Pentetrazol-induced Convulsions Research Articles

Moringa oleifera Lam Seed Oil Augments Pentobarbital-Induced Sleeping Behaviors in Mice via GABAergic Systems.

Moringa oleifera Lam. (MO), which is widely consumed as both food and herbal medicine in tropical and subtropical regions, has a wide spectrum of health benefits. Yet, whether the oil obtained from MO seeds could affect (improve) the sleep activity remains unclear. Herein, we used the locomotor activity, pentobarbital-induced sleeping, and pentetrazol-induced convulsions test to examine sedative-hypnotic effects (SHE) of MO oil (MOO) and explored the underlying mechanisms. Besides, the main components of MOO like oleic acid, β-Sitosterol, and Stigmasterol were also evaluated. The results showed that they possessed good SHE. Except for oleic acid and Stigmasterol, they could significantly elevate γ-amino butyric acid (GABA) and reduce glutamic acid (Glu) levels in the hypothalamus of mice. Moreover, SHE was blocked by picrotoxin, flumazenil, and bicuculline, except for oleic acid, which could not be antagonized by picrotoxin. Molecular mechanisms showed that MOO and β-Sitosterol significantly upregulated the amount of protein-level expression of Glu decarboxylase-65 (GAD65) and α1-subunit of GABAA receptors in the hypothalamus of mice, not affecting GAD67, γ2 subunits. These data indicated that MOO modulates sleep architectures via activation of the GABAA-ergic systems.

Anticonvulsant and behavioral effects of muscimol in immature rats

Potentiation of GABAergic inhibition is a mechanism of action of many antiepileptic drugs. The potential use of an agonist of GABAA receptors, muscimol, as an antiepileptic drug was studied in immature rats by assessing anticonvulsant activity and side effects on motor activities. Anticonvulsant action was tested in two models of seizures (pentetrazol-induced convulsions and cortical epileptic afterdischarges). Off target effect on motor performance was assessed in a battery of tests and in the open field in three age groups (12-, 18- and 25-day-old rats). Muscimol was administered in doses from 0.1 to 1mg/kg i.p. Only the 1 mg/kg dose exhibited marked anticonvulsant effect against pentetrazol-induced convulsions in 12- and 18-day-old rats, proconvulsant effect was observed in the second model in 18- and 25-day-old rats as prolongation of afterdischarges. Even the 0.5 mg/kg dose suppressed spontaneous locomotion and heavily compromised motor performance. The effect on motor activity was marked in the youngest group and decreased with age. Due to the low anticonvulsant potency and serious side effects, systemic administration of a competitive agonist of GABAA receptors in immature animals is not a promising strategy for new anticonvulsants.

The influence of reboxetine on the protective effect of phenobarbital and ethosuximide in the test of pentetrazolinduced convulsions in mice

The influence of reboxetine on the protective effect of phenobarbital and ethosuximide in the test of pentetrazolinduced convulsions in mice

Plasma concentrations of clobazam and its N-desmethyl metabolite; protection against pentetrazol-induced convulsions in mice.

The anticonvulsant effects of acute administration of clobazam and its principal metabolite N-desmethylclobazam were studied in mice. Pentetrazol, given by slow intravenous infusion 1 or 2 h after the anticonvulsant dose, was used as the convulsant stimulus. Log dose response relationships for both clobazam and N-desmethylclobazam appeared linear, but there was no correlation between plasma concentrations of clobazam and protection. However, correlation between plasma concentrations of N-desmethylclobazam and protection was significant in both cases.

Chronic but not acute antidepressant treatment increases pentetrazol-induced convulsions in mice

Traitement des convulsions induites par le pentetrazol chez la souris par des antidepresseurs tricycliques (Imipramine et desipramine). Comparaison entre traitement chronique ou aigu, avant ou apres l'injection de pentetrazol

Anticonvulsant action of 2-chloroadenosine against pentetrazol-induced seizures in immature rats is due to activation of A1 adenosine receptors

Potentiation of adenosinergic inhibitory modulation is one of possible strategies to develop new antiepileptic drugs. Nonspecific receptor agonist 2-chloroadenosine was tested against pentetrazol-induced convulsions in immature (7, 12, 18 and 25days old) and adult rats. Doses of 1-15mg/kg i.p. suppressed tonic phase of generalized tonic-clonic seizures (GTCS) in the two youngest groups, whereas GTCS were abolished in older rats. Minimal clonic seizures in 18-day and older rats were suppressed by high doses of 2-chloroadenosine. The role of A1 and A2A adenosine receptors was studied in 12- and 25-day-old rats. Action of an agonist of A1 receptors CCPA is similar to that of 2-chloroadenosine. An agonist of A2A receptors CGS 21680 exhibits an anticonvulsant action only in the dose-inducing catalepsy; an A2A antagonist ZM 241385 moderately suppressed tonic phase of GTCS only in 12-day-old animals. Anticonvulsant action of adenosine agonists is due to their effects on A1 receptors.

Antagonists of group I metabotropic glutamate receptors and cortical afterdischarges in immature rats

Antagonists of group I metabotropic glutamate receptors (mGluRs) are known to exhibit anticonvulsant action without serious side effects. Recently we found anticonvulsant effects of specific antagonists of mGluR subtypes 1 and 5 (AIDA and MTEP) against pentetrazol-induced convulsions in developing rats. In order to determine if the effects of these two antagonists are not exclusively restricted to pentetrazol-induced seizures, we studied their action in a novel seizure model involving immature rats. Epileptic afterdischarges were elicited by low-frequency stimulation of sensorimotor cortical region in 12-, 18-, and 25-day-old rats with implanted electrodes. Drugs were administered intraperitoneally after the first afterdischarge: AIDA in doses from 5 to 40 mg/kg; MTEP in doses from 2.5 to 40 mg/kg. The stimulation was then repeated five more times with the same current intensity. Electrocorticographic and motor phenomena were recorded and evaluated. AIDA did not significantly influence movements during stimulation, afterdischarges as well as clonic seizures accompanying afterdischarges. In contrast, MTEP was able to significantly shorten afterdischarges without changes in the two motor phenomena. The effect of MTEP was best expressed in 12-day-old rats; in 25-day-old rats the trials exhibited only a transient shortening of afterdischarges after high doses of MTEP. In contrast to similar action against pentetrazol-induced seizures, AIDA and MTEP substantially differ in their action on cortical epileptic afterdischarges. The anticonvulsant action of MTEP in the present model diminishes with age.

選択的セロトニン取り込み阻害作用を有する新しい抗うつ薬Ｐａｒｏｘｅｔｉｎｅの行動薬理学的研究

The behavioral effects of paroxetine were investigated in mice and rats in comparison with imipramine and amitriptyline. 1) Locomotor activities were decreased by imipramine and amitriptyline but not by paroxetine in both animal species. 2) Paroxetine antagonized methamphetamine-induced hyperactivity in mice as did imipramine and amitriptyline. 3) Paroxetine showed a more potent antimuricidal effect in raphe-lesioned rats than imipramine and amitriptyline, and it also inhibited muricide in olfactory bulbectomized rats. 4) The immobility of rats in the forced swimming test was markedly decreased by imipramine and amitriptyline, but only slightly by paroxetine. 5) Like imipramine and amitriptyline, paroxetine potentiated the methamphetamine- or L-DOPA-induced stereotyped sniffing, and it inhibited oxotremorine-induced tremor. 6) Paroxetine antagonized reserpine-induced hypothermia, tetrabenazine-induced ptosis, and enhanced ether-induced anesthesia, all less potently than imipramine and amitriptyline. 7) The analgesic action of paroxetine was stronger than that of imipramine and amitriptyline. 8) Paroxetine did not antagonize maximal electroshock- or pentetrazol-induced convulsions and haloperidol- or THC-induced catalepsy in rats. In addition, paroxetine neither exerted muscle relaxation nor affected the shuttle-box type conditioned avoidance in rats. From these results, the behavioral effects of paroxetine, as compared with imipramine and amitriptyline, were characterized by its potent antimuricidal action in raphe-lesioned rats and its weak effect in the forced swimming test and by its less potent muscle relaxant, anticonvulsant, anticataleptic and anesthesia-potentiating actions.

Effects of Brotizolam, a New Thieno-Triazolo-Diazepine Derivative, on the Central Nervous System

The effects of brotizolam, a new thieno-triazolo-diazepine derivative, on the central nervous system were analyzed in mice, rats and rabbits. Diazepam, estazolam and triazolam were used as control drugs. Brotizolam inhibited spontaneous motor activities; performances in the rotarod test, staircase test, and maximal electroshock seizure test; and pentetrazol- or bemegride-induced convulsion. Moreover, catalepsy inducing action and potentiating effect ,on sleep elicited by pentobarbital or ethanol were observed. Following intraperitoneal or oral administration of brotizolam to rabbits with chronically implanted electrodes, the electro-encephalographic profile in spontaneous EEG was characterized by slow waves with high amplitudes in the neocortex. The arousal responses by stimulation of the midbrain reticular formation and posterior hypothalamus were slightly inhibited, but the recruiting responses induced by stimulation of the diffuse thalamic projecting system were not inhibited, and seizure discharges induced by stimulation of the dorsal hippocampus were inhibited markedly. When motor activities and pentetrazol-induced convulsions were observed as indices of tolerance for brotizolam, tolerance was not developed by repeated administration of brotizolam up to 14 days. These results suggested that brotizolam, a new thieno-triazolo-diazepine derivative, is judged to be a safer and stronger sleep inducer than diazepam and estazolam.

Behavioral effects of suriclone: A new antianxiety drug of Cyclopyrrolone derivative

The effects of suriclone were investigated in various behavioral tests and compared with those of diazepam (DZP) and loraze-pam (LZP). Suriclone, upon single administration, was as potent as LZP, but less potent than DZP in increasing the lever press response in the punished period of a conflict schedule established by combining foot shock and food reward in rats, and suriclone was much longer in duration of action than DZP and LZP. The anticonflict effect of suriclone was markedly potentiated with repeated administration (10 mg/kg/day for 14 days), and this effect was equipotent as DZP. Muricide and hyperemotionality in rats induced by either olfactory bulbecto-my or midbrain raphe lesions were suppressed by suriclone. Suriclone was much more potent than DZP and comparable to LZP in these effects. In preventing maximal electroshock- and pentetrazol-induced convulsions in mice, suriclone was much less potent than DZP and LZP. In potentiating thiopental, ether and ethanol anesthesia in mice, as well as in impairing rotarod performance in mice and rats, suriclone was much less potent than DZP and LZP. These results indicate that the pharmacological properties of suriclone are similar to those of benzodiazepines, and are characterized by potent anticonflict and taming effects with much weaker anticonvulsant, anesthesia-potentiating and ataxic effects.

Brain levels of tofizopam in the rat and relationship with benzodiazepine receptors.

The effect of tofizopam on 3H-flunitrazepam binding was studied in rat hippocampus and cerebellum. Tofizopam (at a concentration of 10(-7) M) increased 3H-Flu binding through a 30% rise in the Bmax with no modification of Kd in either brain area. Similar results were obtained when the binding was measured in tofizopam (50 mg/kg p.o.) pretreated rats. Even though tofizopam has no anticonvulsive action against pentetrazol-induced convulsions, it significantly potentiated the action of diazepam but with no modification of brain diazepam levels and metabolism. The brain levels of tofizopam are reported and compared to plasma levels after oral administration of 5 and 50 mg/kg to rats.

Changes in Averaged Photopalpebral Reflex in Man by A New Benzodiazepine Derivative

The authors have predicted the clinical effects of some anxiolytic drugs by analyses of changes in the averaged photopalpebral reflex (PPR) observed in healthy human adults administered these drugs. In the present study, effects of a new benzodiazepine derivative, ID-622, which possess a potent antagonistic action to pentetrazol-induced convulsions in mice, on PPR were investigated in 8 normal male subjects aged 32-45 years. One mg and 2mg of ID-662, 5 mg of diazepam and inert placebo were given to the subject 30 min after the lunch in a double-blind, cross-over design. PPR was recorded bipolarly from the electrodes placed on the right upper and lower palpebrae before and 0.5, 1, 1.5, 2, 3, 4 hr after drug ad-ministration. Two latencies, i. e., P1 and P2 latencies, and the amplitude of PPR were measured. They were also requested to fulfil the questionnaire for self-as-sessments of drug effects. Diazepam 5mg, ID-622 1mg and 2mg statistically significantly prolonged both the latencies as compared with placebo but failed to exhibit the significant alteration on the amplitude. Statistically significant pro-longations of P1 and P2 latencies were observed by diazepam 5 mg as compared with both doses of ID-622. All the subjective symptoms were slight, however, among them the drowsiness and vagueness induced by diazepam 5 mg were rela- tively potent. These results suggest that ID-622 possess an anxiolytic action, however, 5 mg of diazepam seems to be more potent than the used doses of ID-622 and it is considered to be not always suitable to determine the equipotent dose based on the anti-pentetrazol action in mice alone.