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Spinal cord regeneration by immunosuppressive drugs and their derivatives

免疫抑制药物及其衍生物的脊髓再生

基本信息

批准号：
11557106
负责人：
FURUKAWA Shoei
金额：
$ 8.45万
依托单位：
Gifu Pharmaceutical University
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 immunosuppressive actions, but the mechanisms under the neurotrophic effects remain unknown. We presumed that immunophilin ligands show the neurotrophic actions by the regulation of synthesis ot 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 immunosuppressive activity is disadvantageous for therapeutic use for general disorders. Therefore, we tried to find an active immunophilin ligand without immunosuppressive activity by focusing the active structure of FK506 and cyclosporin A for binding to immunophilin proteins. Dipeptides composed of hydrophobic amino acid such as Leu-Ile Pro-Leu or Pro-Ile resemble to the active structure of immunosuppressive drugs, and can bind immunophilins. We examined these and their derivatives, and found the Leu-Ile dipeptide and its analogue [A] as active substances with neurotrophic factor synthesis stimulatory activity and without immunosuppressive activity. As both substances were considered to be ideal agents for neuroregeneration, we applied [A] substance once a day for 30 days to the rats with spinal cord semi-transection. Motor activity was started to restore 3 days after the administration, and attained to the level before spinal cord injury. These results suggest that an immunophilin ligand without immunosuppressive activity can stimulate spinal cord regeneration, and may lead to more potent substances valid for clinical use in future.

亲免素配体除了具有免疫抑制作用外，还具有神经营养活性，包括促进神经突起的活性，但其神经营养作用的机制尚不清楚。我们推测亲免素配体通过调节神经营养因子的合成而发挥神经营养作用，并通过体内外实验验证了这种可能性。亲免素配体环孢菌素A（cyclosporin A）和FK 506（FK 506）已被证明在培养的神经元和星形胶质细胞中或在成年大鼠脑中刺激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，提示亲免素配体可能用作某些神经系统疾病的神经保护剂。因此，我们试图通过聚焦FK 506和环孢菌素A与亲免素蛋白结合的活性结构来寻找无免疫抑制活性的亲免素活性配体。由疏水性氨基酸组成的二肽如Leu-Ile、Pro-Leu或Pro-Ile与免疫抑制药物的活性结构相似，能与亲免素结合。我们检查了这些化合物及其衍生物，发现Leu-Ile二肽及其类似物[A]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。由于这两种物质都被认为是神经再生的理想药物，我们将[A]物质每天一次应用于脊髓半横断大鼠，持续30天。给药后3天，运动活动开始恢复，并达到脊髓损伤前的水平。这些结果表明，没有免疫抑制活性的亲免素配体可以刺激脊髓再生，并可能导致更有效的物质在未来的临床使用。