title: FK506 reduces neuroinflammation and dopaminergic neurodegeneration in an α-synuclein-based rat model for Parkinson's disease.
abstract: Alpha-synuclein (α-synuclein) is considered a key player in Parkinson's disease (PD), but the exact relationship between α-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 α-synuclein overexpression rat model. Treatment with FK506 significantly increased the survival of dopaminergic neurons in a dose-dependent manner. No reduction in α-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 α-synuclein-based PD model, pointing to a causal role of neuroinflammation in the pathogenesis of PD.
authors: Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, KU Leuven, Flanders, Belgium.
authors: Anke
authors: A
authors: Van der Perren
authors: Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, KU Leuven, Flanders, Belgium.
authors: Francesca
authors: F
authors: Macchi
authors: Molecular Virology and Gene Therapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Flanders, Belgium.
authors: Jaan
authors: J
authors: Toelen
authors: Molecular Virology and Gene Therapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Flanders, Belgium.
authors: Marianne S
authors: MS
authors: Carlon
authors: Molecular Virology and Gene Therapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Flanders, Belgium.
authors: Michael
authors: M
authors: Maris
authors: Division of Nephrology and Renal Transplantation, Department of Microbiology and Immunology, Leuven University Hospital and KU Leuven, Leuven, Belgium.
authors: Henriette
authors: H
authors: de Loor
authors: Division of Nephrology and Renal Transplantation, Department of Microbiology and Immunology, Leuven University Hospital and KU Leuven, Leuven, Belgium.
authors: Dirk R J
authors: DR
authors: Kuypers
authors: Molecular Virology and Gene Therapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Flanders, Belgium; Leuven Viral Vector Core, KU Leuven, Leuven, Belgium.
authors: Rik
authors: R
authors: Gijsbers
authors: Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, KU Leuven, Flanders, Belgium; Leuven Viral Vector Core, KU Leuven, Leuven, Belgium.
authors: Chris
authors: C
authors: Van den Haute
authors: Molecular Virology and Gene Therapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Flanders, Belgium; Leuven Viral Vector Core, KU Leuven, Leuven, Belgium.
authors: Zeger
authors: Z
authors: Debyser
authors: Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, KU Leuven, Flanders, Belgium; Leuven Viral Vector Core, KU Leuven, Leuven, Belgium. Electronic address: Veerle.Baekelandt@med.kuleuven.be.
authors: Veerle
authors: V
authors: Baekelandt
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents; D016923:Cell Death / Q000187:drug effects; D004195:Disease Models, Animal; D004298:Dopamine / Q000502:physiology; D059290:Dopaminergic Neurons / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D007166:Immunosuppressive Agents; D007249:Inflammation; D008297:Male; D017628:Microglia / Q000473:pathology; D010300:Parkinson Disease / Q000188:drug therapy* / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D066329:Protein Aggregates; D017208:Rats, Wistar; D016559:Tacrolimus / Q000494:pharmacology / Q000627:therapeutic use*; D051844:alpha-Synuclein / Q000235:genetics* / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D007166:Immunosuppressive Agents; D066329:Protein Aggregates; D051844:alpha-Synuclein; D004298:Dopamine; D016559:Tacrolimus
keywords: FK506; Microglia; Neuroinflammation; Parkinson's disease; α-Synuclein