Involvement of excitatory amino acid mechanisms in gamma-hydroxybutyrate model of generalized absence seizures in rats.

gamma-Hydroxybutyric acid (GHB), a naturally occurring compound which is synthesized from gamma-aminobutyric acid (GABA), induces bilaterally synchronous spike wave discharges, associated with behavioral changes, reminiscent of petit mal or generalized absence seizures in rats. In the present study, possible involvement of excitatory amino acids (EAAs) in GHB-induced spike wave discharges was investigated. The noncompetitive antagonist of NMDA receptors, MK-801, attenuated GHB-induced spike wave discharges at all doses tested (0.025-1.0 mg/kg) but dose-dependently induced suppression of EEG bursts in GHB-treated animals. The suppression of bursts was never observed with GHB in control experiments. N-Methyl-D-aspartate (NMDA) had a similar effect on GHB-induced spike wave discharges, when it was administered prior to GHB. This effect of NMDA was partially reversed by MK-801. The competitive antagonists of NMDA receptors, (+/-)CPP and CGP 43487 and the antagonist at the strychnine-insensitive glycine site, HA-966, also suppressed GHB-induced spike wave discharges with the EEG progressing to suppression of bursts but were weaker in this regard than MK-801 or NMDA. These data raise the possibility of involvement of excitatory amino acids in the GHB model of absence seizures.     

Effect of theophylline on diazepam and sodium valproate protection in pentylenetetrazole - kindled seizures in rats

Theophylline is well known for its convulsant and proconvulsant action. Some experimental studies also suggest that theophylline and other methylxanthines may impair the protection of antiepileptic drugs. The interaction of theophylline and the antiepileptic drugs diazepam and sodium valproate was studied in pentylenetetrazole (PTZ) - kindled seizures in rats. Pretreatment with both diazepam 4 mg/kg and sodium valproate 300 mg/kg, i.p., showed protection against PTZ kindled seizures. Theophylline, 50 mg/kg, i.p., when given before the antiepileptic drugs, failed to reverse their protection. Since theophylline has an adenosine receptor antagonist activity which may be responsible for its convulsant potential, the results indicate non-involvement of adenosinergic mechanisms in the mechanisms of actions of these antiepileptic drugs.     

Comparison of antiepileptic action of valproate and ethosuximide in adult and immature rats

The antiepileptic action of ethosuximide and valproate was studied in immature rats in the pentetrazole (PTZ) model. Valproate antagonized the effect of PTZ in rats of all ages, while ethosuximide was effective only in rats of 25 or more days of age: in 18 day old rats it modified the PTZ seizure pattern and was ineffective in younger animals or only slightly affected the PTZ seizure pattern. Similarly, the ECoG studies have shown that valproate antagonizes PTZ action at all ages, while ethosuximide only in mature rats.     

Proconvulsant effect of morphine on seizures induced by pentylenetetrazol in the rat

The chemoconvulsant pentylenetetrazol (PTZ) was administered by a variety of routes to rats pretreated with morphine (10-50 mg/kg s.c.). In a naloxone-reversible, dose-dependent manner, morphine decreased the threshold for seizures induced by the slow intravenous infusion of PTZ. In addition, morphine increased the severity of seizures induced by the intravenous, intraperitoneal, and subcutaneous routes of administration of PTZ. Morphine also caused an increased incidence of multiple seizures following subcutaneous administration of PTZ. These results demonstrate that morphine has a proconvulsant effect on PTZ-induced seizures in the rat.     

Aspirin modulates the anticonvulsant effect of diazepam and sodium valproate in pentylenetetrazole and maximal electroshock induced seizures in mice

Release of prostaglandins in brain after spontaneous and experimentally induced seizures, has been demonstrated. The possible role of prostaglandins in modulation of seizure activity is still inconclusive. In the present study, the effects of aspirin and its interaction with the anticonvulsants (diazepam and sodium valproate) were studied in pentylenetetrazole (PTZ) and maximal electroshock (MES) induced seizures in mice. Aspirin 50, 100, and 500 mg/kg, i.p. was administered 45 min before the pentylenetetrazole (60 mg/kg, i.p.) and MES (60 mA, 0.2 s duration via car clip electrodes) challenge. In MES seizures significant protection was seen with aspirin 100 mg/kg where as higher dose of aspirin 500 mg/kg was required to elicit maximum protection against PTZ seizures. Sub anticonvulsant dose of sodium valproate 150 mg/kg, i.p. and aspirin 50 mg/kg i.p. showed complete protection in MES seizures and the same dose of sodium valproate offered superior protection in PTZ seizures than either drug used alone. When mice were pretreated with combination of diazepam 0.5 mg/kg and aspirin 50 mg/kg protection was significantly enhanced in PTZ seizures. However, aspirin did not show any significant protection with subanticonvulsant dose of diazepam against MES seizures. The present study suggests that prostaglandins may have anticonvulsant potential and also may have modulatory effect on anticonvulsant effect of conventional antiepileptic drugs.     

Differential effects of pentylenetetrazol - and amygdaloid- kindling seizures on emotional memory in rats

Objective： To investigate the effects of repeated seizures induced experimentally on emotional memory in rats. Methods ：Two experimental models of epilepsy were used in the rats ： （a） pentylenetetrazol-kindling seizure, an animal models of human absence epilepsy and myoclonic or generalized tonic-clonic seizures ; （b） amygdaloid - kindling seizure, an animal model of human complex partial epilepsy with secondary generalized seizure. One week after full kindled,     

灵芝孢子粉对癫痫大鼠皮质和海马区NMDAR1免疫反应影响的研究

目的:观察灵芝孢子粉对癫痫大鼠模型皮质和海马区NMDAR1含量及神经元形态学的影响,探索癫痫发病机制以及灵芝孢子粉对癫痫的干预作用.方法:采用戊四氮(PTZ)腹腔注射制作Wistar大鼠慢性点燃模型,并将其分为空白对照组、癫痫模型组和灵芝孢子粉干预组,点燃后断头取脑,行免疫组化染色观察NMDAR1含量的变化及神经元形态学的改变.结果:所有大鼠均达到癫痫模型点燃标准.使用灵芝孢子粉的中药干预组与癫痫模型组相比,脑内NMDAR1含量明显下降(P<0.05),同时神经元形态学改变明显好转.结论:灵芝孢子粉能够有效降低皮质和海马区兴奋性氨基酸受体NMDAR1的含量,使神经元兴奋性减弱,抑制癫痫的发作,从而减轻癫痫发作给神经系统带来的损伤, 以达到抗癫痫作用.所以灵芝孢子粉可能具有减轻痫性发作、保护神经元的作用.     

Reproductive toxicity of sodium valproate in male rats

Objectives:

To assess the effects of sodium valproate on rat sperm morphology, sperm count, motility, and histopathological changes in testis.

Materials and Methods:

Male Wistar rats (12 week old) were treated with sodium valpraote and sacrificed at the end of 2^nd, 4^th, 5^th, 7^th, 10^th and 15^th week after the last exposure to sodium valproate. Epididymal sperm count, sperm motility, sperm morphology, and histopathology of testes were analyzed.

Results:

Sperm count and sperm motility were decreased significantly by sodium valproate. The percentage of abnormal sperms increased in a dose-dependent manner. A histopathological study revealed that sodium valproate had caused sloughing of epithelial cells in testes.

Conclusion:

Sodium valproate causes reversible change in sperm motility, sperm count, morphology, and cytoarchitecture of testes.     

The anticonvulsant activity of ketamine against seizures induced by pentylenetetrazol and mercaptopropionic acid

The activity of the dissociative anaesthetics ketamine and γ-hydroxybutyrate against seizures induced by mercaptopropionate and pentylenetetrazol have been determined. Ketamine (90 mg/kg) prevented the seizures induced by both convulsants, but γ-hydroxybutyrate had negligible anticonvulsant activity. Mercaptopropionate (150 mg/kg) produced a rapid fall in whole brain glutamate decarboxylase activity which correlated with the onset of convulsions. Ketamine given prior to the mercaptopropionate prevented the convulsions, but had no effect on the reduction of enzyme activity. It was concluded that although ketamine was an anticonvulsant it did not act by preventing the inhibition of glutamate decarboxylase responsible for mercaptopropionate-induced convulsions.     

Influence of sodium valproate on sodium and chloride urinary excretion in rats, gender differences

Evidence exists indicating that sodium valproate (VPA) increases diuresis in rats. The chloriuretic and natriuretic effect of VPA has not previously been investigated, so the aim of the present study was to define the peculiarities of 24-hour urinary sodium (Na) and chloride (Cl) excretion in young adult Wistar rats of both genders, and to evaluate the effects of VPA. 24-hour urinary Na, Cl, creatinine and pH levels were measured in 28 control intact Wistar rats and 26 Wistar rats after a single intragastric administration of 300 mg/kg VPA. After VPA administration, 24-hour diuresis and 24-hour diuresis per 100 g of body weight were significantly higher in VPA rats of both genders. 24-hour urine Na and Cl excretion were significantly higher in VPA male and VPA female rats than in gender-matched controls. The 24-hour urinary Cl excretion was found to be significantly higher in VPA male than in VPA female rats. The study data show that VPA, alongside the diuretic effect, enhances Na and Cl excretion with urine. The 24-hour chloriuretic response to VPA in male rats was significantly higher than in female rats. The mechanism of such a gender-related effect is not yet clear.     

Development of tolerance to the anticonvulsant effect of valproate but not to ethosuximide in a rat model of absence epilepsy

Ethosuximide and valproic acid were tested for 4 and 2 weeks, respectively, in rats showing the spontaneous spike-wave syndrome. Ethosuximide suppressed the syndrome at plasma concentrations of 75-100 micrograms/ml. High doses of valproate (170 mg/kg i.p., t.i.d.), resulting in plasma concentrations of about 500 micrograms/ml, were necessary to suppress the syndrome, but signs of tolerance to the drug developed from day 5. Tolerance was confined to the number of spike-wave complexes, whereas the duration of the discharges was shortened to 60% of the control value, without there being signs of tolerance. It is assumed that increases in cerebral GABA, induced by the high concentration of valproate, counteracted the anti-absence effect of the drug in this model.     

The effect of sodium valproate on acetic acid-induced colitis in rats

Ulcerative colitis is a chronic recurrent disease with incomplete treatment options. The current article evaluated the effect of sodium valproate on acetic acid-induced ulcerative colitis in rats. Rats were randomly distributed into six groups including Sham group, colitis control group, sodium valproate treatment groups (50, 100 and 300 mg/kg, i.p.) and dexamethasone-treatment group. Dexamethasone was used as a reference drug. Colitis was induced by intracolonic instillation of 2 mL of 3% acetic acid solution. The efficacy of sodium valproate was evaluated by macroscopical and histopathological scoring systems, hematocrit measurement as well as biochemical analysis including myeloperoxidase (MPO) and pro-inflammatory cytokines assessment. Sodium valproate, particularly with doses of 100 and 300 mg/kg significantly improved weight loss, and macroscopic damage, reduced ulcer area, colon weight, microscopic colitis index and elevated hematocrit level. Biochemical experiments showed elevated levels of colonic MPO activity, interleukin 1β (IL-1β), interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α) in colitis control group. Treatment with sodium valproate at the doses of 100 and 300 mg/Kg) decreased the MPO activity and colonic concentrations of IL-1β, IL-6 and TNF-α. The results provide evidence that sodium valproate has a protective effect in acetic acid-induced ulcerative colitis which might be due to its anti-inflammatory activities, and it may be useful in patients with ulcerative colitis.     

Paradoxical enhancement of seizures in the gerbil after chronic treatment with sodium valproate

Handling-induced seizures in male and female gerbils, at 1 year of age, were significantly increased following continuous administration of sodium valproate throughout postnatal life (600 mg/l in drinking fluid of gerbil dams and of the offspring after weaning; 82-111 mg/kg daily). The weight of the brain and gain in body weight of the valproate-treated gerbils were not significantly changed. Three components of the GABAA receptor complex were examined in cerebral cortical tissue from control gerbils and gerbils chronically treated with valproate. No significant differences were found in saturation binding of [35S]-t-butyl-bicyclophosphorothionate or [3H]flunitrazepam, or in the ability of GABA to stimulate the binding of [3H]flunitrazepam. Further studies of this enhancement of susceptibility to seizures are required since it may be of potential clinical relevance.     

Pentylenetetrazol-induced seizures in pigeons and the effects of ethosuximide thereon

Previous research has shown that ethosuximide in high enough doses disrupts operant responding in pigeons. Whether or not these same doses protect against seizure activity in this species has not been determined. In the present study a system for scoring pentylenetetrazol-induced seizures in pigeons was developed and the effects of ethosuximide on such seizures were evaluated. Pentylenetetrazol at 15, 27 and 47 mg/kg reliably induced seizures in Experiment 1. In Experiment 2 six doses of ethosuximide were tested for their seizure-controlling effectiveness. Doses of 20, 40, 80, 160 and 320 mg/kg ethosuximide had little effect on seizures induced by 27 mg/kg pentylenetetrazol; 640 mg/kg significantly reduced but did not completely eliminate seizures. This dose (640 mg/kg) is several times higher than the doses found to disrupt operant behavior in our previous studies.     

丙戊酸钠对大鼠碳酸锂血清水平的影响

目的探讨丙戊酸钠对碳酸锂血清水平的影响。方法20只大鼠,♀♂各半,随机分成2组,每组各10只。研究组灌喂碳酸锂15 mg.d-15 d后,于d 6开始灌喂丙戊酸钠10 mg.d-1,2种药物共同灌喂3 wk;对照组仅喂碳酸锂15 mg.d-1。分别于d 5、12、19、26抽取尾血2 mL,用于测定碳酸锂血清水平。结果2组4次的碳酸锂血清水平分别是:研究组,(0.198±0.051)(、0.215±0.062)(、0.137±0.042)(、0.177±0.122)mmol.L-1,F=1.949,P=0.139;组内差异无显著性。对照组,(0.172±0.057)(、0.185±0.054)(、0.186±0.059)(、0.180±0.029)mmol.L-1,F=0.166,P=0.919;组内差异无显著性。研究组与对照组血清锂水平比较,仅第3次差异有统计学意义(P<0.05)。结论动物实验表明,丙戊酸钠对碳酸锂的血清水平几乎没有影响,不会引起碳酸锂水平的增高。     

Cardioprotective effects of sodium gamma-hydroxybutyrate (GHB) on brain induced myocardial injury.

Gamma-hydroxybutyrate (GHB) was evaluated as a protective agent in a gerbil model of non-lethal myocardial injury that follows brain ischaemia. The accumulation of fat droplets in myocardial fibers following brain infarction was measured by electron microscopic morphometry and expressed as a percentage of the area of the sarcoplasm. GHB treatment significantly reduced the area occupied by lipid droplets compared with that found in saline treated controls measured both 10 hours (p less than .005) and 24 hours (p less than 0.05) after unilateral carotid ligation. GHB did not affect the ischaemic swelling of the brain.     

Beneficial interaction between vigabatrin and valproate against seizures induced by pentylenetetrazole in mice.

The anticonvulsant effects of adding a non-protective dose of vigabatrin (VGB) to increasing single doses of sodium valproate (VPA) against seizures induced by 110 mgkg(-1) of pentylenetetrazole (PTZ) or by 4.5 mgkg(-1) of picrotoxin (PIC) were compared in CD1 mice with those of VPA alone and vice versa. Neurotoxicity was evaluated by the rotarod test. The study also assessed changes in concentrations of anticonvulsants, gamma-aminobutyric acid (GABA) and glutamate in the whole brain. VGB increased the potency ratio of VPA against PTZ (1.62, P < 0.05) but not against PIC (1.08, n.s.). VGB slightly decreased the neurotoxicity of VPA (0.93, n.s.) and the protective index of VPA was, therefore, increased from 1.93 to 3.34 for the PTZ model and from 1.40 to 1.61 for the PIC model. VGB did not modify brain concentrations of VPA, and increased brain GABA in relation to VPA alone. On the other hand, VGB did not achieve a complete protection neither against seizures induced by PTZ nor against seizures induced by PIC and a non-protective dose of VPA did not significantly modify the effects of increasing doses of VGB. In conclusion, the addition of a non-protective dose of VGB increased the anticonvulsants effects and the protective index of VPA in the PTZ model. A more than expected brain GABA increase together with the lack of a pharmacokinetic interaction support a pharmacodynamic basis for this interaction.