FK506 reduces neuroinflammation and dopaminergic neurodegeneration in an α-synuclein-based rat model for Parkinson's disease

NEUROBIOLOGY OF AGING

卷:36

Article

Toelen, Jaan¹  Carlon, Marianne S.¹  Maris, Michael¹  de Loor, Henriette^2,3  Kuypers, Dirk R. J.^2,3  Gijsbers, Rik^1,4  Van den Haute, Chris⁴  Debyser, Zeger^1,4  Baekelandt, Veerle⁴ 

[1] Katholieke Univ Leuven, Dept Pharmaceut & Pharmacol Sci, Mol Virol & Gene Therapy, Flanders, Belgium

[2] Leuven Univ Hosp, Dept Microbiol & Immunol, Div Nephrol & Renal Transplantat, Leuven, Belgium

[3] Katholieke Univ Leuven, B-3000 Leuven, Flanders, Belgium

[4] Katholieke Univ Leuven, Leuven Viral Vector Core, B-3000 Leuven, Flanders, Belgium

关键词: alpha-Synuclein;    Parkinson's disease;    FK506;    Neuroinflammation;    Microglia;   

DOI  :  10.1016/j.neurobiolaging.2015.01.014

来源: Elsevier

【 摘 要 】

Alpha-synuclein (alpha-synuclein) is considered a key player in Parkinson's disease (PD), but the exact relationship between alpha-synuclein aggregation and dopaminergic neurodegeneration remains unresolved. There is increasing evidence that neuroinflammatory processes are closely linked to dopaminergic cell death, but whether the inflammatory process is causally involved in PD or rather reflects secondary consequences of nigrostriatal pathway injury is still under debate. We evaluated the therapeutic effect of the immunophilin ligand FK506 in a rAAV2/7 alpha-synuclein overexpression rat model. Treatment with FK506 significantly increased the survival of dopaminergic neurons in a dose-dependent manner. No reduction in alpha-synuclein aggregation was apparent in this time window, but FK506 significantly lowered the infiltration of both T helper and cytotoxic T cells and the number and subtype of microglia and macrophages. These data suggest that the anti-inflammatory properties of FK506 decrease neurodegeneration in this alpha-synuclein-based PD model, pointing to a causal role of neuroinflammation in the pathogenesis of PD. (C) 2015 Elsevier Inc. All rights reserved.

【 授权许可】

Free