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 interplay of 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 examine whether oxidative-nitrogen stress (ONS) is one of the underlying pathophysiological mechanisms of EAE, which may be changed in terms of health improvement by iTBS or cTBS. Dark Agouti strain female rats were tested for the effects of EAE and TBS. The rats were randomly divided into the control group, rats specifically immunized for EAE and nonspecifically immuno-stimulated with Complete Freund’s adjuvant. TBS or sham TBS was applied to EAE rats from 14th–24th post-immunization day. 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 with the climax of ONS. The most critical result refers to TrxR, which immensely responded against the applied stressors of the central nervous system (CNS), including immunization and TBS. We found that the compensatory neuroprotective role of TrxR upregulation is a positive feedback mechanism that reduces the harmfulness of ONS. iTBS and cTBS both modulate the biochemical environment against ONS at a distance from the area of stimulation, alleviating symptoms of EAE. The results of our study increase the understanding of FRs’ interplay and the role of Trx/TrxR in ONS-associated neuroinflammatory diseases, such as EAE. Also, our results might help the development of new ideas for designing more effective medical treatment, combining neuropsychological with noninvasive neurostimulation–neuromodulation techniques to patients living with MS.

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

“…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. Significant reduction in duration, disability, and weight loss were observed after CTBS treatment, compared to both sham and naïve animals, as previously published (Figure 2) [37,39].…”

“…Up to date, the efficacy of different TBS protocols has been explored in animal studies using EAE, as an experimental paradigm of RRMS. The studies have demonstrated reduced oxidative stress [37,38], attenuation of gliosis [39], and increased expression of brain-derived neurotrophic factor (BDNF) [40]. Therefore, the present study aims to explore the effect of continuous theta-burst stimulation (CTBS) protocol on purinergic system activity in the context of neuroinflammation associated with experimental autoimmune encephalomyelitis in Dark Agouti rats.…”

Intermittent Theta Burst Stimulation Ameliorates Cognitive Deficit and Attenuates Neuroinflammation via PI3K/Akt/mTOR Signaling Pathway in Alzheimer’s-Like Disease Model

“…Inflammatory phenomena are tightly coupled with the overproduction of reactive oxygen and nitrogen species, which may produce neuronal degeneration. Improvement in oxidative status following iTBS, and its antioxidative potential ( Medina-Fernández et al, 2018 ; Stevanovic et al, 2020 ) could be mediated via nuclear factor (erythroid-derived 2)-like 2 (Nrf2) that is involved in transcriptional regulation of antioxidative enzymes ( Jaiswal, 2004 ). Previous studies reported that TMS increases the expression of Nrf2 in neuroinflammatory conditions ( Tasset et al, 2013 ; Liang et al, 2021 ), which could also be the mechanism in TMT-mediated oxidative stress.…”

“…Oxidative stress was assessed by measuring several parameters in appropriate hippocampal fraction ( n = 4–5 animals/group) as described in detail elsewhere ( Stevanovic et al, 2020 ). Briefly, total superoxide dismutase activity (tSOD) was assessed by spectrophotometric determination of spontaneous epinephrine autooxidation decrease rate at 480 nm and expressed as units per milligram of total protein (U/mg).…”

“…However, the full cellular and molecular mechanisms underlying these effects are largely unknown and the need for more comprehensive clinical trials still exists. Previous studies have shown that rTMS can attenuate reactive gliosis ( Dragic et al, 2020 ), reduce neuronal apoptosis by regulating the expression of Bcl-2 and Bax protein family members ( Uzair et al, 2022 ), restore pathological downregulation/induce activation of certain signaling pathways including mTOR ( Yang et al, 2021 ), PI3K/Akt ( Hou et al, 2021 ), modulate the biochemical environment against oxidative-nitrogen stress at a distance from the area of stimulation ( Stevanovic et al, 2020 ) and affect cellular and molecular mechanisms underlying different forms of synaptic plasticity such as long-term potentiation and long-term depression ( Fujiki et al, 2020 ). Observed neuroprotective effects have put rTMS on a list of promising therapeutic approaches in the treatment of neurodegenerative disorders such as AD, but very few studies on experimental models of neurodegenerations have been performed up to date.…”