetamine. Depletion of dopamine in the striatum was also antagonized when LY274614 was given after the injection of amphetamine; LY274614 protected when given up to 4 hr after but not when given 8 or 24 hr after amphetamine. The prolonged depletion of dopamine in the striatum in mice, given multiple injections of methamphetamine, was also antagonized dose-dependently and completely by LY274614. The data strengthen the evidence that the neurotoxic effect of amphetamine and related compounds toward nigrostriatal dopamine neurons involves NMDA receptors and that LY274614 is an NMDA receptor antagonist with long-lasting in vivo effects in rats.

Topics: Amino Acids; Amphetamine; Animals; Corpus Striatum; Dizocilpine Maleate; Dopamine; Dose-Response Relationship, Drug; Iprindole; Isoquinolines; Male; Methamphetamine; Mice; Nervous System Diseases; Neurons; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate

Previous studies from this laboratory demonstrated that (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801), an N-methyl-D-aspartate (NMDA) receptor antagonist, did not prevent neurotoxicity to dopaminergic neurons in mice produced by systemic treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). However, Turski et al. [Nature 349, 414-418 (1991)] reported that extended treatment of rats with NMDA receptor antagonists (six injections at 4-h intervals) did prevent the loss of nigral dopaminergic neurons resulting from an intranigral infusion of 1-methyl-4-phenylpyridinium (MPP+), the neurotoxic metabolite of MPTP. The present studies examined if a similar extended treatment with MK-801 would protect mice from the neurotoxicity of systemically administered MPTP. Six intraperitoneal injections of MK-801 given at 4-h intervals did not protect mice against the MPTP-induced neostriatal dopamine loss measured 1 week after treatment. In other experiments, designed to replicate and expand on the results of Turski et al. (1991), the extended treatment of rats with MK-801 did not prevent MPP(+)-induced cell loss in the infused substantia nigra pars compacta or the dopamine depletion in the ipsilateral neostriatum at 7-11 days after MPP+ infusion. These results do not support the hypothesis that NMDA receptors are involved with MPTP/MPP(+)-induced neurodegeneration.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 1-Methyl-4-phenylpyridinium; Animals; Dizocilpine Maleate; Dopamine; Male; Mice; Mice, Inbred Strains; Nervous System Diseases; Rats; Rats, Inbred Strains; Substantia Nigra

Protection by the NMDA receptor antagonist MK-801 against transient spinal cord ischemia-induced hypersensitivity was studied in rats. The spinal ischemia was initiated by vascular occlusion resulting from the interaction between the photosensitizing dye Erythrosin B and an argon laser beam. The hypersensitivity, termed allodynia, where the animals reacted by vocalization to nonnoxious mechanical stimuli in the flank area, was consistently observed during several days after induction of the ischemia. Pretreatment with MK-801 (0.1-0.5 mg/kg, iv) 10 min before laser irradiation dose dependently prevented the occurrence of allodynia. The neuroprotective effect of MK-801 was not reduced by maintaining normal body temperature during and after irradiation. There was a significant negative correlation between the delay in the administration of MK-801 after irradiation and the protective effect of the drug. Histological examination revealed slight morphological damage in the spinal cord in 38% of control rats after 1 min of laser irradiation without pretreatment with MK-801. No morphological abnormalities were observed in rats after pretreatment with MK-801 (0.5 mg/kg). The present results provide further evidence for the involvement of excitatory amino acids, through activation of the NMDA receptor, in the development of dysfunction following ischemic trauma to the spinal cord.

Topics: Amino Acids; Animals; Dizocilpine Maleate; Female; Ischemia; Lasers; Nervous System Diseases; Pain; Radiation Injuries, Experimental; Rats; Rats, Inbred Strains; Receptors, Amino Acid; Receptors, Cell Surface; Sensation; Sensory Thresholds; Spinal Cord

1. The effect of a novel, highly potent and selective kappa-opioid receptor agonist, GR89696, has been evaluated in two animal models of cerebral ischaemia: transient bilateral carotid artery occlusion in the Mongolian gerbil and permanent, unilateral middle cerebral artery occlusion in the mouse. 2. In the Mongolian gerbil model, administration of GR89696 (3 to 30 micrograms kg-1, s.c.), immediately before and at 4 h after insult, produced a dose-dependent reduction in the hippocampal CA1 neuronal cell loss resulting from a 7-min bilateral carotid occlusion. Similar effects were obtained with two other kappa-agonists, GR86014 (1 mgkg-1, s.c.) and GR91272 (1 mgkg-1, s.c.). The neuroprotective effect of GR89696 was completely blocked by prior administration of the opioid receptor antagonist, naltrexone, at 10 mgkg-1, s.c. Repeated post-treatment with GR89696 (100 micrograms kg-1, s.c.) or GR44821 (10 mgkg-1, s.c.) was also effective in protecting completely the hippocampal CA1 neurones from ischaemia-induced neurodegeneration. 3. In the permanent, unilateral middle cerebral artery occlusion model in the mouse, repeated administration of GR89696 at 300 micrograms kg-1, s.c. produced a 50% reduction in cerebrocortical infarct volume. In these experiments GR89696 was dosed 5 min, 4, 8, 12, 16, 20 and 24 h after occlusion on the first day and then three times daily for the next three days. GR89696 (300 micrograms kg-1) also produced a significant 35% reduction in infarct volume in this model when the initiation of dosing was delayed for 6 h after the insult. 4. The results indicate that the potent kappa-opioid receptor agonist, GR89696, is neuroprotective in both global and focal cerebral ischaemia models and suggest that, with this class of compound, there may be a considerable time window for pharmacological intervention.

Topics: Animals; Brain Ischemia; Carotid Artery Diseases; Dizocilpine Maleate; Dose-Response Relationship, Drug; Female; Gerbillinae; Male; Mice; Nervous System Diseases; Piperazines; Pyrrolidines; Receptors, Opioid; Receptors, Opioid, kappa

Evidence from animal stroke models suggests that the proximate cause of neuronal degeneration after ischemia is massive release of glutamate and activation of NMDA receptors. However, in the physiologic presence of oxygen and glucose in the rat hippocampal slice preparation, the neurotoxicity of glutamate, as measured by inhibition of protein synthesis, requires high concentrations and is not prevented by glutamate receptor antagonists. Thus, the NMDA receptor-mediated neurotoxic effects of extracellular glutamate accumulation during ischemia might depend on additional factors, such as neuronal depolarization. In the experiments reported here, slices were exposed to glutamate in a medium intended to mimic the ionic conditions found during ischemia, high potassium (128 mM) and low sodium (26 mM). This depolarizing medium itself inhibited protein synthesis in a manner which was partially mediated by NMDA receptor activation, since it was significantly reversed by the noncompetitive NMDA antagonist, MK-801. Furthermore, the effect of glutamate under depolarizing conditions was also significantly decreased by MK-801, suggesting that glutamate was acting at NMDA receptors. Thus, depolarization appears to enhance the sensitivity of neurons to toxic NMDA receptor activation by glutamate. Under conditions that mimic ischemia, hypoxia plus hypoglycemia, a similar protective effect of NMDA receptor antagonists was observed. Depolarization and ischemia both appeared to attenuate the neurotoxicity of non-NMDA receptor agonists. It appears that under conditions of normal glucose and oxygen, high concentrations of bath applied glutamate inhibit protein synthesis at sites other than the NMDA receptor. However, when the Na+ gradient is decreased, as occurs during ischemia, glutamate's NMDA effects predominate. These findings suggest that ionic shifts may play a central role in permitting NMDA receptor-mediated ischemic neuronal damage.

Topics: Animals; Brain Ischemia; Dizocilpine Maleate; Glucose; Glutamates; Hippocampus; In Vitro Techniques; Membrane Potentials; Nervous System Diseases; Neuromuscular Depolarizing Agents; Neurons; Oxygen; Potassium; Rats; Receptors, Glutamate; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Sodium; Time Factors

Neurotoxicity of glutamate in conjunction with subcritical hypoxia was determined in vitro using hippocampal neurons obtained from 18-day-old rat fetuses. Neurons were plated at a low density and maintained for 3 days in a chemically defined medium without glutamate. When glutamate + was added after subcritical hypoxic stress, a low dose of glutamate, even at 10 microM, could cause significant neuronal loss in the following 24 h. The observed neurotoxicity to low glutamate dose (10-100 microM) could completely be prevented by 5 microM of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). This protective effect of CNQX was more potent than that of MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate). The mechanism by which glutamate is transformed from a neurotransmitter to a neurotoxin is discussed.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Female; Glutamates; Glutamic Acid; Hippocampus; Hypoxia; Nervous System Diseases; Neurons; Pregnancy; Quinoxalines; Rats; Rats, Inbred Strains; Receptors, AMPA; Receptors, Kainic Acid; Receptors, Neurotransmitter

Thrombolytic therapy is likely to be effective in some patients with stroke, but further improvements may require combination treatment with neuroprotective agents that can be given rapidly with relative safety. We tested the effects of tissue plasminogen activator (t-PA) with the glutamate antagonist MK-801 or the calcium channel blocker nimodipine in an embolic stroke model. We found that MK-801, followed by t-PA, was more effective than t-PA alone in reducing neurologic damage. Nimodipine plus t-PA was not better than t-PA alone. Combined glutamate antagonist and thrombolytic therapy may provide increased efficacy and safety for stroke treatment.

Topics: Animals; Cerebrovascular Disorders; Dizocilpine Maleate; Drug Therapy, Combination; Excitatory Amino Acid Antagonists; Glutamic Acid; Intracranial Embolism and Thrombosis; Nervous System Diseases; Nimodipine; Rabbits; Tissue Plasminogen Activator

Aminooxyacetic acid (AOAA) is an inhibitor of several pyridoxal phosphate-depedent enzymes in the brain. In the present experiments intrastriatal injections of AOAA produced dose-dependent excitotoxic lesions. The lesions were dependent on a pyridoxal phosphate mechanisms because pyridoxine blocked them. The lesions were blocked by the noncompetitive N-methyl-D-aspartate (NMDA) antagonist MK-801 and by coinjection of kynurenate, a result indicating an NMDA receptor-mediated excitotoxic process. Electrophysiologic studies showed that AOAA does not directly activate ligand-gated ion channels in cultured cortical or striatal neurons. Pentobarbital anesthesia attenuated the lesions. AOAA injections resulted in significant increases in lactate content and depletions of ATP levels. AOAA striatal lesions closely resemble Huntington's disease both neurochemically and histologically because they show striking sparing of NADPH-diaphorase and large neurons within the lesioned area. AOAA produces excitotoxic lesions by a novel indirect mechanism, which appears to be due to impairment of intracellular energy metabolism, secondary to its ability to block the mitochondrial malate-aspartate shunt. These results raise the possibility that a regional impairment of intracellular energy metabolism may secondarily result in excitotoxic neuronal death in chronic neurodegenerative illnesses, such as Huntington's disease.

Topics: Aminooxyacetic Acid; Animals; Cells, Cultured; Cerebral Cortex; Corpus Striatum; Dizocilpine Maleate; Dose-Response Relationship, Drug; Energy Metabolism; Injections, Intraventricular; Male; Nervous System Diseases; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate

The two heterocyclic aspartic acid and glutamic acid analogues derived from ibotenic acid, (RS)-2-amino-2-(3-hydroxy-5-methylisoxazol-4-yl)acetic acid (AMAA) and (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) have previously been shown to be selective agonists at N-methyl-D-aspartic acid (NMDA) and AMPA receptors, respectively. Two analogous series of AMAA and AMPA derivatives have now been synthesized and characterized in receptor binding studies and neuropharmacological experiments. AMAA was shown to be a very potent NMDA agonist in cortical tissue preparations, slightly more active than NMDA, whereas N-methyl-AMAA was less potent and N,N-dimethyl-AMAA almost inactive. (RS)-3-Hydroxy-4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridine-4-carboxylic acid (4-HPCA), a bicyclic analogue of AMAA, exhibited weak NMDA agonist effects similar to those of quinolinic acid. The relative potency as AMPA receptor agonists of AMPA, N-methyl-AMPA, N,N-dimethyl-AMPA and (RS)-3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-5-carboxylic acid (5-HPCA), a bicyclic analogue of AMPA, was distinctly different from that of the AMAA series of compounds as NMDA agonists. The pharmacological and toxicological profiles of AMAA and 4-HPCA, compared with those of quinolinic acid, are consistent with heterogeneity of NMDA receptors.

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Cerebral Cortex; Choline O-Acetyltransferase; Corpus Callosum; Dizocilpine Maleate; Ibotenic Acid; In Vitro Techniques; Nervous System; Nervous System Diseases; Piperazines; Rats; Receptors, Glycine; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Stimulation, Chemical

Acute intrastriatal injection of quinolinic acid (QA) caused a significant reduction of choline acetyltransferase (ChAT) and glutamic acid decarboxylase (GAD) activities as well as a decrease of the specific binding of [3H]hemicholinium-3. Pretreatment with MK-801 completely blocked the QA-induced neurotoxicity. Continuous infusion of QA into the lateral ventricle resulted in a reduction of hippocampal and cortical ChAT activities while GAD activities were unchanged. These results suggest that continuous infusion of QA into the lateral ventricle could be a useful technique for the study of chronic neurodegenerative diseases including Alzheimer's disease.

Topics: Animals; Brain; Cerebral Cortex; Choline O-Acetyltransferase; Corpus Striatum; Dizocilpine Maleate; Glutamate Decarboxylase; Hemicholinium 3; Hippocampus; Injections; Injections, Intraventricular; Male; Nervous System Diseases; Quinolinic Acid; Quinolinic Acids; Rats; Rats, Inbred Strains

The purpose of the present study was to test whether the anticonvulsant, memantine (1-amino-3,5-dimethyladamantane), can protect neurons against hypoxic or ischemic damage. To this end, we used a rat model of transient forebrain ischemia and cultured neurons from chick embryo cerebral hemispheres. Ischemia was induced for 10 min by clamping both carotid arteries and lowering the mean arterial blood pressure to 40 mm Hg; the rats were allowed to recover for 7 days. Cultured neurons were made hypoxic with 1 mmol/l NaCN added to the incubation medium for 30 min followed by a recovery period of 3 days. The possible effects of memantine were compared with those produced by a typical non-competitive NMDA antagonist, dizocilpine. Similar effects were obtained with both drugs. The drugs reduced the damage caused by transient ischemia to neurons of the hippocampal CA1 subfield. Memantine (10 and 20 mg/kg) had a dose-dependent effect when administered intraperitoneally to the rats 1 h before ischemia. Dizocilpine was active in this model at a dosage of 1 mg/kg. When administered after ischemia, 10 mg/kg memantine significantly protected CA1 neurons against ischemic damage. Furthermore, the drugs protected cultured neurons against hypoxic damage. The lowest effective concentration was 0.1 mumol/l for dizocilpine and 1 mumol/l for memantine. Thus, memantine possesses neuroprotective activity but is less potent than dizocilpine.

Topics: Adenosine Triphosphate; Animals; Brain Ischemia; Cell Hypoxia; Cells, Cultured; Chick Embryo; Dizocilpine Maleate; Memantine; Nerve Tissue Proteins; Nervous System Diseases; Neurons; Potassium Cyanide; Rats; Rats, Inbred Strains

The in vivo neurophysiological interactions of the non-competitive NMDA receptor antagonist MK801 with the High Pressure Neurological Syndrome have been investigated in the primate Papio anubis. A hyperbaric chamber was used to achieve environmental pressures of 61 ATA (atmospheres absolute) over a period of 5 hr. Eight animals underwent 2 compressions each, one following pretreatment with 0.03 mg/kg (i.v.) MK801, the other a control. Half of the animals received MK801 on their first exposure. Mild signs of the high pressure neurological syndrome, e.g. paw and limb tremor were first observed between 10 and 20 ATA and more severe signs, e.g. whole body tremor, myoclonus and vomiting, appeared after 50 ATA. The onset pressures for the various signs were increased by 10-17 ATA when the animals received MK801 (P = 0.06) and the severity of the signs, over the whole range of pressures at which they appeared, was significantly reduced (P less than 0.001). Additional experiments showed that MK801 afforded considerable protection, at pressures up to 81 ATA, but doses larger than those used for the main experiment produced signs of tranquilisation and sedation. Changes in the EEG were observed in channels associated with the frontal, parietal and occipital regions. Amplitude and frequency spectra were calculated and trends with pressure in the 4 conventional wavebands were analysed. The most striking change was a decrease in amplitude of delta waves (P less than 0.001), which was ameliorated by MK801 (P less than 0.001).

Topics: Animals; Atmospheric Pressure; Dizocilpine Maleate; Electroencephalography; Electromyography; Female; Nervous System Diseases; Papio; Syndrome; Tremor

The ability of MK-801 to protect striatal neurons from the excitotoxic action of quinolinic acid was evaluated by means of apomorphine-induced rotational behavior and by measurement of striatal choline acetyltransferase (ChAT) and glutamic acid decarboxylase (GAD) activity, neurochemical markers for cholinergic and GABAergic neurons, respectively. Animals with a unilateral quinolinic acid lesion of the striatum exhibited a vigorous rotational response when challenged with apomorphine (0.5 mg/kg, s.c.) 6 days later and were found to have an 88 90% depletion of striatal ChAT and GAD activity. Treatment with a high dose of MK-801 (10 mg/kg, i.p.) prior to intrastriatal injection of quinolinic acid eliminated the subsequent rotational response to apomorphine and resulted in complete protection of striatal ChAT and GAD activity. Lower doses of MK-801 (1, 3 and 5 mg/kg, i.p.) failed to significantly reduce the rotational response to apomorphine but provided partial, dose-dependent protection of both ChAT and GAD activity. The rotational response to apomorphine correlated with the percent reduction in both ChAT activity (r = 0.57, P less than 0.0005) and GAD activity (r = 0.49, P less than 0.0005). Rotational behavior may thus provide a means to evaluate the functional integrity of the striatum.

Topics: Animals; Anticonvulsants; Apomorphine; Choline O-Acetyltransferase; Corpus Striatum; Dibenzocycloheptenes; Dizocilpine Maleate; Glutamate Decarboxylase; Male; Nervous System Diseases; Pyridines; Quinolinic Acid; Quinolinic Acids; Rats; Rats, Inbred Strains; Stereotyped Behavior