Abstract
Electroacupuncture has been shown to promote remyelination in a demyelinating model of multiple sclerosis (MS) through enhanced microglial clearance of degraded myelin debris. However, the mechanisms involved in this process are yet to be clearly elucidated. It has been revealed that TAM receptor tyrosine kinases (Tyro3, Axl, and MerTK) play pivotal roles in regulating multiple features of microglia, including the phagocytic function and myelin clearance. Therefore, the aim of this study is to further confirm whether electroacupuncture improves functional recovery in this model and to characterise the involvement of the TAM receptor during this process. In addition to naive control mice, a cuprizone-induced demyelinating model was established, and long-term electroacupuncture treatment was administrated. To evaluate the efficiency of functional recovery following demyelination, we performed beam-walking test and rotarod performance test; to objectify the degree of remyelination, we performed transmission electron microscopy and protein quantification of mature oligodendrocyte markers. Oil Red O staining was used to evaluate the deposit of myelin debris. We confirmed that, in cuprizone-treated mice, electroacupuncture significantly ameliorates motor-coordinative dysfunction and counteracts demyelinating processes, with less deposit of myelin debris accumulating in the corpus callosum. Surprisingly, mRNA expression of TAM receptors was significantly upregulated after electroacupuncture treatment, and we further confirmed an increased protein expression of Axl and MerTK after electroacupuncture treatment, indicating their involvement during electroacupuncture treatment. Finally, LDC1267, a selective TAM kinase inhibitor, abolished the therapeutic effect of electroacupuncture on motor-coordinative dysfunction. Overall, our data demonstrate that electroacupuncture could mitigate the progression of demyelination by enhancing the TAM receptor expression to facilitate the clearance of myelin debris. Our results also suggest that electroacupuncture may be a potential curative treatment for MS patients.
Highlights
Multiple sclerosis (MS) is a progressive disease characterised by inflammation-induced demyelination of the central nervous system (CNS); currently, MS affects >2.5 million people worldwide [1]
The mechanism that underlies the beneficial effect of electroacupuncture remains unclear, and more methods are needed to further evaluate and confirm the therapeutic effect of electroacupuncture, especially transmission electron microscopy, which is regarded as the gold-standard technique to assess myelination
The severity of clinical symptoms of MS patients, which are evaluated by a standardised neurological examination (Expanded Disability Status Scale) that focuses on the frequent symptoms of MS and is used in clinical trials of MS for the assessment of
Summary
Multiple sclerosis (MS) is a progressive disease characterised by inflammation-induced demyelination of the central nervous system (CNS); currently, MS affects >2.5 million people worldwide [1]. Studies have shown that the therapeutic effects of electroacupuncture on CNS disease are related to its neuroprotective effect and the prevention of secondary injury [10,11,12]. In MS treatment, a number of clinical reports have shown that electroacupuncture can significantly improve symptoms such as limb weakness, pain, and numbness in patients [13, 14]; electroacupuncture alleviates neuroinflammation and neurological impairment in the classical MS animal model experimental autoimmune encephalomyelitis [11]. Our group found that electroacupuncture treatment from the disease peak improves remyelination in a cuprizone-induced demyelinating model [15]. Our previous bulk tissue RNA-seq data revealed a potential involvement of the TAM receptor family after electroacupuncture treatment. erefore, we identified the TAM receptor family as a target for further investigation
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