Anticonvulsant-induced changes in tissue manganese, zinc, copper, and iron concentrations in Wistar rats.

Human epileptics have been reported to have low blood manganese (Mn) concentrations in comparison to nonepileptics, an observation that is important because Mn deficiency can increase seizure susceptibility in experimental animals. Factors that have been suggested to contribute to the low blood Mn levels in epileptics include anticonvulsant use, seizure-induced tissue redistribution of Mn, and genetics; in the present study, the first of these possibilities was tested. Wistar rats were fed semipurified diets containing diphenylhydantoin ([DPH] 3 g/kg diet), phenobarbital ([PB] 2 g/kg diet), or primidone ([PRIM] 3 g/kg diet) for 7 weeks, at which time they were killed and tissues collected and analyzed for Mn, zinc (Zn), copper (Cu), and iron (Fe) concentrations. In comparison to pair-fed rats, DPH- and PRIM-fed rats had significantly elevated liver Mn concentrations, while Mn concentrations in blood, brain, heart, and kidney were unaffected by anticonvulsant exposure. Changes in the concentrations of Zn, Cu, and Fe in specific tissues were also found. Overall, these findings suggest that the anticonvulsants tested do not lead to significant derangements in the metabolism of Mn.

Effects of age on seizure susceptibility in genetically epilepsy-prone rats (GEPR-9s).

To study the effect of age on seizure latency, intensity, reproducibility, and mortality in genetically epilepsy-prone rats of the severe colony (GEPR-9s), 472 seizure-naive rats, ranging in age from 14 to 65 days, received a series of three audiogenic stimulations. Both the percentage of rats having one or more seizures and the percentage of seizures that were stage 9 generally increased with advancing age of the animal at the time of the first stimulation. Mean latency to seizure onset decreased while seizure intensity increased with increasing age of the animal. Reproducibility of seizure stage also increased with advancing age of the animal. The effects of senescence on seizure susceptibility were also investigated in an additional 18 prepubescent rats (25-35 days) who received three audiogenic stimulations and were tested again between the ages of 480 and 540 days with identical testing procedures. No significant changes occurred with either latency to seizure onset or seizure intensity in rats tested during prepubescence and again at senescence. Although GEPR-9s provide an excellent model of inherited seizures, latency to seizure onset, seizure intensity, and seizure reproducibility is dependent on age of the animal. Once established, however, audiogenic-induced seizures persist throughout life.

Effects of seizures on learning, memory, and behavior in the genetically epilepsy-prone rat.

To determine whether frequent seizures can cause deficits in learning and behavior, immature genetically epilepsy-prone rats (GEPRs) were subjected to 66 audiogenic stimulations (Group 1). GEPR littermates were handled and placed in the sound chamber but were not stimulated (Group 2). Group 3 comprised genetically epilepsy-resistant rats (GERRs) who received audiogenic stimulations but had no seizures. After 3 weeks of stimulations the rats were tested for learning, memory, and behavior using the T-maze, water maze, open field activity test, home cage intruder test, and handling test. When compared with the control GEPRs and GERRs, Group 1 rats reached criteria less frequently in the T-maze, required longer times to find the platform in the water maze, and were less active in the open field activity test, less aggressive in the home cage intruder test, and more irritable and aggressive in the handling test. This study demonstrates that frequent, brief seizures in immature animals result in significant detrimental changes in learning, memory, activity level, and behavior.