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Updated: May 6, 2026
Rat Model of Widespread Cerebral Cortical Demyelination Induced by an Intracerebral Injection of Pro-Inflammatory Cytokines
Published on: September 21, 2021
Effects of intraventricular methotrexate administration on Cuprizone-induced demyelination in mice
Andre M Mueller1, Adam Nassery, Hana Conlon
1Tisch MS Research Center of New York New York, NY, USA.
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.
Insights
Methotrexate treatment reduced demyelination and reactive astrocyte accumulation in a progressive multiple sclerosis (MS) model. This suggests a potential therapeutic mechanism beyond anti-inflammatory effects, possibly involving Insulin-like Growth Factor 1 (IGF1).
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Multiple sclerosis (MS) patients with progressive disease show poor response to anti-inflammatory therapies.
- Intrathecal methotrexate previously demonstrated slowed disability progression in progressive MS.
- Understanding methotrexate's protective mechanism in non-inflammatory demyelination is crucial.
Purpose of the Study:
- To investigate the mechanism of methotrexate's protective effects in progressive multiple sclerosis (MS).
- To analyze methotrexate's impact on a non-inflammatory cuprizone-induced demyelination model.
- To explore methotrexate's influence on astrocyte activation and remyelination processes.
Main Methods:
- Intracerebroventricular administration of low-dose methotrexate in a cuprizone-induced demyelination model.
- Analysis of demyelination, GFAP+ reactive astrocytes, and remyelination post-cuprizone withdrawal.
- In vitro and in vivo assessment of Insulin-like Growth Factor 1 (IGF1) expression.
Main Results:
- Methotrexate reduced demyelination and GFAP+ reactive astrocyte accumulation in the corpus callosum.
- Methotrexate administration post-cuprizone did not delay remyelination or affect astrocyte numbers.
- Methotrexate increased IGF1 expression, a factor known to protect oligodendrocytes and limit astrocyte activation.
Conclusions:
- Methotrexate impacts pathogenic processes in demyelination models independent of primary inflammation, mirroring neurodegenerative mechanisms in progressive MS.
- Intrathecal methotrexate may modulate astroglial activation in progressive MS.
- Methotrexate's protective effects could be mediated by promoting central nervous system (CNS) production of IGF1.
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