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

2020 ◽  
Author(s):  
Ivana Stevanovic ◽  
Milica Ninkovic ◽  
Bojana Mancic ◽  
Marija Milivojevic ◽  
Ivana Stojanovic ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Superoxide Anion ◽  
Thioredoxin Reductase ◽  
Female Rats ◽  
Theta Burst Stimulation ◽  
Burst Stimulation ◽  
Autoimmune Encephalomyelitis ◽  
Theta Burst ◽  
Experimental Autoimmune

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 overproduction of reactive oxygen, nitrogen, and thiol species induced by EAE has not been entirely investigated, just as the effect of iTBS or cTBS on oxidative-nitrogen stress (ONS) in EAE rats. Dark Agouti strain female rats were tested for the effects of EAE and TBS. The rats were randomly divided into the following groups: C - control, EAE - rats immunized for EAE, CFA - rats immunized with Complete Freund's adjuvant; iTBS and cTBS groups, and EAE+iTBS and EAE+cTBS - health and EAE rats exposed to iTBS and cTBS, respectively; EAE+iTBSsh and EAE+cTBSsh - sham stimulated EAE rats with the same noise artifacts of iTBS and cTBS, respectively. 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, based on the increase of superoxide anion and lipid peroxidation; depletion of total thiols, GSH and NADPH; and decrease of SOD activity. The TrxR imposed the most sensitive response against the applied central nervous system (CNS) stressors to rats. We concluded that the TrxR upregulation meritoriously compensates decreased ROS sequestrating and GSH systems in EAE. Both iTBS and cTBS modulate the biochemical environment at a distance from the area of stimulation against ONS, accomplish a similar effect on TrxR activity to EAE and healthy rats, and alleviate symptoms of EAE.

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

Molecules ◽  
2020 ◽  
Vol 25 (17) ◽  
pp. 3922
Author(s):  
Ivana Stevanovic ◽  
Milica Ninkovic ◽  
Bojana Mancic ◽  
Marija Milivojevic ◽  
Ivana Stojanovic ◽  
...  
Keyword(s):  
Experimental Autoimmune Encephalomyelitis ◽  
Thioredoxin Reductase ◽  
Female Rats ◽  
Health Improvement ◽  
Theta Burst Stimulation ◽  
Burst Stimulation ◽  
Autoimmune Encephalomyelitis ◽  
Theta Burst ◽  
Experimental Autoimmune

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.

Continuous versus intermittent theta burst stimulation in the treatment of experimental autoimmune encephalomyelitis: a glutamate transporters study

2020 ◽  
Author(s):  
Milica Ninkovic ◽  
Mirjana Djukic ◽  
Bojana Mancic ◽  
Petar Milosavljevic ◽  
Ivana Stojanovic ◽  
...  
Keyword(s):  
Glutamate Transporter ◽  
Glutamate Transporters ◽  
Dark Agouti ◽  
Theta Burst Stimulation ◽  
Burst Stimulation ◽  
Autoimmune Encephalomyelitis ◽  
Glial Glutamate Transporter ◽  
Elevated Expression ◽  
Underlying Mechanisms ◽  
Theta Burst

Abstract Background: Synaptic overload with glutamate aggravates neurotransmission and worsen the progression of the neurodegenerative disease, such as multiple sclerosis (MS). The experimentally induced autoimmune encephalomyelitis (EAE) in rats is a well-established animal model to study MS. Glutamate reuptake occurs by glial glutamate transporter (GLT-1), and glutamate-aspartate transporter (GLAST) localized predominantly in astrocytes terminals. The focus of the study addressing the expression of these transporters in EAE rats and those subjected to theta burst stimulation (TBS), that promotes long-lasting modulation of neuronal activity in rats/humans. Leading by the reported outcomes of TBS, we examined if TBS underlying mechanisms refer to astroglial glutamate transporters status.Methods : We studied changes in the expression of glial glutamate transporter GLT-1 and glutamate-aspartate transporter (GLAST), and glial fibrillary acidic protein (GFAP), in the spinal cord of EAE rats, subjected to intermittent (iTBS) and continuous (cTBS) theta burst stimulation. We quantified the expression of GLAST, GLT-1, and GFAP by immunofluorescence in control and experimental groups of Dark Agouti rats.Results: EAE elevated expression of GFAP, GLAST, and GLT-1. Both TBSs reduced the expression of GFAP. Continual TBS did not interfere with glutamate transporters in EAE rats, while iTBS decreased GLT-1, and increased GLAST.Conclusion: Continual TBS reduced astrogliosis more efficiently than iTBS, in EAE rats. Besides, it did not mitigate the glutamate transporters' expression; thus, glutamate reuptake remained upraised in cTBS exposed EAE rats. Accordingly, we concluded that cTBS might advance the remyelination of damaged neuronal cells in EAE rats. The future clinical trials on the treatment of MS may consider the data of this pre-clinical animal study.

scholarly journals The Function of the Hypothalamic–Pituitary–Adrenal Axis During Experimental Autoimmune Encephalomyelitis: Involvement of Oxidative Stress Mediators

2021 ◽  
Vol 15 ◽  
Author(s):  
Svetlana Trifunovic ◽  
Ivana Stevanovic ◽  
Ana Milosevic ◽  
Natasa Ristic ◽  
Marija Janjic ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Hpa Axis ◽  
Superoxide Anion ◽  
Adrenal Glands ◽  
Demyelinating Disease ◽  
Unknown Origin ◽  
Autoimmune Encephalomyelitis ◽  
Hypothalamic Pituitary Adrenal ◽  
Experimental Autoimmune

Multiple sclerosis (MS) is an inflammatory, demyelinating disease with an unknown origin. Previous studies showed the involvement of the hypothalamic–pituitary–adrenal (HPA) axis to susceptibility to autoimmune diseases, including MS, and its best-characterized animal model, experimental autoimmune encephalomyelitis (EAE). During MS/EAE, innate immune cells are activated and release cytokines and other inflammatory mediators, leading to a vicious cycle of inflammation. In response to inflammation, the activated HPA axis modulates immune responses via glucocorticoid activity. Because the mechanisms involving oxidative stress to the HPA axis are relatively unrevealed, in this study, we investigate the inflammatory and oxidative stress status of HPA axis during EAE. Our results reveal an upregulation of Pomc gene expression, followed by POMC and ACTH protein increase at the peak of the EAE in the pituitary. Also, prostaglandins are well-known contributors of HPA axis activation, which increases during EAE at the periphery. The upregulated Tnf expression in the pituitary during the peak of EAE occurred. This leads to the activation of oxidative pathways, followed by upregulation of inducible NO synthase expression. The reactive oxidant/nitrosative species (ROS/RNS), such as superoxide anion and NO, increase their levels at the onset and peak of the disease in the pituitary and adrenal glands, returning to control levels at the end of EAE. The corticotrophs in the pituitary increased in number and volume at the peak of EAE that coincides with high lipid peroxidation levels. The expression of MC2R in the adrenal glands increases at the peak of EAE, where strong induction of superoxide anion and malondialdehyde (MDA), reduced total glutathione (GSH) content, and catalase activity occurred at the peak and end of EAE compared with controls. The results obtained from this study may help in understanding the mechanisms and possible pharmacological modulation in MS and demonstrate an effect of oxidative stress exposure in the HPA activation during the course of EAE.

scholarly journals 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

2021 ◽  
Vol 11 (6) ◽  
pp. 736
Author(s):  
Milorad Dragić ◽  
Milica Zeljković ◽  
Ivana Stevanović ◽  
Marija Adžić ◽  
Andjela Stekić ◽  
...  
Keyword(s):  
Transcranial Magnetic Stimulation ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Glial Cells ◽  
Magnetic Stimulation ◽  
Purinergic Signaling ◽  
Cranial Bone ◽  
Autoimmune Encephalomyelitis ◽  
Anti Inflammatory ◽  
Theta Burst ◽  
Experimental Autoimmune

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.

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