Downregulation of CD73/A2AR-Mediated Adenosine Signaling as a Potential Mechanism of Neuroprotective Effects of Theta-Burst Transcranial Magnetic Stimulation in Acute Experimental Autoimmune Encephalomyelitis.

Milorad Dragić,Nela Ilić,Andjela Stekić,Nadežda Nedeljković,Ivana Stevanović,Ivana Grković,Milica Zeljković,Marija Adžić,Milica Ninković,Tihomir V Ilić,Katarina Mihajlović

doi:10.3390/brainsci11060736

Milorad Dragić, Nela Ilić + Show 9 more

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https://doi.org/10.3390/brainsci11060736

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Journal: Brain sciences	Publication Date: Jun 1, 2021
Citations: 12	License type: CC BY 4.0

Affiliation: University of Belgrade, Military Medical Academy

Abstract

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/A2AR/A1R 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-ir 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 A2AR expression from glia to neurons, contrary to EAE, where tight coupling of eN/CD73 and A2AR on glial cells is observed. Finally, increased glial A1R expression following CTBS supports anti-inflammatory adenosine actions and potentially contributes to the overall neuroprotective effect observed in EAE animals after CTBS treatment.

Highlights

Multiple sclerosis (MS) is a progressive demyelinating and neurodegenerative disorder driven by the adaptive immune response [1,2] and inflicts primary damage to the myelin sheath [3]
Protocol (EAE+continuous theta-burst stimulation (CTBS)), the stimulation was applied to start from 14 dpi for 10 consecutive days
The effect of the CTBS noise artifact was explored in the sham group of animals (EAE+CTBSpl), which were subjected to the noise artifact according to the same experimental scheme

Summary

Introduction

Multiple sclerosis (MS) is a progressive demyelinating and neurodegenerative disorder driven by the adaptive immune response [1,2] and inflicts primary damage to the myelin sheath [3]. Succeeding inflammation and glial cell activation result in diffuse plaques of demyelination and axonal loss in multiple areas of the brain and spinal cord, which are the main cause of progressive neurological disability and motor dysfunctions in MS [4]. The most common form of MS is relapse-remitting MS (RRMS), occurring in 85% of patients, characterized by symptomatic loss-of-function periods (relapses), followed by complete or partial remissions. Even though a compelling improvement is made regarding the introduction of new diseasemodifying treatments, a significant number of patients will still develop a secondary progressive form of MS (SPMS) [6]. New therapeutic, neuroprotective, and myelination supportive approaches able to ameliorate neuroinflammation and neurotoxic reactive phenotype of astrocytes and microglia are major unmet clinical needs in MS [7]

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