title: Anti-inflammatory Therapy With Simvastatin Improves Neuroinflammation and CNS Function in a Mouse Model of Metachromatic Leukodystrophy.
abstract: Metachromatic leukodystrophy (MLD) is a lysosomal storage disease caused by a functional deficiency of the lysosomal enzyme arylsulfatase A. The prevailing late-infantile variant of MLD is characterized by widespread and progressive demyelination of the central nervous system (CNS) causing death during childhood. In order to gain insight into the pathomechanism of the disease and to identify novel therapeutic targets, we analyzed neuroinflammation in two mouse models reproducing a mild, nondemyelinating, and a more severe, demyelinating, variant of MLD, respectively. Microgliosis and upregulation of cytokine/chemokine levels were clearly more pronounced in the demyelinating model. The analysis of the temporal cytokine/chemokine profiles revealed that the onset of demyelination is preceded by a sustained elevation of the macrophage inflammatory protein (MIP)-1α followed by an upregulation of MIP-1β, monocyte chemotactic protein (MCP)-1, and several interleukins. The tumor necrosis factor (TNF)-α remains unchanged. Treatment of the demyelinating mouse model with the nonsteroidal anti-inflammatory drug simvastatin reduced neuroinflammation, improved the swimming performance and ataxic gait, and retarded demyelination of the spinal cord. Our data suggest that neuroinflammation is causative for demyelination in MLD mice and that anti-inflammatory treatment might be a novel therapeutic option to improve the CNS function of MLD patients.
authors.affiliation: Institut für Biochemie und Molekularbiologie, Rheinische Friedrich-Wilhelms Universität, Bonn, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Stein
authors.affiliation: Laboratory of Biological Psychology, Department of Psychology, University of Leuven, Leuven, Belgium.
authors.forename: Stijn
authors.initials: S
authors.lastname: Stroobants
authors.affiliation: Institut für Biochemie und Molekularbiologie, Rheinische Friedrich-Wilhelms Universität, Bonn, Germany.
authors.forename: Volkmar
authors.initials: V
authors.lastname: Gieselmann
authors.affiliation: Laboratory of Biological Psychology, Department of Psychology, University of Leuven, Leuven, Belgium.
authors.forename: Rudi
authors.initials: R
authors.lastname: D'Hooge
authors.affiliation: Institut für Biochemie und Molekularbiologie, Rheinische Friedrich-Wilhelms Universität, Bonn, Germany. Electronic address: matzner@uni-bonn.de.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Matzner
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage; D002490:Central Nervous System / Q000187:drug effects* / Q000503:physiopathology; D018932:Chemokine CCL2 / Q000096:biosynthesis; D054407:Chemokine CCL4 / Q000096:biosynthesis; D003711:Demyelinating Diseases / Q000188:drug therapy / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000503:physiopathology; D007966:Leukodystrophy, Metachromatic / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D019821:Simvastatin / Q000008:administration & dosage*; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D000893:Anti-Inflammatory Agents; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D054407:Chemokine CCL4; D014409:Tumor Necrosis Factor-alpha; D019821:Simvastatin