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Development of the agents to stimulate neurotrophin synthesis -An approach for spinal cord regeneration-

神经营养蛋白合成刺激剂的开发-脊髓再生的方法-

基本信息

批准号：
11557111
负责人：
FURUKAWA Yoshiko
金额：
$ 7.55万
依托单位：
Aichi Bunkyo Women's College
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2001
项目状态：
已结题

项目摘要

Immunophilin ligands have been reported to possess neurotrophic activities including neurite-promoting activity in addition to well-known inimunosuppressive actions, but the mechanisms under the neurotrophic effects remain unknown. We presumed that immunophilin ligands show the neurotrophic actions by the regulation of synthesis of neurotrophic factors, and examined this possibility by in vitro and in vivo experiments. Immunophilin ligands, cyclosporin A and FK506, have been proved to stimulate synthesis of brain-derived neurotrophic factor (BDNF) and/or glial cell line-derived neurotrophic factor (GDNF) in cultured neurons and astrocytes or in adult rat brain, suggesting a possible use of immunophilin ligands as neuroprotective agents in some neurological disorders. However, the inimunosuppressive activity is disadvantageous for therapeutic use for general disorders. Therefore, we tried to find an active immunophilin ligand without immunpsuppressive activity by focusing the active structure of FK506 and cyclosporin A for binding to immunophilin protein. Dipeptides composed of hydrophobic aminiacid such as Leu-Ile, Pro-Leu or Pro-He that resemble to the active structure of immunosuppressive drugs, and can bind immunophilins. We examined these and their derivatives, and found the Leu-Ile dipeptide as active substances with neurotrophic factor synthesis stimulatory activity and without immunosuppressive activity." As Leu-Ile was considered to bean ideal agent for neuroregeneration, we applied it once a day for 30 days to the rats with spinal cord semi-transection. However, motor activity was not improved even 30 days after the administration. Much more investigation is necessary to evaluate the Leu-Ile activity on the spinal cord nerve regeneration. Particular points to examine are methods for administration and dosage of the drug.

据报道，亲免疫蛋白配体具有神经营养活性，除了众所周知的免疫抑制作用外，还包括促进神经突的活性，但其神经营养作用的机制尚不清楚。我们推测亲免疫素配体通过调节神经营养因子的合成而表现出神经营养作用，并通过体外和体内实验验证了这一可能性。免疫亲素配体环孢素A和FK506已被证明可以刺激培养的神经元和星形胶质细胞或成年大鼠脑中的脑源性神经营养因子（BDNF）和/或胶质细胞系源性神经营养因子（GDNF）的合成，这表明免疫亲素配体可能用作某些神经系统疾病的神经保护剂。然而，免疫抑制活性不利于一般疾病的治疗使用。因此，我们试图通过聚焦FK506和环孢素A的活性结构与亲免疫蛋白结合，寻找一种无免疫抑制活性的活性亲免疫蛋白配体。由疏水氨基酸组成的二肽，如Leu-Ile、Pro-Leu或Pro-He，类似免疫抑制药物的活性结构，可以结合亲免疫蛋白。我们检查了这些物质及其衍生物，发现亮氨酸二肽是具有神经营养因子合成刺激活性而无免疫抑制活性的活性物质。”由于Leu-Ile被认为是理想的神经再生药物，我们将其应用于脊髓半横断大鼠，每天1次，连续30天。然而，即使在给药后30天，运动活动也没有改善。Leu-Ile活性对脊髓神经再生的影响有待进一步研究。特别要检查的是给药方法和给药剂量。