Abstract Title:

Anti-inflammatory Therapy With Simvastatin Improves Neuroinflammation and CNS Function in a Mouse Model of Metachromatic Leukodystrophy.

Abstract Source:

Mol Ther. 2015 Jul ;23(7):1160-8. Epub 2015 Apr 21. PMID: 25896249

Abstract Author(s):

Axel Stein, Stijn Stroobants, Volkmar Gieselmann, Rudi D'Hooge, Ulrich Matzner

Article Affiliation:

Axel Stein


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 theswimming 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.

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