Abstract
Promoting remyelination is crucial for patients with demyelinating diseases including multiple sclerosis. However, it is still a circuitous conundrum finding a practical remyelinating therapy. Electroacupuncture (EA), originating from traditional Chinese medicine (TCM), has been widely used to treat CNS diseases all over the world, but the role of EA in demyelinating diseases is barely known. In this study, we examined the remyelinating properties and mechanisms of EA in cuprizone-induced demyelinating model, a CNS demyelinating murine model of multiple sclerosis. By feeding C57BL/6 mice with chow containing 0.2% cuprizone for 5 weeks, we successfully induce demyelination as proved by weight change, beam test, pole test, histomorphology, and Western Blot. EA treatment significantly improves the neurobehavioral performance at week 7 (2 weeks after withdrawing cuprizone chow). RNA-seq and RT-PCR results reveal up-regulated expression of myelin-related genes, and the expression of myelin associated protein (MBP, CNPase, and O4) are also increased after EA treatment, indicating therapeutic effect of EA on cuprizone model. It is widely acknowledged that microglia exert phagocytic effect on degraded myelin debris and clear these detrimental debris, which is a necessary process for subsequent remyelination. We found the remyelinating effect of EA is associated with enhanced clearance of degraded myelin debris as detected by dMBP staining and red oil O staining. Our further studies suggest that more microglia assemble in demyelinating area (corpus callosum) during the process of EA treatment, and cells inside corpus callosum are mostly in a plump, ameboid, and phagocytic shape, quite different from the ramified cells outside corpus callosum. RNA-seq result also unravels that most genes relating to positive regulation of phagocytosis (GO:0050766) are up-regulated, indicating enhanced phagocytic process after EA treatment. During the process of myelin debris clearance, microglia tend to change their phenotype toward M2 phenotype. Thus, we also probed into the phenotype of microglia in our study. Immuno-staining results show increased expression of CD206 and Arg1, and the ratio of CD206/CD16/32 are also higher in EA group. In conclusion, these results demonstrate for the first time that EA enhances myelin debris removal from activated microglia after demyelination, and promotes remyelination.
Highlights
Multiple sclerosis (MS) is an autoimmune-mediated demyelinating disease of central nervous system (CNS), with a hallmark of extensive demyelination in the CNS
CPZ feeding can lead to extensive demyelination in many regions of brain including hippocampus, cerebellum, cortex, and with corpus callosum (CC) the most vulnerable one, which results in motor coordination impairment
We demonstrated the following: (1) EA promotes remyelination in CPZ-induced demyelinating model and ameliorates the subdued motor coordination impairments resulting from extensive CNS demyelination; (2) EA significantly eliminates the accumulated degraded myelin debris in CC; (3) the clearance and removal of degraded myelin debris caused by EA is associated with more microglia assembling into the area of CC; (4) microglial cells in CC are mostly ameboid-shaped phagocytic cells with relatively higher M2 property during EA treatment
Summary
Multiple sclerosis (MS) is an autoimmune-mediated demyelinating disease of central nervous system (CNS), with a hallmark of extensive demyelination in the CNS. There is no ideal treatment for MS hitherto, disease modifying therapies (DMTs) are the mainstream for MS treatment (Oh and O’Connor, 2015). Approved DMTs are immunosuppressive and immunomodulatory agents. These agents help prevent disease relapse and reduce the severity of relapse to some extent (Cross and Naismith, 2014; Wingerchuk and Carter, 2014). DMTs can only partially postpone the relapse of MS and slightly reduce the accumulation of physical disabilities. The process of remyelination is directly and closely related to the restoration of neuronal function and the amelioration of clinical disabilities (Nave, 2010; Harlow et al, 2015; Olsen and Akirav, 2015). No practical remyelinating therapy has been applied clinically and most potential remyelinating methods are still under development (Hartley et al, 2014)
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