Search PubMed⌕ Search

Biomedical subjects

L Turski

Publications and source records attributed to L Turski.

At least 37 records · Page 2Linked to original sources
PubMed1993

Diazepam dependence prevented by glutamate antagonists.

Long-term treatment leads to tolerance to and dependence on benzodiazepines. Abrupt termination of benzodiazepine administration triggers the expression of signs of dependence. Mice withdrawn from chronic treatment with diazepam showed a time-related evolution of anxiety, muscle rigidity, and seizures between days 4 and 21 after treatment discontinuation. A period between withdrawal days 1 and 3 was symptom-free. Surprisingly, during this "silent phase" the susceptibility of mice to alpha-amino-3-hydroxy-5-tert-butyl-4-isoxazolepropionate (ATPA) and kainate seizures and the magnitude of monosynaptic reflexes mediated by non-N-methyl-D-aspartate (NMDA) mechanisms were enhanced. In apparent contrast, the "active phase", between withdrawal days 4 and 21, was characterized by increased susceptibility to NMDA seizures and enhanced magnitude of polysynaptic reflexes, which are NMDA dependent. Treatment of mice with alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) antagonists 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI 52466) or 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline but not with the NMDA antagonist 3-[(+/-)-2-carboxypiperazin-4-yl]-propyl-1-phosphonate (CPP) during the silent phase prevented signs of dependence. In contrast, treatment with CPP but not with GYKI 52466 during the active phase prevented the symptoms. The development of tolerance to and dependence on diazepam was prevented by concurrent treatment of mice with CPP but was not prevented by GYKI 52466. These data indicate that NMDA-dependent mechanisms contribute to the development of tolerance to diazepam and to the expression of signs of dependence in mice after termination of long-term treatment with diazepam. Nevertheless, the non-NMDA-mediated silent phase is essential for triggering the symptoms. Therefore, AMPA antagonists may offer a therapeutic approach for preventing dependence on benzodiazepines that is an alternative to NMDA antagonism.

Animals↗
PubMed1993

Toward an understanding of the role of glutamate in experimental parkinsonism: agonist-sensitive sites in the basal ganglia.

Increased glutamatergic transmission in the basal ganglia is implicated in the pathophysiology of Parkinson's disease. However, the mechanisms by which activation of glutamate receptors produce parkinsonism are unknown. Therefore, we examined whether the glutamate agonists N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), kainate, and trans-(+/-)-1-amino-1,3-cyclopentanedicarboxylate produce parkinsonism in rats after microapplication into different subregions of the basal ganglia. Electromyographic activity was used as a measure of parkinsonian rigidity. We found that in the rostral striatum, excitation mediated by NMDA but not by non-NMDA receptors led to parkinsonism. In the substantia nigra pars reticulata, internal pallidal segment/entopeduncular nucleus, and subthalamic nucleus, activation of AMPA/kainate and metabotropic receptors but not of NMDA receptors led to parkinsonian rigidity. Rigidity occurred also in animals bearing ibotenate-induced lesions of the posterior part of the striatum and of the external pallidal segment, but not in animals with lesions of the anterior striatum, subthalamic nucleus, internal pallidal segment/entopeduncular nucleus, or substantia nigra pars reticulata. These observations suggest that the activation of glutamate receptor subtypes in the basal ganglia may be differentially involved in the expression of parkinsonian symptoms.

Animals↗
PubMed1993

The antiparkinsonian agent budipine is an N-methyl-D-aspartate antagonist.

Budipine (1-t-butyl-4,4-diphenylpiperidine) is a novel antiparkinsonian agent. Its clinical efficacy has been proven in double-blind placebo-controlled trials. The mechanism of action of budipine, however, is unknown. Budipine selectively increased the threshold of N-methyl-D-aspartate (NMDA)-induced seizures in mice. Similar to known specific NMDA antagonist, budipine depressed polysynaptic spinal reflexes in mice, but had no consistent effect on spinal monosynaptic reflexes. In receptor binding experiments, budipine displaced thienylcyclohexylpiperidyl-3,4-[3H]-(n) ([3H]-TCP) from its binding site with an IC50 of 36 microM suggesting that budopine acts as a non-competitive NMDA antagonist with moderate receptor affinity. It is concluded that the newly discovered NMDA antagonistic action of budipine is at least partly responsible for its antiparkinsonian activity. Our findings are additional evidence for the hypothesis that NMDA antagonists may be useful in the treatment of Parkinson's disease (PD).

Amino Acids↗
PubMed1993

Kindling to the benzodiazepine receptor inverse agonist, FG 7142: evidence for involvement of NMDA, but not non-NMDA, glutamatergic receptors.

Repeated administration of the beta-carboline FG 7142 to mice leads to the development of kindled convulsions. In order to investigate a role for glutamatergic mechanisms in the processes underlying FG 7142 kindling, the N-methyl-D-aspartate (NMDA) antagonist, 2-amino-7-phosphono-heptanoic acid (AP7; 25 nmol), was administered intracerebroventricularly (i.c.v.) daily before administration of FG 7142 (40 mg/kg, i.p.). Under these conditions, kindling to FG 7142 did not occur. Administration of two antagonists at non-NMDA excitatory amino acid receptors, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and gamma-D-glutamylaminomethylsulphonic acid (gamma-D-GAMS; both 25 nmol) did not prevent the development of seizures; these doses were, however, adequate and selective in protecting against seizures induced by respectively quisqualic and kainic acids given by i.c.v. The susceptibility of mice kindled with FG 7142 to seizures induced by NMDA, or kainate or quisqualate was similar in mice which had shown 5 kindled seizures to that seen in drug-naive mice; mice which had shown 10 kindled seizures showed a decreased sensitivity to NMDA-induced convulsions (ED50 was increased from 0.24 to 0.31 nmol). No changes were seen in the convulsant thresholds of either NMDA or non-NMDA agonists. These observations suggest that although NMDA receptors appear to be involved in the processes underlying FG 7142 kindling, such kindling is not necessarily associated with an increased sensitivity of glutamate receptors, and in animals which have convulsed, a decreased sensitivity to NMDA agonists occurs.

Animals↗
PubMed1993

Long-term treatment with abecarnil does not induce diazepam-like dependence in mice.

Abecarnil (isopropyl-6-benzyloxy-4-methoxymethyl-beta-carboline-3-carboxylate) is a metabolically stable anxiolytic and anticonvulsant beta-carboline derivative with few sedative and muscle relaxant effects in rodents. Abecamil binds with high affinity to benzodiazepine receptors. Because long-term treatment with benzodiazepines leads to development of dependence, we evaluated in mice whether abecarnil also possesses a potential for producing dependence, using electroencephalographic and electromyographic monitoring, and behavioral assessment of anxiety to detect withdrawal responses after chronic treatment. Diazepam was used as a reference. Mice withdrawn from chronic treatment with diazepam (15 mg/kg/day for 12 days) showed a time-related evolution of anxiety, muscle rigidity and seizures between days 4 and 21 after discontinuation of the treatment. A period between withdrawal days 1 and 3 was symptom free. Mice withdrawn from chronic administration of abecarnil (6 mg/kg/day for 12 days) showed no anxiety and no changes in seizure susceptibility and muscle tone. The doses of diazepam and abecarnil used for chronic treatment were equivalent in terms of kinetics and binding to benzodiazepine receptors. These data indicate that long-term treatment with abecarnil does not induce benzodiazepine-like dependence in mice. Thus, it may be predicted that chronic treatment with abecarnil in humans may offer an important alternative to benzodiazepines in the treatment of anxiety.

Animals↗
PubMed1993

Effect of the beta-carboline abecarnil on spinal reflexes in mice and on muscle tone in genetically spastic rats: a comparison with diazepam.

Abecarnil is a beta-carboline agonist at benzodiazepine receptors with potent anxiolytic activity but no muscle relaxant side effects in rodents. Clinical experience suggests that changes in the muscle tone induced by benzodiazepines are related to their effects on spinal reflexes. The authors therefore analyzed the effect of treatment with abecarnil on spinal monosynaptic (Hoffmann reflexes) and polysynaptic (flexor) reflexes in mice and the influence of abecarnil on muscle tone in genetically spastic rats. The i.v. administration of abecarnil in mice (dose range, 0.02-1 mg/kg) depressed flexor reflexes in a dose-dependent manner; Hoffmann reflexes remained unchanged. Administration of diazepam i.v. (0.01-1 mg/kg) also reduced flexor reflexes and had little or no effect on Hoffmann reflexes. In genetically spastic rats, i.v. administration of abecarnil (10-30 mg/kg) decreased the muscle tone in a dose- and time-dependent manner. A similar muscle relaxant effect was observed in such rats after i.v. administration of diazepam (0.1-0.8 mg/kg). By contrast, i.p. administration of abecarnil in mice did not influence spinal reflexes up to the dose of 1 mg/kg and, in genetically spastic rats, did not affect muscle tone up to the dose of 100 mg/kg. Administration of diazepam i.p. (1 mg/kg) depressed flexor reflexes in mice and over the range 0.2 to 5 mg/kg produced a dose- and time-dependent decrease of muscle tone in genetically spastic rats. The muscle relaxant effect of i.p. diazepam could be antagonized by i.p. administered abecarnil. These studies thus demonstrate that i.v. but not i.p. administration of abecarnil may result in muscle relaxant action in mice and in genetically spastic rats.

Animals↗
PubMed1993

Modulation of the seizure threshold for excitatory amino acids in mice by antiepileptic drugs and chemoconvulsants.

A novel method for the assessment of the threshold for clonic seizures induced by excitatory amino acids based on continuous infusion of the glutamate agonists [alpha-amino-3-hydroxy-5-terbutyl-4-isoxazolepropionate (ATPA), kainate or N-methyl-D-aspartate (NMDA)] into the lateral brain ventricle of unrestrained mice is reported. Using this novel method of seizure threshold determination, it was found that systemically administered diphenylhydantoin and carbamazepine elevated the threshold for ATPA and had negligible effects on the threshold for kainate and NMDA. Phenobarbital and trimethadione elevated the threshold for all excitatory amino acids tested, whereas valproate elevated the threshold for ATPA and kainate seizures. Ethosuximide elevated the threshold for ATPA and kainate and decreased the threshold for NMDA seizures. The quisqualate antagonists [2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline and 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine] elevated the threshold for ATPA and less so for kainate seizures, whereas the NMDA antagonist 3-((+-)2-carboxypiperazine-4-yl)-propyl-1-phosphonate elevated the threshold for NMDA seizures. 1-(4-Aminophenyl)4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine in higher doses was also active against NMDA seizures, whereas 3-((+-)2-carboxypiperazine-4-yl)-propyl-1-phosphonate did so with kainate seizures. Among seven different convulsants, pentylenetetrazol, picrotoxin and the beta-carboline methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate lowered the threshold for seizures induced by excitatory amino acids. Pentylenetetrazol and picrotoxin did so with kainate seizures, whereas methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate lowered ATPA thresholds. Bicuculline, 3-mercaptopropionate, strychnine and pilocarpine were inactive.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗
PubMed1992

Inhibition of cisplatin-induced emesis in ferrets by the non-NMDA receptor antagonists NBQX and CNQX.

The excitatory amino acid (EAA) receptor antagonists, 2,3-dihydroxy-6-nitro-7-sulphamoylbenzo(f)quinoxaline (NBQX) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), which preferentially block non-N-methyl-D-aspartate (non-NMDA) subtypes of EAA receptors, effectively inhibit cisplatin-induced emesis in ferrets. A high dose of cisplatin (10 mg/kg i.v.) was used which induced emesis in all saline-treated control ferrets. At 10 mg/kg i.v., NBQX totally prevented cisplatin-induced emesis in 5 of 6 ferrets and CNQX totally prevented emesis in 3 of 5 ferrets. By comparison, each of the 5-HT3 inhibitors, zacopride and ondansetron, at 1.0 mg/kg i.v. (a dose considered in the high therapeutic range for controlling emesis by these compounds), totally prevented emesis in 2 of 5 ferrets. It is concluded that non-NMDA antagonists effectively inhibit cisplatin-induced emesis. They are potential antiemetic compounds, alone or in combination with 5-HT3 antagonists or other more conventional drugs of choice.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1992

Excitatory amino acid antagonists protect mice against MPP+ seizures.

Administration of 1-methyl-4-phenyl-pyridinium ion (MPP+) into the lateral ventricle of mice induced clonic convulsions and lethality in a dose- and age-dependent manner. MPP+ failed to induce seizures in 4-day-old mice, and the convulsant response to MPP+ was enhanced in aged mice. The seizures triggered by MPP+ in adult mice were blocked by coadministration of L-glutamate antagonists active at kainate/AMPA receptors such as gamma-D-glutamylaminomethylsulphonate and 2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo[f]quinoxaline. The N-methyl-D-aspartate (NMDA) antagonist 2-amino-7-phosphonoheptanoate, but not kynurenate, also protected mice against MPP+ convulsions. Similarly, the benzodiazepine midazolam and the adenosine A1 agonist 2-chloroadenosine, but not antiepileptic drugs such as phenobarbital, trimethadione, ethosuximide, or acetazolamide, showed a protective efficacy against seizures. Additionally, the excitatory amino acid antagonists as well as phenobarbital, midazolam and 2-chloroadenosine protected mice against MPP+ lethality. These data suggest that convulsant action of MPP+ and its lethality in rodents may be mediated by excitatory amino acids.

Aging↗
PubMed1992

Relief of experimental spasticity and anxiolytic/anticonvulsant actions of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline.

Spasticity is characterized by pathological overactivity in spinal stretch reflex circuits and may be associated with disturbances in excitatory amino acid-mediated transmission in the cord. A genetically determined syndrome of spasticity in the rat permits the quantitative evaluation of the antispastic effects of drugs by recording activity in the electromyogram (EMG) from a hind limb extensor muscle. In genetically spastic rats, systemic administration of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) antagonist, 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F) quinoxaline (NBQX), normalized pathologically increased EMG activity, whereas the AMPA agonist, alpha-amino-3-hydroxy-5-tertbutyl-4-isoxazolepropionate (ATPA), exacerbated the EMG measures of spasticity. The reflex mechanisms in the spinal cord can be studied in mice using EMG recordings from the tibial muscle (Hoffmann reflex) or from the plantar foot muscle (flexor reflex) after electrical stimulation of the tibial nerve. Systemic and i.t. administration of NBQX blocked Hoffmann reflexes in mice, leaving flexor reflexes unchanged. ATPA enhanced Hoffmann, and had no effect on flexor reflexes. The effects of NBQX on spinal reflexes were seen in doses which do not affect locomotor activity, but show anxiolytic and some antiepileptic activity in rodents. These data suggest that the design of novel muscle relaxant drugs acting at the AMPA subtype of glutamate receptors may be feasible.

Animals↗
PubMed1991

Protection of substantia nigra from MPP+ neurotoxicity by N-methyl-D-aspartate antagonists.

Intake of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) leads to symptoms of Parkinson's disease and produces degeneration of nigrostriatal dopaminergic neurons in humans, giving rise to the hypothesis that this disorder may be caused by endogenous or environmental toxins. Excitation mediated by dicarboxylic amino acids such as L-glutamate or L-aspartate, has been claimed to be involved in pathogenesis of neurodegenerative disorders. We therefore sought to determine whether antagonists active at the NMDA or quisqualate subtypes of L-glutamate receptors prevent toxicity of either MPP+ (1-methyl-4-phenyl-pyridinium ion, the active metabolite of MPTP) or the selective dopaminergic neurotoxin 6-OHDA in the rat substantia nigra pars compacta. We report here that certain selective NMDA antagonists (AP7, CPP, MK-801), but not the preferential quisqualate antagonists CNQX and NBQX, provided short-term (up to 24 h) protection against MPP+ toxicity when coadministered into the substantia nigra. Systemic administration of CPP or MK-801 also offered temporary protection for up to 4 h against MPP+ toxicity. Repeated systemic administration of either compound prolonged protection against MPP+ challenge. Repeated administration for at least 24 h also led to permanent protection, still evident 7 days after intranigral administration of MPP+.

1-Methyl-4-phenylpyridinium↗
PubMed1991

The AMPA receptor antagonist NBQX has antiparkinsonian effects in monoamine-depleted rats and MPTP-treated monkeys.

Abnormally increased subthalamic nucleus output to the internal pallidal segment and the reticular part of the substantia nigra plays a critical pathophysiological role in the development of parkinsonism. Because synaptic transmission of subthalamic output is glutamatergic and mediated, in part, by the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) subtype of glutamate receptor, AMPA receptor antagonists may possess antiparkinsonian properties. We report that in monoamine-depleted rats, 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX) (Novo-Nordisk, Copenhagen, Denmark)--a selective antagonist of the AMPA subtype of glutamate receptor--suppressed muscular rigidity but had no effect on akinesia. NBQX microinjected into the subthalamic nucleus, internal pallidal segment, and reticular part of the substantia nigra, but not into the laterodorsal neostriatum of the rats, stimulated locomotor activity and reduced muscular rigidity. In aged Rhesus monkeys with bilateral 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism, intramuscular NBQX produced clinically apparent improvement in akinesia, tremor, posture, and gross motor skills. NBQX also potentiated the antiparkinsonian effects of L-3,4-dihydroxyphenylalanine in both rats and monkeys. Blockade of excitatory synaptic transmission by AMPA receptor antagonists may provide a new therapeutic strategy for Parkinson's disease (PD).

Animals↗
PubMed1991

Paradoxical anticonvulsant activity of the gamma-aminobutyrate antagonist bicuculline methiodide in the rat striatum.

Bicuculline methiodide (BMI), a gamma-aminobutyrate (GABA) antagonist, is a powerful convulsant agent when injected into the cerebral ventricles, amygdala, hippocampus, thalamus, neocortex, and deep prepiriform cortex in rats. In contrast, bilateral microinjection of BMI into the rat striatum confers protection against seizures induced by the cholinergic agonist pilocarpine (380 mg/kg, i.p.), with an ED50 of 94 fmol (range 45-195 fmol). No topographical variation in the anticonvulsant action of BMI was detected throughout rostrocaudal and dorsoventral aspects of the striatum. The anticonvulsant action of BMI in the striatum was reversed by coadministration of the GABA agonist muscimol or by blocking GABA-mediated inhibition in either the substantia nigra pars reticulata or in the entopeduncular nucleus. The results show that blockade of GABA-mediated inhibition in the striatum has a powerful anticonvulsant effect in the pilocarpine model, suggesting that GABAergic transmission in the striatum modulates the seizure propagation in the forebrain.

Animals↗