Contents lists available at ScienceDirect Brain Research Bulletin journal homepage: www.elsevier.com/locate/brainresbull Theta burst stimulation ameliorates symptoms of experimental autoimmune encephalomyelitis and attenuates reactive gliosis Milorad Dragic a, *, Milica Zeljkovic b , Ivana Stevanovic c,d , Tihomir Ilic d , Nela Ilic e,f , Nadezda Nedeljkovic a , Milica Ninkovic c,d a Department for General Physiology and Biophysics, Faculty of Biology, University of Belgrade, Serbia b Institute for Biological Research"Sinisa Stankovic", University of Belgrade, Serbia c Institute of Medical Research, Military Medical Academy, Belgrade, Serbia d Medical Faculty of Military Medical Academy, University of Defense, Serbia e Medical Faculty, University of Belgrade, Belgrade, Serbia f Clinic of Physical Medicine and Rehabilitation, Clinical Center of Serbia, Belgrade, Serbia ARTICLEINFO Keywords: EAE rTMS Reactive gliosis Attenuation Myelin Vimentin ABSTRACT Multiple sclerosis (MS) is a chronic neurodegenerative disease caused by infammatory processes in the central nervous system (CNS). Decades of research led to discovery of several disease-modifying therapeutics strategies with moderate success. Experimental autoimmune encephalomyelitis (EAE) is currently the most commonly used experimental model for MS and for studying various therapeutic approaches. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neurostimulation technique with multiple benefcial efects on healthy as well as CNS with pathology. However, the molecular and cellular mechanisms of rTMS on acute EAE are scarce. Our study demonstrated benefcial efects of theta-burst stimulation (TBS), an experimental paradigm of rTMS, on disease course of acute EAE. TBS treatment attenuated reactive gliosis, restored myelin sheet and down-regulated expression of vimentin in EAE rats. These efects were refected through reduced clinical parameters, shorter duration of illness and days spent in paralysis. Based on our research, rTMS deserves further considerations for its neuroprotective efect on EAE, and is an excellent candidate for further research and points that it could be used for more than for simple symptomatic therapy. 1. Introduction Multiple sclerosis (MS) is a progressive demyelinating and neuro- degenerative disease caused by continuous or recurring infammation driven by auto-reactive T cells that infltrate the central nervous system (CNS). Except for traumatic brain injury, MS is the most frequent cause of neurological disability in the young population (Leray et al., 2016). Due to vague etiology, complex pathogenesis, and highly hetero- geneous course, decades of comprehensive clinical research so far lead to the development of disease-modifying therapies that slow the pro- gression of the disease, while the efective cure for MS is still lacking (Lassmann and van Horssen, 2011). The most common form of MS is relapsing-remitting form, defned by symptomatic loss-of-function periods (relapses) interspaced by asymptomatic periods, with partial or complete recovery (remission). The histopathology is defned by focal areas of demyelination inficted by infltrated immune cells that attack myelin sheath components. After the initial relapsing phase, the majority of MS patients develop sec- ondary progressive form (Comabella and Khoury, 2012). During this phase, the systemic infammatory process weakens, while an intrinsic neuroinfammatory process provides a perpetual signal(s) for sustained microglia and astrocyte activation. Reactive microglial cells infict tissue damage, leaving behind multiple areas of demyelination, axonal loss, and neurodegeneration, which result in progressive worsening of neurological symptoms (Kutzelnigg and Lassmann, 2014). Several anti- infammatory disease-modifying treatments for the relapsing form have been developed so far (Wingerchuk and Carter, 2014), while secondary progressive MS still represents a major unmet clinical need. Given that neurodegeneration and the failure of myelin repair are the key aspects of fully blown MS pathology, neuroprotective treatments and treat- ments which ameliorate neuroinfammation and neurotoxic reactive phenotype of microglia and astrocytes are currently intensively https://doi.org/10.1016/j.brainresbull.2020.06.013 Received 8 April 2020; Received in revised form 11 June 2020; Accepted 19 June 2020 Abbreviations: cTBS, continuous theta-burst stimulation; iTBS, intermittent theta-burst stimulation; rTMS, repetitive transcranial magnetic stimulation ⁎ Corresponding author at: Department for General Physiology and Biophysics, Faculty of Biology, University of Belgrade, Studentski trg 3, Belgrade, Serbia. E-mail address: milorad.dragic@bio.bg.ac.rs (M. Dragic). Brain Research Bulletin 162 (2020) 208–217 Available online 26 June 2020 0361-9230/ © 2020 Elsevier Inc. All rights reserved. T