title: Modulation of calcineurin activity in mouse brain by chronic oral administration of cyclosporine A.
abstract: Calcineurin (CN) is an important phosphatase that mediates many physiological and pathological processes. The regulators of calcineurin (RCAN1) and Cu, Zn superoxide dismutase (SOD1) are two endogenous modulators of CN activity. Cyclosporine A (CsA) is a well-known exogenous inhibitor of CN and used as an immunosuppressive drug after transplantation and for the treatment of immune diseases. The degree of CN inhibition by CsA varies among each tissue. The brain accumulates low levels of CsA due to the blood-brain barrier after oral administration. In our study, we investigated RCAN1 and SOD1 expression in long-term CsA-treated mouse brain. Using Western blot, we found that chronic CsA treatment had caused significant up-regulation of RCAN1-1L and RCAN1-4 protein isoforms after 25 days in mouse brain. At the same time, chronic CsA treatment also resulted in decreased expression of SOD1. We simultaneously found more dramatic CN inhibition in mouse brain. It was suspected that the significant reduction of CN activity in vivo resulted partially from up-regulated RCAN1 and down-regulated SOD1 expression. In contrast, CsA treatment in SY5Y cells affected SOD1 expression and CN activity significantly, but had no obvious effects on RCAN1-1 mRNA expression. The changes of RCAN1, SOD1, and CN activity may be part of maladaptive responses, resulting in neuropathological conditions. These data might partially explain CsA neurotoxicity despite the low concentration of CsA in brain.
authors: Department of Biochemistry and Molecular Biology, Beijing Normal University, Gene Engineering and Biotechnology Beijing Key Laboratory, Beijing, People's Republic of China.
authors: Haipeng
authors: H
authors: Liu
authors: Linghui
authors: L
authors: Tu
authors: Qianru
authors: Q
authors: Wang
authors: Yue
authors: Y
authors: Sun
authors: Yipeng
authors: Y
authors: Ma
authors: Juren
authors: J
authors: Cen
authors: Qun
authors: Q
authors: Wei
authors: Jing
authors: J
authors: Luo
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001921:Brain / Q000187:drug effects*; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism*; D002135:Calcium-Binding Proteins; D045744:Cell Line, Tumor; D016572:Cyclosporine / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D051379:Mice; D009124:Muscle Proteins / Q000235:genetics; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D002135:Calcium-Binding Proteins; C511512:DSCR1 protein, mouse; D007166:Immunosuppressive Agents; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; C000606290:SOD1 protein, human; D016572:Cyclosporine; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D019703:Calcineurin