Diazepam-atenolol combination antagonizes aminophylline-induced convulsions and lethality in mice

The present study was undertaken to identify protective drugs against aminophylline (240 mg/kg i.p.)-induced convulsions and lethality in mice. Diazepam (10 mg/kg) and valproic acid significantly prevented the convulsions, but were not effective in preventing mortality. Phenytoin, atropine, carbamazepine and atenolol were ineffective in protecting against convulsions and death. Ketamine gave partial protection against convulsions, but was not effective in preventing mortality. Diazepam (10 mg/kg) and atenolol (5 mg/kg) administered together gave total protection against convulsions and death. These results show that aminophylline-induced convulsions are relatively resistant to antiepileptic drugs, and that a combination of diazepam and a beta-blocker (atenolol) has potential as an anti-aminophylline agent.     

Inhibition of aminophylline-induced convulsions in mice by antiepileptic drugs and other agents

Common antiepileptic drugs and agents affecting different neurotransmitter systems were studied against aminophylline (280 mg/kg i.p.)-induced convulsions in mice. All drugs and agents were administered i.p. Diazepam and phenobarbital antagonized the whole seizure pattern and the respective ED50 values for the clonic phase were 3.5 and 62 mg/kg. Valproate at 500 mg/kg protected fewer than 50% of mice against the clonic phase. The remaining antiepileptics (acetazolamide, up to 1,000 mg/kg; carbamazepine and diphenylhydantoin, up to 50 mg/kg; ethosuximide, 500 mg/kg and trimethadione, 400 mg/kg) were totally ineffective in this respect. Propranolol (up to 20 mg/kg), baclofen (20 mg/kg), gamma-hydroxybutyric acid (300 mg/kg), aminooxyacetic acid (20 mg/kg), clonidine (up to 0.2 mg/kg), ketamine (30 mg/kg), atropine (20 mg/kg), papaverine (50 mg/kg) and L-phenylisopropyladenosine (2 mg/kg) did not affect the clonic phase either. Only antagonists of N-methyl-D-aspartic acid excitation, 2-amino-5-phosphonopentanoic acid and 2-amino-7-phosphonoheptanoic acid afforded protection against aminophylline-induced clonic seizure activity. The results show that aminophylline convulsions are relatively resistant to antiepileptic drugs and suggest that antagonists of excitatory transmission are potential antiaminophylline drugs.     

Toluene exposure increases aminophylline-induced seizure susceptibility in mice

The effects of toluene on the sensitivity to seizures induced by aminophylline were investigated. Mice were pretreated with an ip injection of corn oil or toluene (100-500 mg/kg) followed by a timed intravenous infusion of aminophylline at various time intervals to assess the seizure thresholds and lethal doses. Toluene increased seizure susceptibility to aminophylline in a dose- and time-dependent manner. Toluene-induced enhancement of seizure susceptibility to aminophylline occurred as early as 30 min and persisted for at least 3 days after a single administration of toluene (500 mg/kg). Treatment of benzaldehyde, one of toluene's metabolites, also showed an increase in the susceptibility to aminophylline. The enhancing effect was also observed in caffeine-induced seizures 1 h, but not 1 day after toluene treatment. These results suggest that individuals with toluene exposure may increase the risk for convulsive and even lethal complications associated with the therapeutic use of aminophylline.     

Effect of histamine receptor antagonists on aminophylline-induced seizures and lethality in mice

The aim of this study was to evaluate the effects of H(1) (antazoline and astemizole) or H(2) (cimetidine and famotidine) histamine receptor antagonists on the clonic phase, tonic seizures and morality of mice challenged with aminophylline to induce convulsions in mice. Moreover, the total plasma and brain concentrations of theophylline were evaluated. Astemizole (1 mg/kg) did not affect the threshold for aminophylline-induced seizures, but when administered at a dose of 2 mg/kg, it significantly reduced the CD(50) value of aminophylline from 249 mg/kg to 211 mg/kg (p < 0.01). The remaining histamine receptor antagonists studied i.e., antazoline (up to 1 mg/kg), cimetidine (up to 40 mg/kg) and famotidine (up to 10 mg/kg) had no impact on seizure susceptibility in aminophylline-induced convulsions. Furthermore, astemizole (2 mg/kg) decreased latency to the clonic phase of aminophylline-induced convulsions from 51.1 +/- 4.5 to 32.1 +/- 4.3 min (p < 0.01). It is noteworthy that astemizole, a novel H(1) receptor antagonist, did not alter the brain and plasma levels of theophylline, so the existence of pharmacokinetic interactions was excluded. Our results indicate that some interactions between methylxanthines and histamine receptor antagonists may be clinically important since these drugs are usually combined during the treatment of status asthmaticus.     

Effect of fentanyl on lidocaine-induced convulsions in mice

This study was undertaken to examine the effect of fentanyl on lidocaine-induced convulsions in mice. Seventy-five male mice were used and divided into five groups, 15 in each. Convulsions were obtained by lidocaine injection subcutaneously (150 mg/kg), in a dose volume of 0.1 ml/10 g body weight over the upper back. The five groups were: (a) control group: pretreated with normal saline; (b) F50 group: pretreated with fentanyl 50 microg/kg; (c) F100 group: pretreated with fentanyl 100 microg/kg; (d) F200 group: pretreated with fentanyl 200 microg/kg, and (e) F100+N group: pretreated with fentanyl 100 mug/kg plus naloxone 1 mg/kg. The pretreatments were given intraperitoneally (i.p.) 5 min prior to lidocaine injection. After lidocaine injection, the latency to the onset of generalized convulsions was observed for 12 min and recorded. The severity of convulsions was assessed and scored as 1 = mild, 2 = moderate, and 3 = severe. The recovery or death of the mice were also recorded. Student's t, Mann-Whitney U, and Fisher's exact tests were used to analyze the data. Compared with the control group (431.7 +/- 37.3 s), the latencies of onset of convulsions in the fentanyl groups were dose-dependently decreased (F50: 331.0 +/- 37.1 s; F100: 240.3 +/- 28.6 s, p < 0.001; F200: 188.7 +/- 19.4 s, p < 0.001), and the decreased latency was reversed by naloxone (F100+N: 412.9 +/- 34.1 s). Compared with the control group (1.13 +/- 0.19), the severities of convulsions in the fentanyl groups were also increased in a dose-dependent manner (F50: 1.47 +/- 0.19; F100: 1.93 +/- 0.21, p < 0.05; F200: 2.46 +/- 0.17, p < 0.001). Similarly, the increased severity was reversed by naloxone (F100+N: 1.33 +/- 0.16). There was no death in the control and naloxone-treated groups. The incidences of death were 2/15 in F50 group, 5/15 in F100 group, and 7/15 in the F200 group (p < 0.05). The results of this study demonstrated that fentanyl potentiates the lidocaine-induced convulsions in a dose-dependent manner in mice, and this effect may be mediated by an opioid mechanism.     

Effect of nicotinamide on generalized convulsions in mice

It was shown in acute experiments on mice that nicotinamide in doses of 250-500 mg/kg given intraperitoneally increased the latent period of corasole clonico-tonic convulsions without affecting their expressiveness and mortality. When given in a dose of 1000 mg/kg nicotinamide prevented clonico-tonic convulsions and mortality, and considerably raised the latent period of convulsions and the lifespan of the animals intoxicated with thiosemicarbazide and strychnine. The expressiveness of the nicotinamide effects depended on the time of its administration.     

Effect of sigma ligands on the cocaine-induced convulsions in mice

It has been hypothesized that some of negative effects exerted by cocaine are mediated via sigma (sigma) receptors. This report demonstrates the effects of selective sigma ligands, panamesine, DTG, rimcazole and SA 4503, on the cocaine-induced convulsions in mice and locomotor hyperactivity in rats. Only panamesine decreased both these effects of cocaine, whereas DTG and rimcazole increased the total time of cocaine-evoked convulsions and locomotor activity. SA 4503 slightly enhanced and prolonged cocaine-induced convulsions but it was ineffective in locomotor hyperactivity test. Moreover, the increase in cocaine-induced locomotor hyperactivity evoked by DTG was antagonized by panamesine. The obtained results indicate that panamesine, a selective sigma ligand with a preference for sigma1 receptor subtype and potential antagonistic activity, decreased the effects of cocaine. DTG and rimcazole (potential sigma1/sigma2 sites agonists) as well as SA 4503 (potential sigma1 site agonist) showed rather opposite effects. These findings support the idea that sigma2 receptor subtype is involved in psychomotor stimulant effects of cocaine while sigma1 receptor subtype participates in the cocaine-induced convulsions. In addition, sigma receptor antagonists (especially sigma1 ones) are able to antagonize toxic effects of cocaine while sigma agonists facilitate them.     

Effect of toxaphene exposure on immune responses in mice

Toxaphene was fed to female weanling Swiss-Webster mice at dosages of 10, 100, and 200 ppm for 8 wk. Immunologic assays revealed depressed IgG antibody formation in those animals receiving 100 and 200 ppm toxaphene, as compared to controls. Cell-mediated immune responses were not affected in the toxaphene-exposed mice. In another experiment, mature female mice fed the same amounts of toxaphene were mated 3 wk after feeding began and were maintained on the diets until 3 wk after parturition, at which time the pups were weaned onto the control ration. Assays performed on the offspring 8 wk after their birth revealed suppressed antibody formation in the 100-ppm-toxaphene group and enhanced antibody formation in the 200-ppm group. The cell-mediated immune response was suppressed in the offspring from the 100-ppm group, while no change from the controls occurred in the other groups. Phagocytic ability of macrophages was significantly reduced in all toxaphene-treated groups, but to a greater extent in the offspring of the mice that consumed 100 ppm toxaphene.     

Pyrazole exacerbates handling-induced convulsions in mice

Severity of handling-induced convulsions was reduced in mice in comparison to the scores on an initial test administered 4 days earlier. Daily injections of pyrazole, an inhibitor of alcohol dehydrogenase, prevented the reduction of convulsions in handled mice and exacerbated convulsions in mice tested for the first time after injection. The effects of pyrazole were dose-related.     

Antagonistic effect of quninuclidinyl-benzilate on nicotine-induced convulsions in mice

<正> Quninuclidinyl-benzilate (QNB) has long been recognized as a competitive antagonist of muscarinic acetylcholine receptors, while its effects on brain nicotinic acetylcholine receptors were not examined. The results of our preliminary experiments indicated that iv QNB in rats could prevent EEG seizures induced by nicotine 1.0 mg/kg iv. The purpose of this experiment is to examine the effects of QNB on brain nicotinic acetylcholine receptors. Intravenous injection of QNB COHld dose-dependcrltly prevent both behavioral convulsio/is and clonic—tonjc EEG-seizure discharges indaced by nicotine base at the dose of 1.0 mg/kg iv in mice.ED_(50)±CL_(95)=2.0±0.6mg/kgiv,b±S_b=2.8±0.5,r=0.94.The ED_(50) of QNB against nicotine-convulsions was twenty times of that of     

Lack of effect of sildenafil on cocaine-induced convulsions in mice

The convulsant action of cocaine and the proconvulsant effects of sildenafil, a drug which is widely used in the treatment of erectile dysfunction, have been documented both in humans and mice. Since it was reported that sildenafil alone, and in conjunction with cocaine, is used recreationally, the present study was performed to examine the influence of sildenafil on cocaine-induced seizures in mice. We showed that administration of sildenafil (5–20 mg/kg, ip) did not affect latency to clonic seizures induced by ip administration of cocaine at a dose of 85 mg/kg, nor did it influence seizure incidence and mortality. We conclude that sildenafil does not significantly increase the risk of seizures when co-administered with cocaine.     

Effect of prenatal ultrasound exposure on adult behavior in mice

Pregnant Swiss mice were exposed to diagnostic levels of ultrasound (3.5 MHz, Maximum acoustic output: I_SPTP = 1 W/cm² and I_SATA = 240 mW/cm², acoustic power = 65 mW) min on days 11.5 or 14.5 postcoitus (PC). At 3 and 6 months postpartum, offspring were subjected to the following behavioral tests: bright and dark arena test for locomotor/exploratory activity and passive avoidance test for learning and memory. Anxiolytic activity and latency in learning were noticed in the ultrasound-treated animals. The effect was more pronounced in the 14.5 days PC group than in the 11.5 days PC group. But memory was not affected in the ultrasound-exposed animals. There was a nonsignificant decrease in the total locomotor activity at 6 months of age in all the exposed animals. Thus, the present data demonstrate that exposure to diagnostic ultrasound during late organogenesis period or early fetal period in mice may cause changes in postnatal behavior as evidenced by selected adult offspring behavioral tests. However, any conclusive statement in this regard should await results from more detailed investigations.     

Effects of androsterone on convulsions in various seizure models in mice

It is believed that a deficiency of androgens, including free testosterone, may promote the development of convulsions. The present study revealed differences in the action of androsterone (AND), a major excreted metabolite of testosterone and a neurosteroid, in three commonly used seizure models in mice. AND administered intraperitoneally exhibited dose-dependent protection against tonic-clonic convulsions caused by maximal electroshock (MES) with ED₅₀ (effective dose₅₀) of 227 mg/kg. The compound also inhibited the convulsive action of pentylenetetrazole (PTZ), increasing its CD= (convulsive dose₅₀) for clonic convulsions from 77.2 (PTZ + saline) to 93.9 (p < 0.05) for PTZ +AND40 mg/kg and 113.9 mg/kg (p < 0.001) for PTZ +AND60 mg/kg. In mice pretreated with 60 mg/kg AND, the CD₅₀ for PTZ-induced tonic convulsions increased from 102 to 127.6 mg/kg (p < 0.01). Surprisingly, doses of 50 and 100 mg/kg AND lowered the CD₅₀ for kainate (KA)-induced convulsions from 40.8 to 28.7 (p < 0.05) and 25.4 mg/kg (p < 0.001), respectively. In summary, for two of the mouse seizure models, our findings confirmed previous studies that demonstrated protective activity of AND. However, the potentiation of KA-induced convulsions by AND was somewhat unexpected and suggested that AND may also possess proconvulsant activity.     

Effect of short-term lead exposure on PTZ-induced seizure threshold in mice

This study was designed to determine the effect of different concentrations of lead acetate on seizure threshold. Balbc male mice were randomly divided into one control group provided with tap water and four experimental groups received lead acetate in drinking water for 30 days at concentrations of 50, 100, 200 and 400 ppm. Intravenous infusion of pentylenetetrazole (PTZ) was used to induce seizure signs and elapsed time was recorded to calculate the threshold dose. At the end of the experiments blood samples were taken to measure the blood lead level. Threshold doses of PTZ were significantly lower in 100, 200 and 400 ppm lead exposed groups for the induction of all seizure stages. Blood lead level increased in all experimental groups compared to control dose-dependently. Considering the lack of any response induced by 50 ppm concentration of lead, it may be concluded that 100 ppm of lead was the minimal effective dose. Therefore, lead acetate at a concentration of 100 ppm that produces similar blood level in human populations approves the enhancement of convulsive attack risk. Considering the effect of low levels of lead in the reduction of seizure threshold, more investigations should be carried out to clarify the exact mechanisms.     

Effect of adenosine A1 and A2 receptor stimulation on hypoxia-induced convulsions in adult mice.

Clinical observations indicate that seizures induced by hypoxia are common kind of convulsive activity in both infants and elderly patients. The occurrence of seizure episode during hypoxia is important risk factor of epilepsy development in the future. Experimental hypoxia was obtained by exposure of adult (20-23 g) Albino Swiss mice to spontaneous breathing in gas mixture composed of 5% oxygen and 95% nitrogen. The latency time to convulsive activity was determined. Single sublethal episode of seizures induced by hypoxia (HS) resulted in higher susceptibility to pentetrazol (PTZ), bicuculline (BCC), N-methyl-D-aspartic acid (NMDA) but not in electrically induced convulsions. Adenosine A1 receptor agonist, R(-)N6-(2-phenyl-isopropyl)adenosine (R-PIA) (0.01; 0.05; 0.1 mg/kg, i.p.) prolonged the latency to HS-induced convulsions. A1 receptor antagonist, 8-cyclopentyltheophylline (CPT), reversed the protective action of R-PIA. A2 receptor agonist, N(6)-[2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)]ethyladenosine (DPMA), only at the highest dose (5 mg/kg i.p.) prolonged the latency time to convulsive activity. This effect was only partially reversed by A2 antagonist 3,7-dimethyl-1-propargylxanthine (DMPX). Administered immediately after episode of HS R-PIA diminished the higher susceptibility to PTZ, BCC, NMDA at 3rd day after HS, while DPMA appeared to be ineffective. These results confirm the important role of adenosine A1 receptor agonist in protection against acute and chronic epileptogenic effect of hypoxia. The role of adenosine A2 receptors seems to be of minor importance.     

Effect of pretreatment with monoamine oxidase inhibitors or (+)-amphetamine on leptazol convulsions in mice and rats

IT has been claimed that monoamine oxidase inhibitors inhibit the actions of leptazol in experimental animals (Chow & Hendley, 1959; Prockop, Shore & Brodie, 1959; Yen, Salvatore & others, 1962). But other workers have failed to confirm this anticonvulsant action (Kobinger, 1958; Lessin & Parkes, 1959) and some have claimed a proconvulsant effect (Sansome & Dell'Omodarme, 1963; Spoerlein & Ellman, 1961). Reports of the effect of (+)-amphetamine on leptazol convulsions are equally conflicting. Small doses capable of antagonizing electroshock convulsions are described as ineffective against leptazol according to Wolff & Stock (1966), whilst Friebel & Klatt (1959) demonstrated a proconvulsant action. Reserpine enhances the effect of leptazol in animals, the greatest effect appearing to coincide with maximal depletion of tissue amines. If the animals are pretreated with a monoamine oxidase inhibitor before receiving reserpine, however, the subsequent sensitivity of the animal to leptazol is reduced (Pfeifer & Galambos, 1967) or is unaffected (Chen & Bohner, 1961; Spoerlein & Ellman, 1961). We report initial observations during a re-examination of the interaction between leptazol and five representative monoamine oxidase inhibitors.     

Nitric oxide and convulsions in 4-aminopyridine-treated mice

We studied whether N(G)-nitro-L-arginine (NNA), an inhibitor of nitric oxide (NO) synthase as well as L-arginine and molsidomine, two agents elevating NO, influenced convulsions caused by 4-aminopyridine, a K+ channel blocker in mice. NNA, in a dose known to decrease level of NO (40 mg x kg(-1)), enhanced the seizure susceptibility to intraperitoneal (i.p.) and intracerebroventricular (i.c.v.) 4-aminopyridine. L-arginine (500 mg x kg(-1)) and molsidomine (20 mg x kg(-1)) alone did not influence 4-aminopyridine-induced seizure activity. Surprisingly, the proconvulsant effect of NNA upon clonic and tonic seizures was potentiated by molsidomine (20 mg x kg(-1)). No influence of L-arginine on the proconvulsant effect of NNA was found.Taking into account the proconvulsant effect of NNA, an involvement of NO-mediated events in the mechanism of convulsive activity of 4-aminopyridine might be postulated. However, the ineffectiveness of L-arginine and molsidomine to suppress the convulsive activity of 4-aminopyridine as well as a paradoxical potentiation of the proconvulsant effect of NNA by molsidomine seem to exclude the impact of NO pathway on 4-aminopyridine-induced convulsions in mice. Our data suggest that the proconvulsant effect of NNA in this seizure model is caused by other, not related to NO, mechanisms.     

Ethacrynic acid-induced convulsions and brain noradrenaline in mice

The intracerebroventricular injection of ethacrynic acid (a 50% convulsive dose; 50 micrograms/mouse) accelerated brain noradrenaline turnover and decreased noradrenaline contents. The decrease in noradrenaline contents was antagonized by 2-amino-5-phosphonovalerate but not by diazepam. Both 2-amino-5-phosphonovalerate and diazepam suppressed the incidence of ethacrynic acid-induced convulsions while reserpine, alpha-methyl-para-tyrosine or FLA-63 augmented it. The results suggest that stimulation by ethacrynic acid of excitatory amino acid neurons enhances-noradrenergic neuronal anticonvulsive activity.     

硝酸钐染毒对雄性小鼠性行为的影响

目的 探讨不同剂量硝酸钐给药后对雄性小鼠性行为的影响.方法 ICR品系雄性小鼠随机分设5组,自由饮用含硝酸钐0,5,50,500,2000mg/L的溶液90d,运用动物行为学方法观察小鼠各性行为指标的变化.结果 硝酸钐染毒后,雄性小鼠爬跨潜伏期随着染毒剂量的增加而延长,呈现直线变化的剂量对数-效应关系,y:134.5904 34.9810lgx(r=0.9521,P<0.05).其中高剂量(2000mg/L)组小鼠爬跨潜伏期、射精潜伏期和射精间隔期与对照组相比明显延长(P<0.01;P<0.05;P<0.01),而爬跨次数与射精次数明显减少(P<0.01;P<0.05).结论 硝酸钐染毒会对雄性小鼠性行为产生影响.在本实验染毒剂量与研究条件下,亚慢性硝酸钐染毒90d的生殖毒性阈剂量是50mg/L.