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PubMedDate not supplied

Effects of a benzodiazepine, bretazenil (Ro 16-6028), on rhythmic metrazol EEG activity: comparison with standard anticonvulsants.

A novel anticonvulsant benzodiazepine bretazenil (Ro 16-6028) was studied electrophysiologically in a model of human absence seizures: rhythmic metrazol activity (RMA) in rats. The effects of Ro 16-6028 pretreatment (0.01, 0.05, or 0.1 mg/kg intraperitoneally, i.p.) were compared with those of clonazepam (CZP, 0.02 or 0.1 mg/kg i.p.), valproate (VPA, 200, 300, or 400 mg/kg) and ethosuximide (ESM, 31.25, 62.5, or 125 mg/kg i.p.) in 45 rats with implanted electrocorticographic electrodes. RMA was elicited by an injection of pentylenetetrazol (metrazol, PTZ) in a dose of 40 or 35 mg/kg i.p. The effects of Ro 16-6028 were similar to those of CZP and VPA, i.e., suppression of RMA episodes, an increase in latency and a decrease in number, and total as well as mean duration. On the other hand, ESM differed from these antiepileptic drugs (AEDs) in inability to shorten the duration of RMA episodes. Based on these results, Ro 16-6028 might be predicted to be efficient against human absence seizures.

Animals↗

PubMedDate not supplied

Anticonvulsant action of oxcarbazepine, hydroxycarbamazepine, and carbamazepine against metrazol-induced motor seizures in developing rats.

Antimetrazol effects of carbamazepine (CBZ, 5, 12.5, 25, or 50 mg/kg), oxcarbazepine (OCBZ, 5, 10, 30, or 60 mg/kg), and hydroxycarbamazepine (HCBZ, the main human metabolite of OCBZ, 10, 30, or 60 mg/kg) were studied in 7-, 12-, 18-, 25-, and/or 90-day-old laboratory rats. No drug tested affected the incidence of minimal (clonic) metrazol seizures (mMs) in animals aged > or = 18 days; in rats aged 7 or 12 days in which mMs are rare under control conditions, the incidence of mMs was increased by lower doses of CBZ and HCBZ. All drugs tested specifically abolished the tonic phase of major generalized tonic-clonic seizures (MMs) in a dose-dependent manner. In addition, CBZ and OCBZ were able to suppress all phases of MMs in the two youngest groups (7- and 12-day-old). There were no marked differences among the three drugs tested (CBZ, OCBZ, and HCBZ) on their action against metrazol-induced seizures during ontogenesis of rats; i.e., all these drugs appeared to possess an identical profile of anticonvulsant action.

Age Factors↗

PubMed1984

Changes in response to metrazole during fever in juvenile rats; a new model for febrile convulsions?

Previous models for febrile convulsions have used environmentally induced hyperthermia as the stimulus to induce convulsions. Changes in response to metrazole during yeast-induced fever in juvenile rats are reported here. Animals were more susceptible to metrazole during the rising phase of fever but showed some resistance to its convulsant effects once the fever was established and following defervescence. It is suggested that this may form the basis of a physiologically more appropriate model for the study of the pathogenesis of febrile convulsions.

Animals↗

PubMed1981

Alterations in local glucose consumption following systemic administration of kainic acid, bicuculline or metrazol.

Using the autoradiographic deoxyglucose method, local consumption of glucose has been visualized during convulsive seizures induced by systemic administration of kainic acid, bicuculline or metrazol. A striking correlation was found between the time course of the electrographic and metabolic alterations in limbic structures following kainic acid administration. In addition, pathological alterations were almost exclusively observed in structures in which there had been a rise in metabolism. In contrast, following bicuculline or metrazol a rise in metabolism was conspicuous primarily in the cerebellum, vestibular nuclei and neocortex.

Animals↗

PubMed1992

Long-term study of brain lesions following soman, in comparison to DFP and metrazol poisoning.

The long-term histopathological effects of acute lethal (95 micrograms kg-1) and sublethal (56 micrograms kg-1) doses of soman were studied in rats and were compared to lesions caused by equipotent doses of either another cholinesterase (ChE) inhibitor, DFP (1.8 mg kg-1), or a non-organophosphorus convulsant, metrazol (100 mg kg-1). Severe toxic signs were noted following one LD50 dose administration of all the compounds, yet only soman induced brain lesions. Moreover, even when administered at a sublethal dose (0.5 LD50), soman induced some histological changes without any clinical signs of intoxication. Soman-induced brain lesions were assessed quantitatively using a computerized image analyser. The analysis was carried out for up to 3 months following administration, and a dynamic pattern of pathology was shown. The cortical thickness and area of CA1 and CA3 cells declined significantly as early as 1 week post-exposure. No pathological findings were detected following DFP and metrazol administration. It is therefore suggested that brain lesions are not common for all ChE inhibitors and that convulsions per se are not the only factor leading to brain damage following the administration of soman. The degenerative process (found also with the sublethal dose of soman) might be due to a secondary effect, unrelated to soman's clinical toxicity, but leading to long-term brain injuries.

Animals↗

PubMed1976

Antagonism of maximal metrazol seizures in rats and its relevance to an experimental classification of antiepileptic drugs.

The antagonism of various components of maximal Metrazol-seizures (MMS) (i.e. tonic hindpaw extension, tonic backward extension of the forepaws, generalized clonic seizures and tremors), ataxia and loss of righting reflex-activity have been studied in a standardized procedure comparing 41 antiepileptics and related compounds. Appropriate analyses (Cluster Analysis and Principal Component Analysis) resulted in the distinction of seven clusters which could be considered along two continua. A first continuum is characterized by a progressive strengthening of loss of righting reflex-inducing properties, a decreasing dissociation of ataxia and loss of righting reflex and the disappearance of a selective anticonvulsant effect. The second continuum is characterized by an increasing relative potency of ataxia-inducing properties, an increasing dissociation of ataxia and loss of righting reflex and a decreasing antagonism of tremors. Three main types of anticonvulsants could be defined: drugs with a complete anti-MMS effect antagonizing both clonic and tonic seizures; drugs selectively abolishing tonic seizures, i.e., tonic extension of hind- and forepaws; and drugs exclusively blocking tonic hind-paw extension. The neurological and clinical significance of these different types of anticonvulsant activity has been discussed. Finally, the described modification of the maximal Metrazol-seizures test is proposed for routine screening purposes.

Animals↗

PubMed1986

Rhythmic metrazol activity and cortical spreading depression.

The incidence of segments of rhythmic metrazol activity (RMA) in cortical leads and in the thalamus and hippocampus was studied in acute experiments on nine male albino laboratory rats. First of all we studied activity after administering metrazol in an i.p. dose of 50 mg/kg, without any further treatment, and then, after a control recording, we induced cortical spreading depression and observed its effect on the incidence and synchronization of RMA in the individual leads. We came to the conclusion that the thalamus is incapable of isolated production of RMA. The cortex is able to produce RMA without participation by the studied structures of the specific thalamus and hippocampus; RMA probably originates in the cortex itself. Generalization is impaired, but not eliminated, by a cortical block. The hippocampus independently produces another type of rhythmic activity.

Animals↗

PubMed1985

Effect of acute acrylonitrile exposure on metrazol induced seizures in the rat.

The effects of acute exposure to acrylonitrile (ACN), 10, 20, or 40 mg/kg by gavage, on the ability of metrazol (MTZ) to induce seizures was studied in adult, male Sprague-Dawley rats. The frequency of seizure occurrence and the frequency of a lethal seizure was greater when the high ACN dosage was given in combination with metrazol. This dosage of ACN was not lethal when given alone. Examination of brain tissue in these animals revealed no difference in cyanide levels when MTZ was combined with ACN. However, brain cytochrome c was significantly lower in animals given ACN+MTZ and brain cholinesterase was significantly higher. These results suggest that the enhanced lethality occurring in animals exposed to the combination of ACN+MTZ is not due to cyanide, a metabolic product of ACN, but rather to a potentiation of other effects of ACN perhaps involving cholinergic neurotransmission.

Acetylcholinesterase↗

PubMed1980

[Different effects of the replacement of extracellular sodium with lithium on the abnormal spike discharges caused by 2 convulsants, Metrazol and strychnine, on an identifiable giant neuron of the mollusc Achatina fulica Ferussac].

The influences of the replacement of sodium with lithium in the extracellular medium on the abnormal spike discharges, caused by two convulsants, metrazol and strychnine, of a giant neurone (TAN, tonically autoactive neurone) identified in the suboesophageal ganglia of the African giant snail (Achatina fulica Férussac) were examined. The slow oscillations of potential caused by metrazol disappeared after this replacement. On the other hand, the abnormal action potentials caused by strychnine, as well as the normal action potentials, still remained after the removal of sodium in the medium.

Action Potentials↗

PubMedDate not supplied

Enhanced cerebrovascular permeability by Metrazol: significance for brain metastases.

Metrazol enhanced the penetration of two proteins (125I human serum albumin and horseradish peroxidase), and the anticancer agent, razoxane, into the central nervous system of anaesthetized rats. Penetration was increased throughout the whole brain. With the exception of the bladder, no peripheral tissue was affected. The increase in brain permeability was temporary and reversed within 4 hours; brain levels of drug and protein were increased by up to three times.

Animals↗

PubMed1980

Metrazol produces conditioned taste aversion in rats.

Employing a two bottle drinking procedure where an animal's preference is measured between plain water and a novel fluid, it was found that the convulsant drug Metrazol produced a conditioned taste aversion to saccharin. This finding is contrary to that of previous reports and highlights the sensitivity of the two bottle method in detecting a taste aversion.

Animals↗

PubMed1975

Lateral geniculate multiple-unit activity related to metrazol potentiated after-discharges.

Following parenteral administration of subconvulsive levels of pentylenetetrazol (Metrazol) photic stimulation induced an augmented rhythmic sequence of late neuron population burst-inhibition periods in the dorsal lateral geniculate nucleus (LGN) of the rat. This late bursting-inhibition activity was in turn observed to be associated with the augmentation of cortically recorded photically evoked after-discharges (PhADs). Multiple-unit activity (MUA) was also recorded from superior colliculus (SC), reticular formation (RF), posterior thalamic area (PTN), and dorsal hippocampus (HIPP). Only SC and RF exhibited an initial discharge to photic stimulation with late bursting infrequently observed and only in the SC. PTN showed some tonic increases in MUA following photic stimulation. HIPP MUA was essentially unaffected by photic pulse stimulation. The results document the neuronal role of the LGN in PhAD activity and were discussed in terms of a recurrent LGN inhibitory system governing cortical PhAD production and elaboration.

Animals↗

PubMed1985

Prenatal chlordiazepoxide effects on metrazol seizures and benzodiazepine receptors density in adult albino rats.

Adult offsprings of rats treated with daily injection of chlordiazepoxide (10 mg/kg, i.p.) during pregnancy showed a significant decrease in benzodiazepine receptors in the cortex and the cerebellum without apparent changes in receptor affinity. A reduced susceptibility to metrazol-induced epileptogenesis paralleled this change. These findings are discussed in relation to the differential vulnerability of various types of benzodiazepine receptors.

Animals↗

PubMed1979

Effects of gamma-acetylenic GABA and gamma-vinyl GABA on metrazol-activated, and kindled seizures.

Pretreatment of adult male Sprague-Dawley rats with a single dose of gamma-vinyl GABA (GVG) (1200 mg/kg, IP) or gamma-acetylenic GABA (GAG) (100 mg/kg, IP) did not affect the threshold of metrazol-activated generalized seizures, but increased their duration to the point of status epilepticus. In rats with epilepsy kindled by amygdaloid stimulation, a single dose of GVG (800 mg/kg, IP) and five subsequent daily administrations of GAG (80 mg/kg, IP) tended to reduce the motor manifestations of seizures leaving unaffected their electrographic pattern. The effects of GVG and GAG are attributed in part to decreased arousal. Practical implications of these findings are discussed.

Alkynes↗

PubMed1986

Computer-assisted predictive mathematical relationship among metrazol dose and time and mortality in mice.

A microcomputer program in BASIC for predicting mortality in mice administered metrazol is designed. A formula published by the author to express the mathematical relationship among the drug dose, the time after administration, and the biological response was used in this program. Analysis of the actual and the computer-assisted predicted mortalities has shown that the program is fairly accurate and reliable in expressing tolerance of mice as a function of the dose and the time.

Animals↗

PubMed1993

Metrazole induction of c-fos and proenkephalin gene expression in the rat adrenal and hippocampus: pharmacological characterization.

We have previously reported that the administration of metrazole (MTZ) produces a sequential, dose-dependent induction of c-fos and proenkephalin (Penk) gene expression in the rat hippocampus and adrenal. The adrenal is more sensitive to induction of these genes by MTZ. In the present study, we have compared the induction of c-fos and Penk in the hippocampus and adrenal, and examined the consequences of selected pharmacological manipulations. Treatment with LY274614, a competitive NMDA-receptor antagonist, blocked MTZ-induced convulsions and the MTZ-induction of c-fos and PPenk mRNAs in the hippocampus, and PPenk mRNA in the adrenal. However, in the adrenal the MTZ-induction of c-fos was only partially inhibited by LY274614. A combination of peripheral acting cholinergic antagonists (chlorisondamine plus methylatropine) prevented the MTZ-induction of adrenal c-fos and PPenk mRNA without significant alterations in the MTZ-induction of hippocampal c-fos mRNA or convulsions. Trifluoperazine, a calcium/calmodulin inhibitor, attenuated the MTZ-induction of c-fos mRNA while potentiating the MTZ-induction of PPenk mRNA in both the hippocampus and the adrenal. These results demonstrate that the MTZ induction of c-fos and Penk gene expression in the rat adrenal can be modulated by drugs acting in the CNS at NMDA receptors, in the periphery at postsynaptic cholinergic receptors and intracellularly at the calcium/calmodulin signal transduction pathway. Furthermore, we provide additional evidence that MTZ-induction of c-fos and Penk mRNAs can be dissociated by drugs acting at these sites.

Adrenal Glands↗

PubMed1995

Differential regulation of c-fos, proenkephalin and tyrosine hydroxylase gene expression by metrazole in the hamster adrenal and hippocampus.

Metrazole (MTZ) induces sequential activation of c-fos, proenkephalin (Penk) and tyrosine hydroxylase (TH) gene expression in the rat adrenal and c-fos and Penk gene expression in the rat hippocampus. As in the rat, MTZ produced a dose-dependent induction of c-fos mRNA in the hamster adrenal and hippocampus together with an increase in adrenal TH mRNA. Although MTZ-induction of preproenkephalin (PPenk) mRNA was observed in the hippocampus of the hamster, the same treatment failed to induce PPenk mRNA in the hamster adrenal. These results indicate that Penk gene expression in the hamster is differentially regulated in the adrenal and hippocampus. Furthermore, the regulation of adrenal Penk gene expression differs significantly when rat and hamster are compared.

Adrenal Glands↗

PubMed1977

The temporal dimensions of anticonvulsant action of some newer benzodiazepines against metrazol induced seizures in mice and rats.

In a time-distribution study, the anticonvulsant effects of four benzodiazepine compounds were compared with those of three standard antiepileptics against metrazol-induced seizures in mice and rats. Ethosuximide and trimethadione had the shortest duration of action in mice, but protected the rats up to 6 hr. Phenobarbitone, diazepam, flurazepam and nitrazepam protected the mice up to 12 hr, but the rats were effectively protected only up to 3-4 hr. Clonazepam, the most potent and effective agent, protected the mice from clonic-tonic seizures up to 18-20 hr and the rats up to 6-7 hr. Comparison of the PD50 from clonic seizure at the peak-effect hours revealed that the benzodiazepines were 16 to 96 times more potent than phenobarbitone on a molar basis, while phenobarbitone itself was 12 to 26 times more potent than ethosuximide and trimethadione. Tonic seizures and mortality were largely suppressed by all drugs until 18-20 hr in mice and 6-7 hr in rats. Seizure latency and mortality patterns varied from drug to drug but not in a dose-dependent manner.

Animals↗