Effects of intraventricular methotrexate administration on Cuprizone-induced demyelination in mice

Andre M Mueller,Esther Jun,Adam Nassery,Hana Conlon,Xinhe Liu,Saud A Sadiq,Massimiliano Cristofanilli,Bo Hyung Yoon

doi:10.3389/fnmol.2013.00034

Abstract

We previously showed that intrathecal administration of methotrexate slowed disability progression in multiple sclerosis (MS) patients with progressive disease. In general MS patients with progressive disease respond poorly to anti-inflammatory therapies. In order to better understand the mechanism by which methotrexate is protective in progressive MS, we analyzed its impact on the non-inflammatory cuprizone-induced demyelination model. When low-dose methotrexate was administered intracerebroventricularly it reduced demyelination and accumulation of GFAP+ reactive astrocytes in the corpus callosum. Administration of methotrexate after the withdrawal of cuprizone neither delayed remyelination nor influenced the number of astrocytes in the corpus callosum suggesting that methotrexate does not interfere with repair processes in the CNS. Moreover, methotrexate increased the expression of IGF1 in vitro and in vivo, a factor known to protect oligodendrocytes and limit the activation of astrocytes. Our studies show that methotrexate has an impact on pathogenic process in a demyelination model whose pathophysiological basis is not primarily related to inflammatory mechanisms, similar to neurodegenerative mechanisms associated with progressive MS. The pronounced inhibitory influence of methotrexate on the accumulation of astrocytes in the corpus callosum suggests that intrathecal methotrexate modulates astroglial activation in progressive MS possibly by promoting CNS production of IGF1.

Highlights

Multiple sclerosis (MS) is characterized pathologically by demyelination, axonal loss and glial scar formation
INFLUENCE OF METHOTREXATE ON CUPRIZONE-INDUCED PATHOLOGY IN THE CORPUS CALLOSUM We aimed to investigate the effect of methotrexate administration on the cuprizone-induced demyelination mouse model that is characterized by a highly reproducible demyelination of distinct brain regions independent of an immune attack on the myelin sheet (Kipp et al, 2009)
We found no significant differences in the number of Iba1+ and GFAP cells and demyelination of the corpus callosum between icv MTX and control treated mice (Figure 4D), corroborating our hypothesis that MTX is not interfering with repair processes in the cuprizone-induced demyelination model

Summary

Introduction

Multiple sclerosis (MS) is characterized pathologically by demyelination, axonal loss and glial scar formation. Most patients have a relapsing-remitting course (RRMS) that over time may become secondarily progressive (SPMS). About 15% of patients have a progressive course from onset (PPMS). Several treatments have been approved by the Food and Drug Administration (FDA) for use in RRMS and SPMS. These therapies are not effective for PPMS and become increasingly ineffective for SPMS especially in the degenerative phase of the disease. More effective therapies need to be developed for the progressive forms of MS (Hawker, 2011)

Objectives

Methods

Results

Conclusion