Advances in Clinical and Experimental Medicine
2020, vol. 29, nr 5, May, p. 535–545
Publication type: original article
Antifungal itraconazole ameliorates experimental autoimmune encephalomyelitis through a novel mechanism of action
1 Department of Neurology, Lishui Hospital, Zhejiang University School of Medicine, China
2 Department of Rehabitation Medicine, Second Hospital of Tianjin Medical University, China
Background. Multiple sclerosis (MS) is an autoimmune disease characterized by a loss of myelin, limb disabilities and dysregulation of gene expression. Unfortunately, there still is no treatment to cure MS.
Objectives. To explore a novel way to treat MS using currently available antifungal drugs.
Material and Methods. We built an experimental autoimmune encephalomyelitis (EAE) model to mimic MS and tested the effect of an antifungal drug – itraconazole – on EAE by comparing it with a phosphate-buffered saline (PBS) control group. We assessed the animal limb deficits with Weaver’s scoring and used histology staining (including luxol fast blue (LFB) and hematoxylin & eosin (H&E) methods) to determine the demyelination in the spinal tissues. We also performed western blotting to quantify the expression changes of proteins related to endoplasmic reticulum (ER) stress response and apoptosis.
Results. The limb disabilities were greatly diminished and the demyelination in the spinal tissues of the EAE mice was mostly reduced following itraconazole treatment. The hyperactivation of the ER stress response and apoptosis pathway in EAE was also significantly diminished by the itraconazole treatment. In addition, the AMPK pathway was downregulated in EAE, its expression level bi-directionally affected the activity of the ER stress response, and its downregulation removed the beneficial effect of itraconazole.
Conclusion. Our study revealed a new method for treating MS using currently approved antifungal drugs.
apoptosis, EAE, itraconazole, ER stress, AMPK
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