Compensatory Neuroprotective Response of Thioredoxin Reductase against Oxidative-Nitrosative Stress Induced by Experimental Autoimmune Encephalomyelitis in Rats: Modulation by Theta Burst Stimulation

Abstract

Cortical theta burst stimulation (TBS) structured as intermittent (iTBS) and continuous (cTBS)could prevent the progression of the experimental autoimmune encephalomyelitis (EAE). The interplayof brain antioxidant defense systems against free radicals (FRs) overproduction induced by EAE,as well as during iTBS or cTBS, have not been entirely investigated. This study aimed to examinewhether oxidative-nitrogen stress (ONS) is one of the underlying pathophysiological mechanisms ofEAE, which may be changed in terms of health improvement by iTBS or cTBS. Dark Agouti strainfemale rats were tested for the effects of EAE and TBS. The rats were randomly divided into the controlgroup, rats specifically immunized for EAE and nonspecifically immuno-stimulated with CompleteFreund’s adjuvant. TBS or sham TBS was applied to EAE rats from 14th–24th post-immunizationday. Superoxide dismutase activity, levels of superoxide anion (O2•–), lipid peroxidation, glutathione(GSH), nicotinamide adenine dinucleotide phosphate (NADPH), and thioredoxin reductase (TrxR)activity were analyzed in rat spinal cords homogenates. The severity of EAE clinical coincided withthe climax of ONS. The most critical result refers to TrxR, which immensely responded against theapplied stressors of the central nervous system (CNS), including immunization and TBS. We foundthat the compensatory neuroprotective role of TrxR upregulation is a positive feedback mechanismthat reduces the harmfulness of ONS. iTBS and cTBS both modulate the biochemical environmentagainst ONS at a distance from the area of stimulation, alleviating symptoms of EAE. The results ofour study increase the understanding of FRs’ interplay and the role of Trx/TrxR in ONS-associatedneuroinflammatory diseases, such as EAE. Also, our results might help the development of new ideasfor designing more effective medical treatment, combining neuropsychological with noninvasiveneurostimulation–neuromodulation techniques to patients living with MS.