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At least 613 records · Page 34Linked to original sources
PubMed1997

Regionally different effects of scopolamine on NMDA antagonist-induced heat shock protein HSP70.

Using immunohistochemical technique, we investigated the regionally different roles of muscarinic receptors in the induction of HSP-70 by NMDA receptor antagonists. The administration of memantine and phencyclidine induced HSP-70 in the retrosplenial cortex of rat brain. Pretreatment with the muscarinic receptor antagonist scopolamine (0.1-1 mg/kg) blocked induction of HSP-70 in layer III of the retrosplenial cortex. However, induction of HSP-70 in layer V was augmented by scopolamine. These results suggest a regional difference in the mechanism of neurotoxicity induced by NMDA receptor antagonists.

Animals↗
PubMed2001

Effects of a novel uncompetitive NMDA receptor antagonist, MRZ 2/579 on ethanol self-administration and ethanol withdrawal seizures in the rat.

It has been repeatedly reported that NMDA receptors may contribute to ethanol-induced discriminative stimulus effects and withdrawal syndrome. However, the role of NMDA receptors in the reinforcing properties of ethanol remains unclear. The aim of the present study was to evaluate effects of the novel low-affinity, uncompetitive NMDA receptor antagonist, 1-amino-1,3,3,5,5-pentamethyl-cyclohexane hydrochloride (MRZ 2/579), on ethanol self-administration and ethanol withdrawal-associated seizures in rats. Both an operant (lever pressing for ethanol) and non-operant two-bottle choice setups were employed to initiate ethanol self-administration. In another procedure, forced treatment with high doses (9--15 g/kg/day) was used to induce physical dependence on ethanol. MRZ 2/579 delivered chronically by osmotic minipumps (9.6 mg/day, s.c.) did not alter either operant or non-operant ethanol drinking behaviour in a maintenance phase of ethanol self-administration. In contrast, repeated daily injections of the drug (5 mg/kg, i.p.) led to a progressive decrease in operant responding for ethanol. MRZ 2/579 (0.5--7.5 mg/kg, i.p.) and another low-affinity NMDA receptor antagonist, memantine (1--10 mg/kg, i.p.) dose-dependently suppressed ethanol withdrawal seizures with efficacies comparable with that of a standard benzodiazepine derivative, diazepam. The results of the present study indicate that: (i) intermittent administration of MRZ 2/579 may lead to a gradual decrease of operant responding for ethanol; and (ii) the group of low-affinity uncompetitive NMDA receptor antagonists may be an interesting alternative to benzodiazepines in the treatment of alcohol withdrawal.

Alcohol Drinking↗
PubMed2002

NMDA receptor antagonists to characterize rat renal organic cation transporter function.

We hypothesized that uncompetitive NMDA glutamate receptor antagonists memantine (2,5-dimethyl-1-adamantanamine), and amino-alkyl-cyclohexane compounds: MRZ 2/579 (1-amino-1,3,3,5,5-pentamethylcyclohexane HCl), MRZ 2/600 (1-amino-1-ethyl-3,3,5,5-tetramethylcyclohexane HCl), and MRZ 2/615 (1-amino-1,3,5,5-tetramethyl-3-ethylcyclohexane HCl), all derivatives of amantadine (1-adamantanamine HCl), would inhibit the energy-dependent uptake of amantadine into rat renal tubules. All compounds displayed a concentration-dependent inhibition of amantadine uptake in the proximal and distal renal tubules. MRZ 2/579 showed a novel distal tubule selectivity of inhibition (P < 0.001). At a therapeutic amantadine concentration, bicarbonate-dependent transporter inhibition selectivity was observed with all compounds (P < 0.05) except MRZ 2/600, the only compound with a sterically bulky group next to the amino group of the cyclohexane ring structure. Steric hindrance around the ionized amino group of the cyclohexane ring appears to prevent bicarbonate-mediated organic cation transport. Furthermore, the distal tubule inhibition selectivity with MRZ 2/579 provides a novel tool to study the relative importance of organic cation transporters (OCTs) in proximal vs. distal renal tubules.

Amantadine↗
PubMed1999

Low-affinity NMDA receptor channel blockers inhibit acquisition of intravenous morphine self-administration in naive mice.

Experimental evidence suggests that NMDA receptor antagonists modulate behavioral effects of morphine in models assessing abuse potential of drugs. The present study sought to evaluate the ability of NMDA receptor channel blockers to affect the acquisition of morphine i.v. self-administration in drug- and experimentally naive mice. DBA/2 mice were allowed to self-administer morphine (0.125-4.0 mg/ml) or saline during the 30-min test. Each nose-poke of the active mouse resulted in a 1.6-microl infusion to both the active mouse and the passive (yoked control) mouse. In vehicle-treated mice, differences between operant activity of active and passive mice were most obvious when active mice were allowed to self-inject morphine at the concentration of 0.5 mg/ml (the optimum concentration). Pretreatment with MRZ 2/579 (1-amino-1,3,3,5,5-pentamethyl-cyclohexan hydrochloride; 1, 3.2 and 10 mg/kg) shifted the optimum concentration to 0.75 mg/ml. Memantine (1-amino-3,5-dimethyladamantane hydrochloride; 0.3, 1, 3.2 and 10 mg/kg) suppressed both the morphine intake and the difference in nose-poke activity of active vs. passive mice across all tested concentrations of morphine. Dizocilpine ((+)-5-methyl-10,11-dihydro-5H-dibenzocyclohepten-5,10-imine maleate; 0.1 mg/kg) was ineffective. Taken together with earlier reports, the present results suggest that low-affinity NMDA receptor channel blockers--in contrast to dizocilpine--attenuate the rewarding potential of morphine.

Analysis of Variance↗
PubMed1998

Role of Na+/Ca2+ exchange in regulation of neuronal Ca2+ homeostasis requires re-evaluation.

In cultured rat cerebellar granule cells an inhibition of plasma membrane Na+/Ca2+ exchange by removal of external Na+ (replacement with NMDG) caused an increase in [Ca2+]i at rest and a considerable delay in [Ca2+]i recovery from Glu-imposed [Ca2+]i load. These effects did not result from Ca2+ influx through reversed Na+/Ca2+ exchange since they were readily abolished or prevented by using the NMDA receptor inhibitor AP-5 (100 microM) or the NMDA channel blocker memantine (25-50 microM). The effect of Na+/NMDG replacement could be enhanced by: (1) an increase in cytoplasmic Na+ concentration by monensin pretreatment of neurons; (2) external alkalinity, pH 8.5; (3) blockade of the mitochondrial Ca2+ uptake with antimycin plus oligomycin. Analysis of the data obtained led us to conclude that all the changes in [Ca2+]i caused by Na+/NMDG replacement are mainly due to a release of endogenous Glu (reversed Glu uptake) and a subsequent Ca2+ influx through NMDA receptor-mediated channels.

2-Amino-5-phosphonovalerate↗
PubMed1996

Apparent independent action of nimodipine and glutamate antagonists to protect cultured neurons against glutamate-induced damage.

A disturbed cellular calcium homeostasis is suggested to play a pivotal role in neuronal damage. Energy deficiency causes depolarization of the neuronal membrane and Ca2+ enters the cells through different ion channels, the voltage-sensitive L-type Ca2+ channels and the NMDA-operated channels being the main gates. In the present study we used primary cultures of rat hippocampal neurons to demonstrate that the dihydropyridine calcium antagonist nimodipine, the non-competitive NMDA antagonists dizocilpine and memantine, as well as the AMPA antagonist NBQX (2,3-dihydroxy-6-nitro -7-sulfamoyl-benzo(F)quinoxaline), attenuate the glutamate-induced neuronal damage dose-dependently. Nimodipine applied simultaneously with NMDA-antagonists and NBQX, respectively, resulted in somewhat greater neuroprotection of glutamate-treated neurons compared with the effects of these agents applied singly. The type of interaction is best described by an independent action in combination, which means that the relative effects of nimodipine were not enhanced. Therefore, it can be considered as a lack of potentiation.

Animals↗
PubMed2001

The role of neurochemical mechanisms of ventromedial hypothalamus in various models of anxiety in rats.

Microinjections of glutamic acid, serotonin, and sulpiride in the ventromedial hypothalamus reduced anxiety in an illuminated platform avoidance task in rats, while dopamine, apomorphine, picrotoxin, and memantine increased it. Similar injections of phenylephrine and yohimbine reduced anxiety in threatening situation task only, while GABA reduced it in both tasks. It is suggested that various emotional and stress phenotypes are realized through functionally different neurochemical mechanisms of ventromedial hypothalamus.

Adrenergic Agents↗
PubMed2003

The ability of new non-competitive glutamate receptor blockers to weaken motor disorders in animals.

The ability of mono- and dicationic phenylcyclohexyl derivatives, which are non-competitive glutamate antagonists, to prevent convulsions induced in mice by intragastric NMDA or kainate, to weaken catalepsy induced in rats by haloperidol and to exert their own influences of movement activity and behavior in animals was studied. The actions of study compounds were compared with those of the known NMDA antagonists memantine and dizocilpine. NMDA-induced convulsions were effectively prevented by both mono- and dications, while only dications were effective against kainate convulsions. Anticataleptic activity was significantly more marked in monocations, which lacked the ability to block non-NMDA receptors. Side effects on motor coordination were less marked with study compounds than with dizocilpine. Thus, the effects of phenylcyclohexyl derivatives in in vivo experimental models correlate with their anti-NMDA and anti-AMPA activity. They can be regarded as potential agents for treating parkinsonism and other motor disorders.

Animals↗
PubMed2003

Comparison of the effect of NT-0409 and antidementia drugs on learning and memory in rats with chronic cerebral cholinergic deficiency.

Systemic oral administration of NT-0409, a new synthetic agonist of AMPA subtype glutamate receptor, to rats with chronic partial AF64A-induced deprivation of cholinergic functions improved their learning in a Morris water maze. NT-0409 is close to memantine by the effect on learning and, in contrast to cholinomimetic arisept, ensures longer retention of the developed habit.

Alzheimer Disease↗
PubMed2004

[Diagnosis and treatment of vascular dementia].

Vascular dementia is the second cause of dementia after Alzheimer's disease. It is a broad term which includes dementia due to: single or multiple infarcts related to large vessel disease, subcortical ischemic pathology linked to small vessel disease, hemorrhages, and hypoperfusion. Furthermore, vascular and Alzheimer lesions often coexist leading to a mixed dementia. The diagnosis should be considered in the presence of dementia, clinical or neuroradiological signs of cerebrovascular disease and a plausible link between the two. Newly identified preventive strategies and encouraging results of recent trials using cholinesterase inhibitors or memantine suggest therapeutic potential.

Aged↗
PubMed2001

Glutamate release promotes growth of malignant gliomas.

Glutamate neurotoxicity has been implicated in stroke, head trauma, multiple sclerosis and neurodegenerative diseases. Although recent data show that cultured glioma cells secrete glutamate, the growth potential of brain tumors has not yet been linked to an excitotoxic mechanism. Using bioluminescence detection of glutamate release from freshly prepared brain slices, we show that implanted glioma cells continue to secrete glutamate. Moreover, gliomas with high glutamate release have a distinct growth advantage in host brain that is not present in vitro. Treatment with the NMDA receptor antagonists MK801 or memantine slowed the growth of glutamate-secreting tumors in situ, suggesting that activation of NMDA receptors facilitates tumor expansion. These findings support a new approach for therapy of brain tumors, based upon antagonizing glutamate secretion or its target receptors.

Amino Acid Transport System X-AG↗
PubMed2000

Antidepressant drugs inhibit glucocorticoid receptor-mediated gene transcription - a possible mechanism.

1. Antidepressant drugs are known to inhibit some changes evoked by glucocorticoids, as well as a hyperactivity of hypothalamic-pituitary-adrenal (HPA) axis, often observed in depression. 2. The aim of present study was to investigate effects of various antidepressant drugs on the glucocorticoid-mediated gene transcription in fibroblast cells, stably transfected with an MMTV promoter (LMCAT cells). 3. The present study have shown that antidepressants (imipramine, amitriptyline, desipramine, fluoxetine, tianeptine, mianserin and moclobemide), but not cocaine, inhibit the corticosterone-induced gene transcription in a concentration- and a time-dependent manner. 4. Drugs which are known to augment clinical effects of medication in depressed patients (lithium chloride, amantadine, memantine), do not affect the inhibitory effects of imipramine on the glucocorticoid receptor (GR)-mediated gene transcription. 5. Inhibitors of phospholipase C (PLC), protein kinase C (PKC), Ca(2+)/calmodulin-dependent protein kinase (CaMK) and antagonists of the L-type Ca(2+) channel also inhibit the corticosterone-induced gene transcription. 6. Inhibitors of protein kinase A (PKA) and protein kinase G (PKG) are without effect on the GR-induced gene transcription. 7. Phorbol ester (an activator of PKC) attenuates the inhibitory effect of imipramine on the GR-induced gene transcription. 8. Imipramine decreases binding of corticosterone-receptor complex to DNA. 9. It is concluded that antidepressant drugs inhibit the corticosterone-induced gene transcription, and that the inhibitory effect of imipramine depends partly on the PLC/PKC pathway.

Amantadine↗
PubMed2004

Mechanisms intrinsic to 5-HT2B receptor-induced potentiation of NMDA receptor responses in frog motoneurones.

In the presence of NMDA receptor open-channel blockers [Mg(2+); (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801); 1-amino-3,5-dimethyladamantane (memantine)] and TTX, high concentrations (30-100 microm) of either 5-hydroxytryptamine (5-HT) or alpha-methyl-5-hydroxytryptamine (alpha-Me-5-HT) significantly potentiated NMDA-induced depolarizations of frog spinal cord motoneurones. Potentiation was blocked by LY-53,857 (10-30 microm), SB 206553 (10 microm), and SB 204741 (30 microm), but not by spiroxatrine (10 microm), WAY 100,635 (1-30 microm), ketanserin (10 microm), RS 102221 (10 microm), or RS 39604 (10-20 microm). Therefore, alpha-Me-5-HT's facilitatory effects appear to involve 5-HT(2B) receptors. These effects were G-protein dependent as they were prevented by prior treatment with guanylyl-5'-imidodiphosphate (GMP-PNP, 100 microm) and H-Arg-Pro-Lys-Pro-Gln-Gln-D-Trp-Phe-D-Trp-D-Trp-Met-NH(2) (GP antagonist 2A, 3-6 microm), but not by pertussis toxin (PTX, 3-6 ng ml(-1), 48 h preincubation). This potentiation was not reduced by protein kinase C inhibition with staurosporine (2.0 microm), U73122 (10 microm) or N-(2-aminoethyl)-5-isoquinolinesulfonamide HCl (H9) (77 microm) or by intracellular Ca(2+) depletion with thapsigargin (0.1 microm) (which inhibits Ca(2+)/ATPase). Exposure of the spinal cord to the L-type Ca(2+) channel blockers nifedipine (10 microm), KN-62 (5 microm) or gallopamil (100 microm) eliminated alpha-Me-5-HT's effects. The calmodulin antagonist N-(6-aminohexyl)-5-chloro-1-naphtalenesulfonamide (W7) (100 microm) diminished the potentiation. However, the calcium/calmodulin-dependent protein kinase II (CaM Kinase II) blocker KN-93 (10 microm) did not block the 5-HT enhancement of the NMDA responses. In summary, activation of 5-HT(2B) receptors by alpha-Me-5-HT facilitates NMDA-depolarizations of frog motoneurones via a G-protein, a rise in [Ca(2+)](i) from the entry of extracellular Ca(2+) through L-type Ca(2+) channels, the binding of Ca(2+) to calmodulin and a lessening of the Mg(2+) -produced open-channel block of the NMDA receptor.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1994

Carbofuran toxicity.

Carbofuran, an anticholinesterase carbamate, is commonly used as an insecticide, nematicide, and acaricide in agricultural practice throughout the world. Due to its widespread use in agriculture, contamination of food, water, and air has become imminent, and consequently adverse health effects are inevitable in humans, animals, wildlife, and fish. Currently, carbofuran's involvement is most frequently encountered in malicious poisoning. The literature on chemical properties, acute toxicity data, poisoning incidences, pharmacokinetics, and mechanism of toxicity of carbofuran is briefly reviewed. Much emphasis is given to the metabolism of carbofuran, and the impact of carbofuran and its two major metabolites (3-hydroxycarbofuran and 3-ketocarbofuran) on overall toxicity. Biochemical (cholinergic and noncholinergic), hematological, and immunological effects induced by carbofuran are discussed in detail. Carbofuran and/or its major metabolites can cross the placental barrier and produce serious effects on the maternal-placental-fetal unit. Carbofuran's toxicity can be potentiated by simultaneous exposure with other cholinesterase inhibitors. Literature on various biomarkers of carbofuran exposure and on induced adverse health effects is also presented. To date, a combination of atropine and memantine remains the most effective antidotal treatment against acute carbofuran toxicity.

Agricultural Workers' Diseases↗
PubMed2005

Simultaneous determination of the binding of amantadine and its analogues to synthetic melanin by liquid chromatography after precolumn derivatization with dansyl chloride.

For the determination of amantadine (1-ADA), 2-adamantanamine (2-ADA), memantine (MEM), and rimantadine (RIM) in melanin binding studies, the simultaneous determination of 1-ADA or 2-ADA, MEM, and RIM is investigated by high-performance liquid chromatographic assay with dansyl chloride as a fluorescent derivative reagent. Dansyl derivatives with fluorescent intensity are detected at an excitation wavelength of 370 nm and an emission wavelength of 506 nm. Retention times of 1-ADA, 2-ADA, MEM, and RIM derivatives are 12.2, 12.2, 15.2, and 16.6 min, respectively. The peak of 1-ADA derivative coelutes with the 2-ADA derivative. The limits of detection for 1-ADA, 2-ADA, MEM, and RIM are 0.014, 0.007, 0.012, and 0.020microM, respectively (signal-to-noise ratio of 3:1). In the intra- and interday assay, the range of standard deviation to the average of 1-ADA, 2-ADA, MEM, and RIM is 4.6-12.7%. Their recovery is also good. The ranking order for synthetic melanin binding among these compounds is RIM > MEM > 2-ADA = 1-ADA. The method is simple, sensitive, and reproducible for simultaneously measuring 1-ADA or 2-ADA, MEM, and RIM. Also, it is useful to investigate their binding kinetics to melanin.

Amantadine↗
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↗
PubMed2000

Clinical issues in current drug therapy for dementia.

Dementia resulting from Alzheimer disease is one of the most prevalent medical problems. Elaborate expert guidelines for the diagnosis and treatment of Alzheimer disease do not always take sufficient account of the resources available in general practice. The focus on pure Alzheimer disease can be inappropriate for the large proportion of mixed dementia cases in old age. Because of such guidelines, treatment with modern and effective drugs is often delayed until conservative dementia criteria are satisfied. Criteria for the discontinuation of antidementia drugs are highly questionable. Antidementia drug sales in Germany demonstrate that the majority of prescribers hold on to conservative attitudes and prefer Ginkgo biloba and memantine to acetylcholinesterase inhibitors. Disappointment after exaggerated expectations and financial restrictions in the health care sector may aggravate current underprescribing of antidementia drugs. Even though contemporary symptomatic treatments for Alzheimer disease are unsatisfactory, modern medicine has been very successful in the early diagnosis and treatment of other potential causes of dementia. Future strategies will include models for the early identification of individuals carrying a high risk of developing cognitive impairment during their lifetime.

Aged↗
PubMed2004

Scopolamine given pre-Trial 1 prevents the one-trial tolerance phenomenon in the elevated plus-maze Trial 2.

A learned avoidance response has been one of the hypotheses proposed to explain the 'one-trial tolerance' (OTT) phenomenon, which represents a drug's loss of anxiolytic-like effect in the elevated plus-maze (EPM) test in experienced rodents. Based on these facts, if some kind of learning occurs throughout Trial 1, then an impairment of its acquisition would maintain the drug's anxiolytic-like effect on Trial 2. Using male Wistar rats, the present study examined whether scopolamine (SCO; 0.5-1.5 mg/kg), a drug that impairs learning acquisition, given 30 min prior to Trial 1, actually prevents the OTT phenomenon to either the midazolam (MDZ; 0.5 mg/kg) or the memantine (MEM; 8.0 mg/kg) anxiolytic-like effect on the EPM Trial 2 (48 h later). According to the results, both MDZ and MEM increased open-arm exploration (indicating anxiolysis) on Trial 2 only in rats that had been treated previously with 1.5 mg/kg SCO. These results were observed in the absence of change in general exploratory activity. The present findings suggest that SCO impaired the acquisition of the behavioral strategy to cope with the subsequent EPM exposure that supposedly underlies the OTT phenomenon, thereby revealing the anxiolytic-like effects of MDZ and MEM on Trial 2.

Adaptation, Psychological↗