2004 Fiscal Year Final Research Report Summary
The development of a new therapeutic system for the senile dementia -Brain delivery of nerve-growth peptides by nasal application-
| Project/Area Number |
15590145
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Medical pharmacy
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| Research Institution | Shujitsu University (2004)
Setsunan University (2003) |
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Principal Investigator |
SAKANE Toshiyasu Shujitsu University, School of Pharmacy, Associate Professor, 薬学部, 助教授 (50215638)
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| Project Period (FY) |
2003 – 2004
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| Keywords | nasal application / peptides / cerebrospinal fluid / brain delivery / senile dementia |
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| Research Abstract |
The microdialysis system and FITC-dextran (FD) were employed as an experimental method and a model non-degradable macromolecule, respectively. The effect of an endocytosis inhibitor on the transport of FD was investigated. No difference was observed between the amounts recovered in the microdialysis probe in the presence or absence of the inhibitor, suggesting small contribution of the axonal transport of FD from the nasal cavity to the brain. It was clarified that FD with the size up to 50 kDa was recovered in the probe. In case of peptides, the upper limit of the size should be smaller because of its degradation and is speculated to be approximate 10 kDa. The transport of oligopeptide (enkephalin analogue, ENK) from the nose to the cerebrospinal fluid (CSF) was studied. ENK could be detected in the CSF following nasal application, while not after intravenous injection. In comparison with other drugs with a similar size, the concentration of ENK in the CSF is much smaller, suggesting that the degradation in the nasal cavity and/or during the transport through nasal epithelium affects the oligopeptide transport to the CSF. The effect of the permeation enhancer is more significant on the absorption of ENK into the systemic circulation than on the direct transport to the CSF. On the other hand, the protease inhibitors enhanced the direct transport of ENK to the CSF markedly, showing that the protease inhibitor is effective for the brain delivery of peptide through the direct transport pathway between the nose and the brain. Taking all these findings into consideration, the best model peptide may be insulin or insulin-like growth factor. The immunoassay system of these peptides is now under the investigation. After finishing development of the immunoassay system, the similar pharmacokinetic study will be carried out on the model peptide.
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