Biomedicine Xagena

Xagena Mappa
Xagena Newsletter
Medical Meeting

Metachromatic leukodystrophy: Simvastatin improves neuroinflammation and CNS function in a mouse model

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 metachromatic leukodystrophy 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, researchers have analyzed neuroinflammation in two mouse models reproducing a mild, nondemyelinating, and a more severe, demyelinating, variant of metachromatic leukodystrophy, 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)-1alpha followed by an upregulation of MIP-1beta, monocyte chemotactic protein (MCP)-1, and several interleukins.

The tumor necrosis factor (TNF)-alpha 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.
The 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 patients with metachromatic leukodystrophy. ( Xagena )

Stein A et al, Mol Ther 2015;23:1160-1168