Reduction of pentylenetetrazol-induced convulsions by the octadecaneuropeptide ODN

Intracerebroventricular injection of the octadecaneuropeptide ODN in mouse, at doses of 12.5-1000 ng, reduced the percentage of convulsing animals and increased the latency of convulsions elicited by pentylenetetrazol (50 mg/kg, intraperitoneal [i.p.]). ODN also reduced the percentage of mortality induced by pentylenetetrazol (100 mg/kg, i.p.). The COOH-terminal octapeptide fragment of ODN was approximately equally effective but acted more rapidly than ODN to reverse the convulsant effect of pentylenetetrazol. ODN (100 ng, intracerebroventricular [i.c.v.]) increased the convulsion latency and reduced the percentage of animals that convulsed after the administration of the inverse agonist of benzodiazepine receptors DMCM (13 mg/kg, i.p.), whereas the benzodiazepine receptor antagonist flumazenil (1 mg/kg, subcutaneously) abrogated the protective effect of ODN (100 ng, i.c.v.) on pentylenetetrazol-induced convulsions. ODN (100 ng, i.c.v.) also reduced the percentage of DBA/2J mice displaying audiogenic convulsions. In contrast, ODN did not reduce the percentage of mice displaying tonic or clonic convulsions when electrical interauricular stimulations were applied. It is concluded that ODN, or more likely a proteolytic fragment derived from ODN, reduces pentylenetetrazol-induced convulsions through activation of central-type benzodiazepine receptors.     

GABA/BZ-and NMDA-receptor interaction in digoxin-induced convulsions in rats.

Digoxin (7.5 micrograms icv) induced 'pop-corn' type of convulsions and 100% mortality. The GABA-ergic agents produced varying degree of protection against digoxin-induced neurotoxicity. Diazepam (4 mg/kg) offered significant protection whereas pentobarbital (5 mg/kg) and baclofen (5 mg/kg) markedly reduced per cent mortality, but ethanol (2 g/kg), progabide (50 mg/kg) and muscimol (0.5 mg/kg) as well as GABA (50 mg/kg) could not offer significant protection in doses used. GABA-ergic agonists; GABA, baclofen, diazepam and pentobarbital when administered along with MK-801 (0.5 mg/kg) a non-competitive NMDA antagonist, a potentiation of anticonvulsant action of MK-801 was observed. MK-801 showed potent anticonvulsant profile in dose range (0.25-1 mg/kg) studied. A synergistic influence of Mg2+ and K+ ions on NMDA receptor antagonism was also observed. A role of GABA-ergic facilitation and NMDA antagonism as a potential anticonvulsant approach in digoxin-induced convulsions in rats has been suggested.     

The effects of perinatal hypoxia on pentylenetetrazol-induced seizures in developing rats

The effects of perinatal hypoxia on susceptibility to seizures due to a single dose (55 mg/kg, i.p.) of pentylenetetrazol (PTZ) were examined, in 15-, 20-, 30-, 60- and 90 to 120-day-old rats. The rats exposed to hypoxia at 10 days of age and the unexposed controls showed similar developmental changes in the types of seizures, ictal electro-encephalograms and severity scores, the last being lowest at 30 days of age. However, the susceptibility to seizures induced by PTZ, which was measured by the mean number of generalized convulsions (GCs) as well as a mean duration of the 1st GC and severity score, was more enhanced in the rats exposed to perinatal hypoxia than in the control group at every age. The present study suggests that hypoxia in rats results in greater seizure susceptibility throughout the developmental period.     

Photic and pentylenetetrazol-induced seizure susceptibility in Macaca mulatta.

Ninety-five out of 100 male Macaca mulatta of varying ages from a restricted habitat in N. India showed no abnormal seizure susceptibility or EEG response to photic stimulation and no electro-clinical features of epilepsy after pentylenetetrazol, 40 mg/kg sc.c. Autopsy studies on the remaining five monkeys with increased seizure proneness revealed depressed skull fractures with cortical trauma in four and a neoplasm in one. Presumably, these factors were responsible for the lowered seizure susceptibility to photic stimulation and pentylenetetrazol activation.     

Serotonin mediation of the protective effect of clonidine against pentylenetetrazol-induced seizures in rats

An intraperitoneal injection of 0.5 mg/kg clonidine significantly increased the latency to the first convulsion and reduced tonic seizures and mortality caused by pentylenetetrazol (PTZ), 90 mg/kg, administered subcutaneously to rats. 1 mg/kg clonidine produced similar effects except that tonic seizures were not significantly affected. No effect was observed with 0.01 or 0.1 mg/kg clonidine. Metergoline (1 mg/kg) and methysergide (10 mg/kg), administered intraperitoneally, completely prevented the effect of 0.5 mg/kg clonidine on PTZ-induced seizures. An intraperitoneal injection of 5 mg/kg of d-fenfluramine, a releaser of 5HT from nerve terminals, significantly reduced tonic seizures and completely blocked mortality caused by PTZ but did not significantly modify the latency to the first convulsion. The results suggest that serotonin plays an important role in the protective effect of 0.5 mg/kg clonidine against PTZ-induced seizures. Possible reasons for the different effects of clonidine on different experimental seizures are discussed.     

Antioxidant activity elicited by low dose of caffeine attenuates pentylenetetrazol-induced seizures and oxidative damage in rats

Although caffeine supplementation has a beneficial effect on people with neurological disorders, its implications for oxidative damage related to seizures are not well documented. Thus the aim of this study was to investigate the effects of two weeks caffeine supplementation (6 mg/kg; p.o.) on seizures and neurochemical alterations induced by pentylenetetrazol (PTZ 60 mg/kg i.p.). Statistical analyses showed that long-term rather than single dose caffeine administration decreased the duration of PTZ-induced seizures in adult male Wistar rats as recorded by cortical electroencephalographic (EEG) and behavioral analysis. The quantification of EEG recordings also revealed that caffeine supplementation protected against a wave increase induced by PTZ. Neurochemical analyses revealed that caffeine supplementation increased glutathione (GSH) content per se and protected against the increase in the levels of thiobarbituric acid reactive substances (TBARS) and oxidized diclorofluoresceine diacetate (DCFH-DA). Also, caffeine prevent the decrease in GSH content and Na⁺, K⁺-ATPase activity induced by PTZ. Our data also showed that the infusion of L-buthionine sulfoximine (BSO; 3.2 μmol/site i.c.v), an inhibitor of GSH synthesis, two days before injecting PTZ reversed the anticonvulsant effect caused by caffeine. BSO infusion also decreased GSH content and Na⁺, K⁺-ATPase activity. However, it increased DCFH-DA oxidation and TBARS per se and reversed the protective effect of caffeine. Results presented in this paper support the neuroprotective effects of low long-term caffeine exposure to epileptic damage and suggest that the increase in the cerebral GSH content caused by caffeine supplementation may provide a new therapeutic approach to the control of seizure.     

Systemic and regional hemodynamics during audiogenic convulsions in rats genetically epilepsy-prone]

Changes in systemic and regional hemodynamic during sound-induced convulsions were measured with microsphere technique in genetically epilepsy-prone rats of Krushinsky-Molodkina (KM-rats) strain. Blood pressure increased from 103 till 178 mm Hg and cardiac index rose from 27.3 till 49.3 ml/min/100 g b. w. during convulsions. Blood flow was increased in the brain and in the heart by 140-700%, whereas in most of internal organs it was decreased by 40-94%.     

Responsiveness of genetically epilepsy-prone rats to intracerebroventricular morphine-induced convulsions

The sensitivity to intracerebroventricular morphine-induced convulsions was determined in members of the severe seizure (GEPR-9) and moderate seizure (GEPR-3) colonies of genetically epilepsy-prone rats as well as in non-epileptic control rats. GEPR-9s were more sensitive to morphine-induced wet-dog shakes, rearing with bilateral forelimb clonus and generalized clonus than controls of GEPR-3s. GEPR-3s were less sensitive to morphine-induced wet-dog shakes and rearing with bilateral forelimb clonus than controls. Both high and extremely low doses of morphine in GEPR-9s elicited tonic extensor convulsions resembling the characteristic sound-induced convulsion of GEPR-9s. The results suggest that opiotergic systems may contribute to the pathophysiology of the seizure-prone condition in GEPR-9s. Further, differences in responsiveness of opiotergic systems in GEPR-3s and GEPR-9s may partially account for differences in seizure severity in the characteristic sound-induced seizures of these two types of GEPRs.     

Evaluation of sphingolipids changes in brain tissues of rats with pentylenetetrazol-induced kindled seizures using MALDI-TOF-MS

Abnormal lipid metabolism has been implicated in the pathogenesis of many neural system diseases, including epilepsy. Pentylenetetrazol (PTZ)-induced kindling in rodents is considered a model of human absence epilepsy and myoclonic, generalized tonic-clonic seizure. In an effort to further understand the mechanism for PTZ-induced seizure, we analyzed crude lipids and sphingolipids in the cortex, hippocampus, and brain stem of normal and PTZ-rats using delayed extraction matrix-assisted laser desorption ionization time-of-flight mass spectrometry (DE MALDI-TOF-MS). It was found that phosphatidylcholines dominated the crude lipids in different tissues and there were no obvious differences in crude lipid profiles of different tissues between normal and PTZ-rats. However, ceramide, sphingomyelins, and ceramide-monohexoside were differently distributed in normal and PTZ-rats. Using the reference mass spectra method established in our laboratory, it was shown that sphingomyelins and ceramide-monohexoside levels were elevated in the brain tissues of PTZ-rats. Ceramide levels were found to be higher in brain stem than in cortex and hippocampus of normal rats, and PTZ caused a general decrease in ceramide levels. These data suggest that changes in sphingolipid metabolism contribute to PTZ-induced seizure.     

Occult pneumococcal bacteraemia and febrile convulsions.

Over two years 29 children had bacteraemia due to Streptococcus pneumoniae at this hospital. In 15 previously healthy children the site of infection could not be identified, and in most of them, bacteraemia was not suspected clinically. All 15 had high total white cell (greater than or equal to 17 x 10(9)/1) and neutrophil (greater than or equal to 11 x 10(9)/1) counts. Twelve children were under 4 years of age, and of these, 10 had been admitted because of a simple febrile convulsion and one had a prolonged febrile convulsion. Occult pneumococcal bacteraemia has been reported in the USA for more than 10 years, but no series has been reported from the United Kingdom. Occult pneumococcal bacteraemia may be an important cause of febrile convulsions. Persisting bacteraemia and the development of focal infections, including pneumococcal meningitis, have been reported. Meningitis did not occur after occult bacteraemia in our patients. Studies to date have been retrospective, and thus the true incidence of the complications and the best treatment are not clear. A prospective study of children with febrile convulsions could provide answers.     

Phencyclidine (PCP) reduces the intensity of caffeine-induced convulsions in rats

The effects of phencyclidine (PCP) on the threshold and intensity of caffeine-induced convulsions in rats were examined. There was a dose-dependent effect of PCP on convulsion intensity with significant reduction in intensity at 4.0 and 8.0 mg/kg PCP. At 16.0 mg/kg PCP, convulsant intensity was reduced in 50% of subjects but potentiated to the point of death in the remaining 50%. PCP had no significant effect on threshold for caffeine-induced convulsions. These results suggest that PCP antagonizes caffeine-induced convulsions and further suggests that the mechanisms involved in onset of caffeine-induced convulsions and the decrease of convulsion intensity are pharmacologically dissociable.