| Summary: | Multiple sclerosis (MS) is a chronic neurodegenerative disease caused by autoimmune-mediated inflammation in the central nervous system. Purinergic signaling is critically involved in MS-associated neuroinflammation and its most widely applied animal model—experimental autoimmune encephalomyelitis (EAE). A promising but poorly understood approach in the treatment of MS is repetitive transcranial magnetic stimulation. In the present study, we aimed to investigate the effect of continuous theta-burst stimulation (CTBS), applied over frontal cranial bone, on the adenosine-mediated signaling system in EAE, particularly on CD73/A<sub>2A</sub>R/A<sub>1</sub>R in the context of neuroinflammatory activation of glial cells. EAE was induced in two-month-old female DA rats and in the disease peak treated with CTBS protocol for ten consecutive days. Lumbosacral spinal cord was analyzed immunohistochemically for adenosine-mediated signaling components and pro- and anti-inflammatory factors. We found downregulated IL-1β and NF- κB-<i>ir</i> and upregulated IL-10 pointing towards a reduction in the neuroinflammatory process in EAE animals after CTBS treatment. Furthermore, CTBS attenuated EAE-induced glial eN/CD73 expression and activity, while inducing a shift in A<sub>2A</sub>R expression from glia to neurons, contrary to EAE, where tight coupling of eN/CD73 and A<sub>2A</sub>R on glial cells is observed. Finally, increased glial A<sub>1</sub>R expression following CTBS supports anti-inflammatory adenosine actions and potentially contributes to the overall neuroprotective effect observed in EAE animals after CTBS treatment.
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