| Project/Area Number |
17390159
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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 | 一般 |
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| Research Field |
Applied pharmacology
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| Research Institution | Fukuoka University |
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Principal Investigator |
KATAOKA Yasufumi Fukuoka University, Faculty of Pharmaceutical Sciences, Professor (70136513)
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| Co-Investigator(Kenkyū-buntansha) |
SAITOU Takao Fukuoka University, Faculty of Medicine, Professor (10125552)
KANEOKA Hidetoshi Fukuoka University, Faculty of Medicine, Professor (20161169)
YAMAUCHI Atsushi Fukuoka University, Faculty of Pharmaceutical Sciences, Associate Professor (90341453)
SHUTO Hideki Fukuoka University, Faculty of Pharmaceutical Sciences, Associate Professor (60412574)
NIWA Masami Nagasaki University, Graduate School of Medicine, Department of Pharmacology 1, Professor (20136641)
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| Project Period (FY) |
2005 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥15,760,000 (Direct Cost: ¥14,800,000、Indirect Cost: ¥960,000)
Fiscal Year 2007: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2006: ¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 2005: ¥8,400,000 (Direct Cost: ¥8,400,000)
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| Keywords | Rheumatoid arthritis / Immunosuppressant / Blood-brain barrier / Pericyte / Microglia / Neurotoxicity / Inflammation / アストロサイト / 脳ペリサイト / TGF-β / 後期糖化反応生成物 / 中枢毒性 |
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| Research Abstract |
Cyclosporin A (CsA) and tacrolimus (TCL), are widely used as a potent immunosuppressant to prevent allograft rejection in solid organ transplantation and to treat various autoimmune diseases including rheumatoid arthritis. Despite its high efficacy, these immunosuppressants have adverse effects including renal dysfunction, hepatopathy, and neurological complications. Our previous findings showed that CsA disrupts the blood-brain barrier (BBB) function by inhibiting transforming growth factor (TGF)-β production. In patients with rheumatoid arthritis (RA), proinflammatory cytokines, S100 / calgranulins and ligands of RAGE (receptor for advanced glycation end products (AGEs)) were highly accumulated in their synovial fluid and plasma. The present study was aimed at elucidatig the mechanism of immunosuppressants-induced neurotoxicity / nephrotoxicity in RA. We hypothesized that these RA-related bioactive substances might be the risk factor of them. Our findings obtained here were summerize
… More
d below.
1. We established an in vitro BBB reconstruction model by co-culturing with rat brain microvascular endothelial cells, pericytes and astrocytes. The coordination among these three cells is suggested to be essential for the expression and maintenance of BBB function. Pericytes contribute to the up-regulation of BBB functions by facilitating TGF-β production. Our in vitro BBB model reconstructed with microvascular endothelial cells, pericytes and astrocytes is useful for BBB research including brain transport assay of drugs.
2. In vitro BBB model, AGEs induced hyperpermeability and P-gp dysfunction via RAGE in brain microvascular endothelial cells.
3. In vitro BBB model, lipopolysaccharide (LPS) induced endothelial barrier dysfunction. In vivo, mice treated with LPS exhibited migration of pericytes from vascular wall and degeneration of basal lamina. In parallel with morphological alterations of pericytes, hyperpermeability and activation of microglia was observed in LPS-treated mice.
4. In co-culture system of rat brain microvascular endothelial cells and microglia, activated microglia induced endothelial barrier dysfunction.
We tentatively concluded that BBB dysfunction induced by ligands of RAGE, proinflammatory cytokines and activation of microglia is included in the risk factors for immunosuppressants-induced neurotoxicity in RA. Less
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