MECHANISMS OF KINDLED SEIZURE SUPPRESSION BY CYSTEAMINE

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Cysteamine has been shown to suppress kindled seizures at doses from 90 mg/kg to 300 mg/kg when given to rats kindled to stage V. This project will involve the careful evaluation of the alterations in brain chemistry and the onset of the suppression of seizures in order to better understand the mechanism of action of cysteamine. The aims of the present project are to better understand the mechanisms by which cysteamine eliminates seizures. Rats which are kindled and sham operated will receive a single intraperitoneal injection of cysteamine(200mg/kg). Following the administration of the drug, the animals will be observed for behavioral changes as well as seizure suppression. The rats will be killed at known time intervals following cysteamine administration, the brain removed, and the cortex, cerebellum, midbrain, ponsmedulla, and hippocampus will be dissected. These tissues will be extracted and evaluated for peptide, amino acid, receptor, and catecholamine levels. The correlation of the chemical changes to the seizure suppression may allow the identification of one chemical alteration with a decrease in seizure activity. The next step in the study will be to determine if antagonists of the compound will also suppress seizures. Studies at present from our laboratory as well as others show that both somatostatin and norepinephrine are decreased as a result of cysteamine administration. The results of the cysteamine experiments have shown that following administration of the drug, the suppression of seizures occurs not at the point where somatostatin is the lowest, but at a point where the levels of somatostatin are the closest to the control levels. These observations suggest that the suppression of the seizures following administration of the drug may be due to a receptor resensitization rather than the decrease of the somatostatin itself. Studies have shown that the decrease of somatostatin closely parallels the block of seizures, and its increase parallels the return of seizures. These observations suggest that the alteration in the levels of somatostatin may play a therapeutic role in seizures.