2004 Fiscal Year Final Research Report Summary
Immunosuppressants neurotoxicity : The mechanism of immunosuppressants-induced neurotoxicity and the prediction of its risk with gene polymorphisms.
| Project/Area Number |
14370789
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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 |
応用薬理学・医療系薬学
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| Research Institution | Fukuoka University |
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Principal Investigator |
KATAOKA Yasufumi Fukuoka University, Faculty of Pharmaoeutical Sciences, Professor, 薬学部, 教授 (70136513)
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| Co-Investigator(Kenkyū-buntansha) |
TAKAHASHI Mitsuo Fukuoka Univ., Faculty of Pharmaceutical Sciences, Prof., 薬学部, 教授 (70299543)
YAMAUCHI Atsushi Fukuoka Univ., Faculty of Pharmaceutical Sciences, Assist.Prof., 薬学部, 助手 (90341453)
NIWA Masami Nagasaki Univ., Graduate School of Medicine, Dept.of Pharmacology 1, Professor, 大学院・医歯学総合研究科, 教授 (20136641)
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| Project Period (FY) |
2002 – 2004
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| Keywords | Immunosuppressants / cyclosporin A / tacrolimus / neurotoxicity / BBB / NO / TGF-β / genetic polymorphism |
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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, theses immunosuppressants have adverse effects including renal dysfunction, cardiovascular disorders, gastrointestinal disorders and neurological complications. These events occur with a relatively high frequency (20-40%) in organ-transplanted patients. The entry of CsA and TCL into the brain is prevented by the tight junctions and P-glycoprotein(P-gp), a multi-drug efflux pump, of the brain microvascular endothelial cells. But the adverse neurolocical effects of CsA and TCL, including tremors, seizures and encephalopathy, strongly suggest the possibility of CsA and TCL transport across the blood-brain barrier(BBB). The objective of this study is to clarify the mechanism of immunosuppressants-induced neurotoxicity and the prediction of its ri
… More
sk with gene polymorphisms.
1.Potentially positive correlations between mutation in the multidrug resistant 1 gene(ABCB1) and neurotoxic events were detected. Mutation at position 2677 in exon 21 of ABCB1 gene may be an useful probe to predict TCL-induced neurotoxicity.
2.The BBB is a highly organized multicellular complex consisting of an endothelium, brain pericytes and astrocytes. Brain pericyte and astrocyte induce and maintain BBB function. The presence of pericytes and astrocytes markedly aggravated CsA-induced hyperpermeability and P-gp dysfunction in brain microvascular endothelial cells. This aggravation appears to occur due to the inhibition of transforming growth factor- □(TGF-□) production in brain pericytes and the enhancement of NO production in astrocytes.
3.The administration of TCL in the light phase produced a significantly greater increase than that in the dark phase in the duration of harmine-induced tremors in rats. This finding suggests that TCL neurotoxicity may be ameliorated by administration in the active phase of the diurnal cycle.
We tentatively conclude that the polymorphism in the ABCB1 gene and the pathological conditions accompanied with the inhibition of TGF-β production and/or the enhancement of NO production in the brain are included in the risk factors for immunosuppressants-induced neurotoxicity. Less
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