DEVELOPMENT OF NEW ANTIEPILEPTIC DRUG FROM BIOTOXIN WITH EFFECT ON NON-NMDARECEPTOR

生物毒素作用于非NMDA受体的新型抗癫痫药物的开发

• 批准号: 07807089
• 负责人: ISHIDA Nobuya
• 金额: $ 1.73万
• 依托单位: SHIGA UNIVERSITY OF MEDICAL SCIENCE
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1995
• 资助国家: 日本
• 起止时间: 1995 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07807089/
• 关键词: ANTIEPILEPTIC DRUG; AMPA RECEPTOR; KINDLING; JORO SPIDER TOXIN; 1-NAPHTYLACETYL-SPERMINE; EPILEPSY; PYRAMIDAL CELL LOSS; NON-NMDA RECEPTOR; ANTLEPILEPTIC DRUG; 1-NAPHTYL ACETYL-SPERMINE; non-NMDA型受容体; ジョロウグモ毒素; アニラセタム; サイクロサイアザイド; てんかん; 細胞障

In order to clear that 1-naphtyl acetyl spermine (1-NA-Spm), an analogue of JORO spider toxin, has anticonvulsant effect on some epileptic models, we used the model of AMPA-induced seizure and kindled animals.It has been known that cyclothiazide affect AMPA receptors as allosteric modulator. In vivo studies showed that cyclothiazide potentiated AMPA receptor mediated current by decreasing desensitization. In this study, cyclothiazide potentiated AMPA-induced convulsive seizures in a dose dependent manner and caused an extensive loss of CA3/4 pyramidal cells. Pretreatment of 1-NA-Spm inhibits both cyclothiazide potentiated AMPA-induced convulsive seizures and degeneration of pyramidal cells.In amygdaloid kindled animals, 1-NA-Spm dose-dependently improved seizures and shortend the discharge duration 30 min after the administration. The anticonvulsant effect was observed even one day after the frug, and then gradually disappeared within 4 days.The present findings demonstrate that 1-NA-Spm acts as a potent and long-acting anticonvulsant and would be possible candidate for new antiepileptic drug.

为了明确JORO蜘蛛毒素的类似物1-萘基乙酰精胺(1-NA-Spm)对某些癫痫模型具有抗惊厥作用，我们使用AMPA诱发癫痫发作的模型并点燃动物。环噻嗪作为变构调节剂影响 AMPA 受体。体内研究表明，环噻嗪通过减少脱敏作用增强 AMPA 受体介导的电流。在这项研究中，环噻嗪以剂量依赖性方式增强 AMPA 诱导的惊厥性癫痫发作，并导致 CA3/4 锥体细胞大量损失。 1-NA-Spm 预处理可抑制环噻嗪增强的 AMPA 诱导的惊厥性癫痫发作和锥体细胞变性。在杏仁核点燃的动物中，1-NA-Spm 剂量依赖性地改善癫痫发作并缩短给药后 30 分钟的放电持续时间。停药一天后即可观察到抗惊厥作用，然后在 4 天内逐渐消失。目前的研究结果表明，1-NA-Spm 是一种强效、长效的抗惊厥药，有可能成为新型抗癫痫药物的候选药物。

项目成果

Ishida, N., Akaike, M., Tsustumi, S., Kanai, H., Masui, A., Sadamatsu, M., Kuroda, Y., Watanabe, Y., McEwen, B.S.and Kato, N.: "Trimethyltin syndrome as a hippocampal degeneration model : temporal changes and neurochemical features of seizure susceptibili

Ishida, N.、Akaike, M.、Tsustumi, S.、Kanai, H.、Masui, A.、Sadamatsu, M.、Kuroda, Y.、Watanabe, Y.、McEwen, B.S. 和 Kato, N.：“

Takazawa, A., Yamazaki, O., Kanai, H., Ishida, N., Kato, N.and Yamauchi, T.: "Potent and long-lasting anticonvulsant effects of 1-naphthylacetil spermine an analogue of Joro spider toxin, against amygdaloid kindled seizures in rats." Brain Research. 706.

Takazawa, A.、Yamazaki, O.、Kanai, H.、Ishida, N.、Kato, N. 和 Yamauchi, T.：“1-萘乙酰精胺（Joro 蜘蛛毒素的类似物）具有有效且持久的抗惊厥作用，

Takazawa, A., Yamazaki, O., Kanai, H.et al: "Potent and long-lasting anticonvulsant effects of 1-naphthylaoetil spermine,an analogue of Joro spider toxin,against amygdaloid kindled seizures in rats." Brain Research. 706. 173-176 (1996)

Takazawa, A.、Yamazaki, O.、Kanai, H.等人：“1-naphthylaoetil 精胺（Joro 蜘蛛毒素的类似物）具有有效且持久的抗惊厥作用，可对抗杏仁核引发的大鼠癫痫发作。”

Akira Takazawa et al.: "Potent and long‐losting anticonvulsant effects of 1‐naphtylacetyl spermine,an analogue of Joro spider toxin,against amygdaloid kindled seizures in rats." Brain Research. 706. 173-176 (1996)

Akira Takazawa 等人：“1-萘乙酰精胺（Joro 蜘蛛毒素的类似物）对大鼠杏仁核癫痫发作具有有效且长期失效的抗惊厥作用。706. 173-176 (1996)。

Ishida, N.Akaike, M.Tsutyumi, S.et al.: "Trimethyltin syndrome as a hippocampal degeneration model : temporal changes and neurochemical features of seizure susceptibility and learning impairment." Neuroscience. 81. 1183-1191 (1997)

Ishida, N.Akaike, M.Tsutyumi, S.等人：“三甲基锡综合征作为海马变性模型：癫痫易感性和学习障碍的时间变化和神经化学特征。”