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Acta Neuropathologica Communications
Published in: Acta Neuropathologica Communications 1/2014

Open Access 01-12-2014 | Research

CNS-targeted glucocorticoid reduces pathology in mouse model of amyotrophic lateral sclerosis

Authors: Matthew C Evans, Pieter J Gaillard, Marco de Boer, Chantal Appeldoorn, Rick Dorland, Nicola R Sibson, Martin R Turner, Daniel C Anthony, Helen B Stolp

Published in: Acta Neuropathologica Communications | Issue 1/2014

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Abstract

Background

Hallmarks of CNS inflammation, including microglial and astrocyte activation, are prominent features in post-mortem tissue from amyotrophic lateral sclerosis (ALS) patients and in mice overexpressing mutant superoxide dismutase-1 (SOD1 G93A ). Administration of non-targeted glucocorticoids does not significantly alter disease progression, but this may reflect poor CNS delivery. Here, we sought to discover whether CNS-targeted, liposomal encapsulated glucocorticoid would inhibit the CNS inflammatory response and reduce motor neuron loss. SOD1 G93A mice were treated with saline, free methylprednisolone (MP, 10 mg/kg/week) or glutathione PEGylated liposomal MP (2B3-201, 10 mg/kg/week) and compared to saline treated wild-type animals. Animals were treated weekly with intravenous injections for 9 weeks from 60 days of age. Weights and motor performance were monitored during this period. At the end of the experimental period (116 days) mice were imaged using T 2-weighted MRI for brainstem pathology; brain and spinal cord tissue were then collected for histological analysis.

Results

All SOD1 G93A groups showed a significant decrease in motor performance, compared to baseline, from ~100 days. SOD1 G93A animals showed a significant increase in signal intensity on T 2 weighted MR images, which may reflect the combination of neuronal vacuolation and glial activation in these motor nuclei. Treatment with 2B3-201, but not free MP, significantly reduced T 2 hyperintensity observed in SOD1 G93A mice. Compared to saline-treated and free-MP-treated SOD1 G93A mice, those animals given 2B3-201 displayed significantly improved histopathological outcomes in brainstem motor nuclei, which included reduced gliosis and neuronal loss.

Conclusions

In contrast to previous reports that employed free steroid preparations, CNS-targeted anti-inflammatory agent 2B3-201 (liposomal methylprednisolone) has therapeutic potential, reducing brainstem pathology in the SOD1 G93A mouse model of ALS. 2B3-201 reduced neuronal loss and vacuolation in brainstem nuclei, and reduced activation preferentially in astrocytes compared with microglia. These data also suggest that other previously ineffective therapies could be of therapeutic value if delivered specifically to the CNS.
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Metadata
Title
CNS-targeted glucocorticoid reduces pathology in mouse model of amyotrophic lateral sclerosis
Authors
Matthew C Evans
Pieter J Gaillard
Marco de Boer
Chantal Appeldoorn
Rick Dorland
Nicola R Sibson
Martin R Turner
Daniel C Anthony
Helen B Stolp
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Acta Neuropathologica Communications / Issue 1/2014
Electronic ISSN: 2051-5960
DOI
https://doi.org/10.1186/2051-5960-2-66

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