| Project/Area Number |
07457527
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (B)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Physical pharmacy
|
|---|
| Research Institution | Kanazawa University |
|---|
Principal Investigator |
TSUJI Akira Kanazawa University, Pharmaceutics, Professor, 薬学部, 教授 (10019664)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
SAI Yoshimichi Kanazawa University, Pharmaceutics, Associate Professor, 薬学部, 助手 (40262589)
TAMAI Ikumi Kanazawa University, Pharmaceutics, Assistant Professor, 薬学部, 助教授 (20155237)
|
|---|
| Project Period (FY) |
1995 – 1996
|
| Project Status |
Completed (Fiscal Year 1996)
|
| Budget Amount *help |
¥7,700,000 (Direct Cost: ¥7,700,000)
Fiscal Year 1996: ¥2,600,000 (Direct Cost: ¥2,600,000)
Fiscal Year 1995: ¥5,100,000 (Direct Cost: ¥5,100,000)
|
|---|
| Keywords | blood-brain barrier / P-glycoprotein / doxorubicin / secondary active transport / beta-alanine / monocarboxylic acid transporter / adsorptive-mediated endocytosis / peptides / blood-brain-barrier / P-glycoprptein / drug efflux pump / amino acids / adsorptive-mediated endocytosis / blood-brain barrer / doxonibicin / taurine / monocarboxylic acid transpoter / MCT1 |
|---|
| Research Abstract |
The purpose of this research project is to clarify the blood-brain barrier (BBB) functions by regulating carrier-mediated influx and efflux of nutrients and xenobiotics. The following results were obtained by two years term of this research project :
1.In transient brain ischemic rats, ATP depletion in the brain resulted in the 17-fold increase of BBB permeability coefficient (PS) of doxorubicin (DOX), whereas no change of PS-value of sucrose by this ischemia. When the ATP content recovered to a normal level by means of cerebral recirculation of blood, the PS-value of DOX recovered to the control PS-value in normal rats. The uptake of DOX by primary cultured bovine brain capillary endothelial cells (BCECs) expressing P-glycoprotein (P-gp) at the luminal membrane was increased significantly by the depletion of ATP level in BCECs. Present evidence for the ATP-dependent transport of DOX and previous results from our laboratory strongly indicate that P-gp in the brain capillaries functions actively as an efflux pump for lipophilic xenobiotics, providing a major mechanism to restrict the transfer of xenobiotics as well as DOX in the brain.
2.Secondary active transport system for beta-alanine and taurine, which are transported in sodium and chloride-ion dependent manner, functions at both the luminal and antiluminal membranes of the BBB.The transport system was highly selective for beta-amino acids, such as beta-alanine, taurine and hypotaurine.
3.The expression of H^+/monocarboxylate transporter MCT1 in the brain capillaries was clarified by RT-PCR and the nucleotide sequence of the PCR product was confirmed to be the same as that of a part of ratMCT1. This result indicates that MCT1 contributes to pH-dependent and carrier-mediated influx and efflux of monocarboxylic acids at the BBB.
4.Peptides were confirmed to be taken up by BCECs via adsorptive-mediated endocytosis which was affected by charge density and/or lipophilicity of peptides.
|
