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M Schmutz

Publications and source records attributed to M Schmutz.

At least 55 records · Page 3Linked to original sources
PubMed1989

CGP 31358 binds to a site on the NMDA receptor that is coupled to both the transmitter recognition site and the channel domain.

CGP 31358, a novel triazole, inhibited the binding of L-[3H]glutamate and [3H]MK-801 to the N-methyl-D-aspartate (NMDA) receptor complex in rat brain synaptic membrane fractions, and showed anticonvulsant activity in mice. It had no effect on the strychnine-insensitive binding of [3H]glycine. Saturation and Hill analyses indicated that CGP 31358 binds to a site on the NMDA receptor which is separate from, but coupled to, both the transmitter recognition site and the channel domain. Available data indicate that this site is distinct from those with which tricyclic antidepressants and ifenprodil interact. CGP 31358 is a new chemical entity with a novel mechanism of action at the NMDA receptor, and as such may form a tool for understanding the molecular pharmacology of this receptor-channel complex.

Animals↗
PubMed1989

CGS 20625, a novel pyrazolopyridine anxiolytic.

CGS 20625 (2-(4-methoxyphenyl)2,3,5,6,7,8,9,10-octa hydrocyclohepta[b]pyrazolo-[3,4-d]pyridin-3-one) is a potent and selective ligand for the central benzodiazepine receptor (IC50 = 1.3 nM), with little or no affinity to several other neurotransmitter receptor binding sites in vitro. CGS 20625 had a gamma-aminobutyric acid ratio of 0.9 and increased t-[35S]butylbicyclophosphorothionate binding by 20% in vitro, a profile indicative of a partial agonist or mixed agonist/antagonist. In vivo, CGS 20625 blocked a pentylenetetrazol discriminative cue with an ED50 = 1.7 mg/kg p.o. The compound selectively increased conflict responding in the Cook-Davidson paradigm with a minimal effective dose of 0.3 mg/kg p.o., as compared with 3.0 mg/kg p.o. for diazepam. At doses as high as 100 mg/kg p.o., CGS 20625 had no effect on variable interval responding, suggesting minimal sedation. Unlike diazepam, CGS 20625 had no effect on rotorod performance at doses up to 100 mg/kg p.o. indicating no overt muscle relaxation, and did not potentiate the action of ethanol in this behavioral paradigm. Also, CGS 20625 had no marked effect on locomotor behavior, did not potentiate hexobarbital sleep time and had no sedative activity at doses up to 300 mg/kg p.o. CGS 20625 was efficacious in preventing pentylenetetrazol-induced seizures (ED50 = 0.7 mg/kg p.o.), had less efficacy with no clear dose-response relationship against picrotoxin-induced seizures and had no effect on either strychnine or electroshock-induced convulsions at doses up to 300 mg/kg p.o.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Valproate enhances GABA-A mediated inhibition of locus coeruleus neurones in vitro.

It has previously been claimed that the anticonvulsant valproate acts by augmenting GABA-ergic transmission, however, the data supporting this claim is controversial. Here we demonstrate that valproate strongly and reversibly potentiates the depressant effects of the GABA-A receptor agonist muscimol on locus coeruleus neurones recorded extracellularly from a midpontine slice preparation of the rat. The depressant effect of muscimol (2 microM) is augmented by bath applied valproate at concentrations of 50 microM, 100 microM and 1 mM. The effect of GABA is also potentiated by valproate. The potentiating effect is selective since the cell inhibition elicited by the GABA-B receptor agonist baclofen is not affected. Valproate on its own had no effect on the firing frequency.

Animals↗
PubMed1988

Gamma-vinyl GABA: comparison of neurochemical and anticonvulsant effects in mice.

Biochemical and pharmacological effects of gamma-vinyl GABA (Vigabatrin, GVG), and irreversible enzyme-activated inhibitor of 4-aminobutyrate: 2-oxoglutarate aminotransferase (EC 2.6.1.19; GABA-T), were measured in mice. This anticonvulsant produced a time- and dose-dependent elevation of the GABA, phenylalanine and lysine contents of cortical tissue and simultaneously decreased glutamate, aspartate and alanine levels. In addition, GVG caused a biphasic change in glutamine concentrations (a decline 1-4 hours after administration, followed 20 hours later by an increase). Moreover, we found a new, as yet unidentified amino acid in the brain eluting with the same retention time as alpha-aminoadipic acid from an HPLC cation-exchange column. The level of this novel chemical entity was greatly increased by GVG 20 hours after injection of the drug. At all tested intervals between 1 and 60 hours after injection, GVG was ineffective against maximal electroshock. The GABA-T inhibitor dose-dependently protected mice against isoniazid-induced seizures, simultaneously causing an increase in brain GABA concentrations. However, this apparent correlation applied only until 4 hours after treatment. To better define the anticonvulsant profile of GVG, groups of mice were treated, 1, 2, 4, and 24 hours prior to challenge with convulsant doses of strychnine, pentetrazole (PTZ), and picrotoxin, and brain amino acid levels, including brain concentrations of GVG, were measured. In all instances, the time dependency of the anticonvulsant effects of GVG and of increases in brain GABA levels differed. Amino acid concentrations in animals treated only with GVG were similar to those in animals given GVG and a chemical convulsant. GVG showed no selectivity for seizures produced by impairment of GABA-ergic neurotransmission. Although GVG is an effective GABA-T inhibitor, it apparently affects several other pyridoxal-phosphate-dependent cerebral enzymes and/or interacts with other neurotransmitter systems as well.

4-Aminobutyrate Transaminase↗
PubMed1988

Inhibition or enhancement of kindling evolution by antiepileptics.

The influence of antiepileptics on the evolution of rat amygdaloid kindling was studied. Under placebo conditions clonic convulsions and a spike-wave EEG pattern developed. Diazepam, clonazepam, clobazam and phenobarbital were most effective in suppressing the evolution of kindling; the effects of valproate sodium, ethosuximide and acetazolamide were somewhat less pronounced in this respect. Carbamazepine, oxcarbazepine and phenytoin, on the other hand, enhanced kindling development, i.e. the increase in duration of after-discharge was faster than in the placebo group. The results indicate that under the above experimental conditions drugs with no anti-absence component can be distinguished from those with an anti-absence component. The mechanism of action underlying the observed effects is not yet known; the hypothesis that under special conditions protective inhibitory neuronal activity can develop to absence type seizures is proposed.

Animals↗
PubMed1988

Evaluation of the anticonvulsant and biochemical activity of CGS 8216 and CGS 9896 in animal models.

CGS 8216, a benzodiazepine-receptor ligand with inverse agonistic properties, and CGS 9896, which possesses partial agonistic or mixed agonist-antagonist properties were compared in a number of epilepsy models. The effect of CGS 9896 on the decrease in GABA levels induced by isoniazid was also investigated. CGS 9896 inhibited the kindling process in rats in that it delayed the development of overt seizures and the increase in the duration of afterdischarges. In a genetic rat model characterized by absence-like EEG patterns, CGS 9896 dose-dependently suppressed these spontaneously occurring discharges, while CGS 8216 had no effect. However, CGS 8216 antagonized the anticonvulsant action of CGS 9896. CGS 9896 protected mice against seizures induced by beta-vinyllactic acid, whereas CGS 8216 shortened the latency period before convulsions occurred. CGS 9896 retarded the onset of convulsive fits caused by isoniazid without preventing the decrease in GABA levels produced by that drug. These results confirm the anticonvulsant activity of CGS 9896 and demonstrate the inverse agonistic activity of CGS 8216. The profile of CGS 9896 in the above tests suggests that it might be an effective anticonvulsant, primarily in absence-type seizures.

Animals↗
PubMed1988

CGS 19755, a selective and competitive N-methyl-D-aspartate-type excitatory amino acid receptor antagonist.

CGS 19755 (cis-4-phosphonomethyl-2-piperidine carboxylic acid) was found to be a potent, stereospecific inhibitor of N-methyl-D-aspartate (NMDA)-evoked, but not KCl-evoked, [3H] acetylcholine release from slices of the rat striatum. The concentration-response curve to NMDA was shifted to the right by CGS 19755 (pA2 = 5.94), suggesting a competitive interaction with NMDA-type receptors. CGS 19755 inhibited the binding of [3H]-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid to NMDA-type receptors with an IC50 of 50 nM, making it the most potent NMDA-type receptor antagonist reported to date. CGS 19755 failed to interact with 23 other receptor types as assessed by receptor binding, including the quisqualate- and kainate-type excitatory amino acid receptors. In crude P2 fractions, no evidence was obtained to suggest that CGS 19755 is taken up by an active transport system. Furthermore, CGS 19755 failed to affect the uptake of L-[3H]glutamate, or to interact with aconitine-induced inhibition of L-[3H]glutamate uptake, the latter finding suggesting a lack of membrane-stabilizing or local anesthetic properties. CGS 19755 selectively antagonized the excitatory effect of iontophoretically applied NMDA in the red nucleus of the rat without affecting the excitatory effects of quisqualate. CGS 19755 blocked the harmaline-induced increase in cerebellar cyclic GMP levels at a dose of 4 mg/kg i.p. with a duration of action exceeding 2 hr. CGS 19755 inhibited convulsions elicited by maximal electroshock in rat (ED50 = 3.8 mg/kg i.p. 1 hr after administration) and in mouse (ED50 = 2.0 mg/kg i.p. 0.5 hr after administration). Likewise, convulsions elicited by picrotoxin were inhibited by CGS 19755, whereas the compound was relatively weak in protecting against convulsions elicited by pentylenetetrazole or strychnine. CGS 19755 produced retention performance deficits in a dark avoidance task. However, CGS 19755 did not show a unique propensity for learning and memory disruption compared to other anticonvulsants.

Acetylcholine↗
PubMed1987

Relevance of kindling and related processes to human epileptogenesis.

1. Kindling and related processes belong to the most extensively investigated models of experimental epilepsy. In this paper an attempt is made to outline their significance to human epileptogenesis. Below the most relevant findings are summarized: 2. Animal data: kindling and related processes are progressive in nature and occur in a great number of animal species including Rhesus monkeys and baboons; progressive epileptogenesis seems dependent on predisposition to seizure susceptibility and develops slower the higher the position of the respective species is in the phylogenetic scale; spontaneously recurrent seizures as well as permanent electroencephalographic, behavioural, electrophysiological and biochemical alterations have been observed following kindling; kindling development can be suppressed by clinically used antiepileptic drugs. These data illustrate the similarity of kindling and related processes to certain aspects of human epilepsy. 3. Human data: one case of human brain kindling and several cases of spontaneously recurrent seizures following electroconvulsive treatment are known; the progressive nature of human epilepsies is exemplified by observations of untreated patients, factors accompanying the failure of monotherapy, and the existence of multiple lesions (mirror foci) in cerebral tumour patients. 4. The material presented clearly indicates that kindling and related processes can occur in man as well as in animals. This should have implications for the treatment of epileptic patients as well as for brain stimulation techniques.

Amygdala↗
PubMed1986

Dose pipecolic acid interact with the central GABA-ergic system?

Several previous studies have suggested a strong GABA-mimetic action of the endogenous brain imino acid, L-pipecolic acid (L-PA). In the present study, these observations were evaluated using electrophysiological and neurochemical methods. In contrast to published data our electrophysiological studies on rat cortical neurones in situ showed only a weak, but bicuculline-sensitive depressant action of L-PA on cortical neurones. Furthermore, L-PA proved to have no affinity for any of the three components of the GABA-benzodiazepine-chloride channel receptor complex. However, using a modification of published methods a weak affinity for the GABA-B receptor site was demonstrated (IC50 = 1.8 X 10(-3) M). L-PA showed no anticonvulsive activity in several tests; in particular, it did not protect mice from seizures induced by inhibition of L-glutamate-1-decarboxylase (EC 4.1.1.15: GAD). L-PA had a very weak action on brain GABA levels of mice, and did not modify the rate of GABA synthesis. In conclusion, these results are not compatible with a strong in vivo interaction between L-PA and GABA-mediated inhibitory transmission.

Animals↗
PubMed1985

Pharmacological and neurochemical aspects of kindling.

Rats implanted with amygdaloid stimulating and cortical recording electrodes were kindled by daily low-intensity electrical stimulation. In one experiment amino acid concentrations were measured in amygdala, cortex and hippocampus at behavioural stages 1, 2 and 4 (Racine). Control groups consisted of unstimulated rats. Only alanine showed a significant enhancement of concentration in the kindled rats (stage 4 of Racine). In a second experiment, a group of rats was treated daily with 10mg/kg p.o. of diazepam. Diazepam significantly inhibited kindling and no changes in amino acid concentrations were observed in this group. Increased alanine levels are seen after various seizure types; since pentetrazole, isoniazid and beta-vinyllactic acid seizures were associated with alanine level increases only after and never before seizure occurrence, it is suggested that the alanine increases are a consequence rather than a cause of convulsions. In 3H-flunitrazepam binding studies, no change in affinity or receptor number could be demonstrated during kindling.

Alanine↗
PubMed1985

The specific protective effect of diazepam and valproate against isoniazid-induced seizures is not correlated with increased GABA levels.

Amino acid concentrations were measured in the cortex, cerebellum and hippocampus of the mouse brain before and during seizures induced by isoniazid (250 mg/kg i.p.), an inhibitor of L-glutamate-1-decarboxylase (EC 4.1.1.15: GAD). Valproate sodium and diazepam dose-dependently delay the onset of convulsive fits caused by isoniazid. However, neither diazepam nor valproate prevented the decrease in GABA concentrations produced by isoniazid alone. Also, these antiepileptic drugs did not modify the rate of GABA depletion elicited by isoniazid. These results, observed in four different brain structures, strengthen those first obtained with beta-vinyllactic acid, another inhibitor of GAD.

Amino Acids↗
PubMed1984

Protective effects of diazepam and valproate on beta-vinyllactic acid-induced seizures.

GABA level and the activity of L-glutamate-1-decarboxylase (GAD) (EC 4.1.1.15) were studied in brains of mice treated with beta-vinyllactic acid, a new, selective and pyridoxal phosphate-independent GAD inhibitor. Valproate and diazepam protected mice against convulsions caused by beta-vinyllactic acid although both anti-epileptic drugs antagonized neither the decrease in GABA concentrations nor the inhibition of GAD observed after treatment with beta-vinyllactic acid alone. Assuming that the anticonvulsant effect measured with both antiepileptics is GABA mediated, these results support the hypothesis of a postsynaptic enhancement of GABAergic transmission by diazepam and valproate.

Animals↗
PubMed1980

The effect of sodium-n-dipropyl acetate on gamma-aminobutyric acid-dependent inhibition in the rat cortex and substantia nigra in relation to its anticonvulsant activity.

1. We have examined the time course of the anticonvulsant property of valproate sodium on electroshock-induced convulsions in rats and a comparison of this has been made with the action of the drug on single unit activity in the rat brain. 2. Intraperitoneal valproate sodium (100 to 400 mg/kg) protected rats from electroshock-induced convulsion. This effect was dose-dependent, the latency of the effect decreasing as a function of dose from 5 to 2 min. 3. The time course of this anticonvulsant property was paralleled by a pronounced inhibition of the spontaneous firing rate of cortical and nigral neurones, following intraperitoneal administration of valproate sodium (100 to 400 mg/kg). 4. The inhibitory action of microiontophoretically applied gamma-aminobutyric acid (GABA) and muscimol on the firing rate of cortical neurones was potentiated within 1 to 3 min of microiontophoretic application of valproate sodium. In contrast, the inhibitory action of glycine on cortical neurones was unaffected during the microiontophoretic application of valproate sodium. 5. Microiontophoretically applied valproate sodium also potentiated inhibitory responses to GABA in rats which had received 100 mg/kg of a GABA-transaminase inhibitor, gabaculine, i.p. 16 h previously. 6. The duration of trans-synaptic inhibitory responses in the substantia nigra and cortex following submaximal electrical stimulation of the striatum and cortex respectively was, in general, unaffected by either intraperitoneal or local application of valproate sodium. 7. These observations are discussed in terms of the mechanisms underlying the rapid onset of the anticonvulsant properties of valproate sodium.

Animals↗