2001 Fiscal Year Final Research Report Summary
Spinal cord regeneration by immunosuppressive drugs and their derivatives
| Project/Area Number |
11557106
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
Cerebral neurosurgery
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| Research Institution | Gifu Pharmaceutical University |
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Principal Investigator |
FURUKAWA Shoei Gifu Pharmaceutical University, Professor, 薬学部, 教授 (90159129)
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| Co-Investigator(Kenkyū-buntansha) |
FURUKAWA Yoshiko Aichi Bunkyo Women's College, Professor, 教授 (20219108)
NITTA Atsumi Gifu Pharmaceutical University, Assisitant Professor, 薬学部, 助手 (20275093)
NOMOTO Hiroshi Gifu Pharmaceutical University, Associate Professor, 薬学部, 助教授 (80164747)
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| Project Period (FY) |
1999 – 2001
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| Keywords | immunosuppressive drugs / neurotrophic factors / spinal cord injury / neuroprotection / nerve regeneration / 損傷報復 |
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| Research Abstract |
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.
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