MECHANISMS OF KINDLED SEIZURE SUPPRESSION BY CYSTEAMINE

半胱胺抑制癫痫发作的机制

• 批准号: 3901578
• 负责人: S NADI
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3901578
• 关键词: aminoacid metabolism; anticonvulsants; brain metabolism; catecholamines; convulsions; cysteamine; dosage; drug administration routes; drug metabolism; injection /infusion; laboratory rat; neurochemistry; neuromuscular disorder chemotherapy; neuropeptides; neuropharmacology; norepinephrine; receptor sensitivity; somatostatin

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.

半胱胺已被证明可以抑制点燃癫痫发作的剂量从90 当给予点燃至第五阶段的大鼠时， 涉及对大脑化学变化的仔细评估， 为了更好地了解癫痫发作的抑制作用， 半胱胺的作用机制。 本项目的目的是通过以下方式更好地了解这些机制： 半胱胺能消除癫痫 点燃和假点燃的大鼠 将接受单次腹膜内注射 半胱胺（200 mg/kg）。 给药后， 将观察动物的行为变化以及癫痫发作 镇压 将在以下时间间隔内处死大鼠 给予半胱胺，取出脑，并将皮质，小脑， 将解剖中脑、脑桥和海马。 这些组织 将提取并评估肽、氨基酸、受体和 儿茶酚胺水平 化学变化与 癫痫发作抑制可允许鉴定一种化学改变 癫痫发作减少 研究的下一步将是 确定化合物的拮抗剂是否也会抑制癫痫发作。 目前我们实验室和其他实验室的研究表明， 生长抑素和去甲肾上腺素由于半胱胺而减少 局 半胱胺实验的结果表明， 在药物给药后，癫痫发作的抑制不是发生在 生长抑素最低的点，但在一个点， 生长抑素最接近对照水平。 这些观察结果 表明，抑制癫痫发作后，管理 药物可能是由于受体再敏感化，而不是减少 生长抑素本身。 研究表明， 生长抑素与癫痫发作的阻滞密切相关， 与癫痫的复发相对应 这些观察表明， 生长抑素水平的改变可能在以下方面发挥治疗作用： 癫痫发作