Abstracts

Rationale: Oxidative stress is a consequence of prolonged seizures and may contribute to seizure-induced brain damage and to the generation of epilepsy. However, a number of herbals products, which have antioxidant activity, have been shown to slow the onset of seizures or completely block the appearance of seizures suggesting that the generation of reactive oxygen species is involved in seizure initiation. This study tested the anticonvulsant activity of 8 antioxidants that have been shown to have activity in the central nervous system.Methods: Trolox® (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid), a water soluble analog of vitamin E (20 mg/kg), vitamin C (250 mg/kg), melatonin (20 mg/kg), curcumin (200 mg/kg), α-lipoic acid (25 mg/kg), deferoxamine (200 mg/kg), and HBED (N,N’-bis(2-hydroxybenzyl) ethylenediamine-N,N’-diacetic acid, 130 mg/kg) were each was tested for activity against acute seizures induced with pilocarpine (300 mg/kg ip preceded by 1 mg/kg methylscopolamine), kainic acid (10 mg/kg ip) or pentylenetetrazol (PTZ, 75mg/kg sc). The antioxidants were administered intraperitoneally and all were dissolved in normal saline, except for melatonin (ethanol) and curcumin (DMSO). The time to onset of behavioral seizure activity for each convulsant was measured, as well as seizure score and mortality. For PTZ, the seizure duration was also measured. Parameters were averaged across animals in each treatment group and compared with a 1-way ANOVA with post-hoc Dunnett’s comparison to control. Mortality was analyzed using a contingency table and Chi-square test.Results: Trolox, vitamin C, and α-lipoic acid had significant anticonvulsant activity in the pilocarpine model, while HBED and deferoxamine increased mortality. The effects of melatonin were intermediate. The efficacy of Trolox was further examined with a dose-response curve, which showed maximal effects with 20 and 30 mg/kg. The results in the kainic acid model were not as distinct. There was a trend towards an anticonvulsant effect with Trolox, vitamin C and melatonin, but only curcumin significantly reduced the seizure score. Again, there was a trend towards an increase in mortality with HBED. None of the antioxidants had a significant effect against PTZ-induced seizures.Conclusions: It was expected that the antioxidants would have the greatest effect on the latency to the first seizure. The results showed that a reduction in seizure score correlated with a trend towards an increase in latency. This would suggest that neuronal activity generates reactive oxygen species, which in turn contributes somewhat to synchronization or spread of the neuronal activity. However the anticonvulsant activity of the antioxidants is not uniform across the 3 experimental models. This group of antioxidants had no effect against PTZ, perhaps because of the rapid onset of the seizures in this model. None of the antioxidants were as consistently effective as a previously tested ginseng extract, which is reported to work as an antioxidant. The iron chelators, which have been shown to have neuroprotective activity, actually appear to increase mortality in these models.