S-Allylmercapto-N-acetylcysteine (ASSNAC) protects cultured nerve cells from oxidative stress and attenuates experimental autoimmune encephalomyelitis

ObjectiveProgressive multiple sclerosis is characterized by chronic inflammation with microglial activation, oxidative stress, accumulation of iron and continuous neurodegeneration with inadequate effectiveness of medications used so far. We now investigated effects of iron on microglia and used the previously identified neuroprotective antipsychotic clozapine in vitro and in chronic experimental autoimmune encephalomyelitis (EAE).MethodsMicroglia were treated with iron and clozapine followed by analysis of cell death and response to oxidative stress, cytokine release and neuronal phagocytosis. Clozapine was investigated in chronic EAE regarding optimal dosing and therapeutic effectiveness in different treatment paradigms. Animals were scored clinically by blinded raters. Spinal cords were analyzed histologically for inflammation, demyelination, microglial activation and iron accumulation and for transcription changes of regulators of iron metabolism and inflammation. Effects on immune cells were analyzed using flow cytometry.ResultsIron impaired microglial function in vitro regarding phagocytosis and markers of inflammation; this was regulated by clozapine, reflected in reduced release of IL-6 and normalization of neuronal phagocytosis. In chronic EAE, clozapine dose-dependently attenuated clinical signs and still had an effect if applied in a therapeutic setting. Early mild sedative effects habituated over time. Histologically, demyelination was reduced by clozapine and positive effects on inflammation strongly correlated with reduced iron deposition. This was accompanied by reduced expression of DMT-1, an iron transport protein.ConclusionsClozapine regulates microglial function and attenuates chronic EAE, even in a therapeutic treatment paradigm. This well-defined generic medication might therefore be considered as promising add-on therapeutic for further development in progressive MS.

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

Frontiers in Neuroscience ◽

10.3389/fnins.2021.649485 ◽

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.

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Extra-Virgin Olive Oil Modifies the Changes Induced in Non-Nervous Organs and Tissues by Experimental Autoimmune Encephalomyelitis Models

Nutrients ◽

10.3390/nu11102448 ◽

2019 ◽

Vol 11 (10) ◽

pp. 2448 ◽

Cited By ~ 3

Author(s):

Cristina Conde ◽

Begoña M. Escribano ◽

Evelio Luque ◽

Montserrat Feijóo ◽

Javier Caballero-Villarraso ◽

...

Keyword(s):

Oxidative Stress ◽

Experimental Autoimmune Encephalomyelitis ◽

Oxidative Damage ◽

Olive Oil ◽

Virgin Olive Oil ◽

Extra Virgin Olive Oil ◽

Male Rats ◽

Dark Agouti ◽

Autoimmune Encephalomyelitis ◽

Experimental Autoimmune

This study reveals the existence of oxidative stress (reactive oxygen species (ROS)) in non-nervous organs and tissues in multiple sclerosis (MS) by means of a model of experimental autoimmune encephalomyelitis (EAE) in rats. This model reproduces a similar situation to MS, as well as its relationship with intestinal microbiota starting from the changes in bacterial lipopolysaccharide levels (LPS) in the outer wall of the gram-negative bacteria. Finally, the administration of extra-virgin olive oil (EVOO), hydroxytirosol (HT), and oleic acid (OA) exert beneficial effects. Twenty-five Dark Agouti two-month-old male rats, weighing around 190 g, were distributed into the following groups: Control, EAE (experimental autoimmune encephalomyelitis group), EAE + EVOO, EAE + HT, and EAE + OA. The glutathione redox system with the EAE was measured in heart, kidney, liver, and small and large intestines. The LPS and the correlation with oxidative stress in the small and large intestines were also investigated. The results showed that (1) the oxidative damage in the EAE model affects non-nervous organs and tissues; (2) The LPS is related to inflammatory phenomena and oxidative stress in the intestinal tissue and in other organs; (3) The administration of EVOO, HT, and OA reduces the LPS levels at the same time as minimizing the oxidative damage; (4) EVOO, HT, and OA improve the disease’s clinical score; and (5) on balance, EVOO offers a better neuroprotective effect.

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Ac-SDKP ameliorates the progression of experimental autoimmune encephalomyelitis via inhibition of ER stress and oxidative stress in the hippocampus of C57BL/6 mice

Brain Research Bulletin ◽

10.1016/j.brainresbull.2019.09.014 ◽

2020 ◽

Vol 154 ◽

pp. 21-31 ◽

Cited By ~ 4

Author(s):

Sina Pejman ◽

Maryam Kamarehei ◽

Gholamhossein Riazi ◽

Shahriar Pooyan ◽

Saeed Balalaie

Keyword(s):

Oxidative Stress ◽

Experimental Autoimmune Encephalomyelitis ◽

Er Stress ◽

Autoimmune Encephalomyelitis ◽

And Oxidative Stress ◽

Experimental Autoimmune

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Mechanism of oxidative stress p38MAPK-SGK1 signaling axis in experimental autoimmune encephalomyelitis (EAE)

Oncotarget ◽

10.18632/oncotarget.17057 ◽

2017 ◽

Vol 8 (26) ◽

pp. 42808-42816 ◽

Cited By ~ 11

Author(s):

Liang Wang ◽

Bin Li ◽

Mo-Yuan Quan ◽

Lin Li ◽

Yuan Chen ◽

...

Keyword(s):

Oxidative Stress ◽

Experimental Autoimmune Encephalomyelitis ◽

Autoimmune Encephalomyelitis ◽

Signaling Axis ◽

Experimental Autoimmune

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Microglial Nox2 Plays a Key Role in the Pathogenesis of Experimental Autoimmune Encephalomyelitis

Frontiers in Immunology ◽

10.3389/fimmu.2021.638381 ◽

2021 ◽

Vol 12 ◽

Author(s):

Chih-Fen Hu ◽

San-Pin Wu ◽

Gu-Jiun Lin ◽

Chi-Chang Shieh ◽

Chih-Sin Hsu ◽

...

Keyword(s):

Oxidative Stress ◽

Experimental Autoimmune Encephalomyelitis ◽

Lupus Erythematosus ◽

Autoimmune Encephalomyelitis ◽

Chemokine Production ◽

Phagocyte Nadph Oxidase ◽

Cytokines And Chemokines ◽

Gene Ablation ◽

The Impact ◽

Experimental Autoimmune

While oxidative stress has been linked to multiple sclerosis (MS), the role of superoxide-producing phagocyte NADPH oxidase (Nox2) in central nervous system (CNS) pathogenesis remains unclear. This study investigates the impact of Nox2 gene ablation on pro- and anti-inflammatory cytokine and chemokine production in a mouse experimental autoimmune encephalomyelitis (EAE) model. Nox2 deficiency attenuates EAE-induced neural damage and reduces disease severity, pathogenic immune cells infiltration, demyelination, and oxidative stress in the CNS. The number of autoreactive T cells, myeloid cells, and activated microglia, as well as the production of cytokines and chemokines, including GM-CSF, IFNγ, TNFα, IL-6, IL-10, IL-17A, CCL2, CCL5, and CXCL10, were much lower in the Nox2−/− CNS tissues but remained unaltered in the peripheral lymphoid organs. RNA-seq profiling of microglial transcriptome identified a panel of Nox2 dependent proinflammatory genes: Pf4, Tnfrsf9, Tnfsf12, Tnfsf13, Ccl7, Cxcl3, and Cxcl9. Furthermore, gene ontology and pathway enrichment analyses revealed that microglial Nox2 plays a regulatory role in multiple pathways known to be important for MS/EAE pathogenesis, including STAT3, glutathione, leukotriene biosynthesis, IL-8, HMGB1, NRF2, systemic lupus erythematosus in B cells, and T cell exhaustion signaling. Taken together, our results provide new insights into the critical functions performed by microglial Nox2 during the EAE pathogenesis, suggesting that Nox2 inhibition may represent an important therapeutic target for MS.

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Memantine Modulates Oxidative Stress in the Rat Brain following Experimental Autoimmune Encephalomyelitis

International Journal of Molecular Sciences ◽

10.3390/ijms222111330 ◽

2021 ◽

Vol 22 (21) ◽

pp. 11330

Author(s):

Beata Dąbrowska-Bouta ◽

Lidia Strużyńska ◽

Marta Sidoryk-Węgrzynowicz ◽

Grzegorz Sulkowski

Keyword(s):

Oxidative Stress ◽

Experimental Autoimmune Encephalomyelitis ◽

Neuronal Degeneration ◽

Glutamate Excitotoxicity ◽

Neurological Deficits ◽

Current Therapy ◽

Autoimmune Encephalomyelitis ◽

Sh Groups ◽

And Oxidative Stress ◽

Experimental Autoimmune

Experimental autoimmune encephalomyelitis (EAE) is an animal model most commonly used in research on the pathomechanisms of multiple sclerosis (MS). The inflammatory processes, glutamate excitotoxicity, and oxidative stress have been proposed as determinants accompanying demyelination and neuronal degeneration during the course of MS/EAE. The aim of the current study was to characterize the role of NMDA receptors in the induction of oxidative stress during the course of EAE. The effect of memantine, the uncompetitive NMDA receptor antagonist, on modulation of neurological deficits and oxidative stress in EAE rats was analyzed using several experimental approaches. We demonstrated that the expression of antioxidative enzymes (superoxide dismutases SOD1 and SOD2) were elevated in EAE rat brains. Under the same experimental conditions, we observed alterations in oxidative stress markers such as increased levels of malondialdehyde (MDA) and decreased levels of sulfhydryl (-SH) groups, both protein and non-protein (indicating protein damage), and a decline in reduced glutathione. Importantly, pharmacological inhibition of ionotropic NMDA glutamate receptors by their antagonist memantine improved the physical activity of EAE rats, alleviated neurological deficits such as paralysis of tail and hind limbs, and modulated oxidative stress parameters (MDA, -SH groups, SOD’s). Furthermore, the current therapy aiming to suppress NMDAR-induced oxidative stress was partially effective when NMDAR’s antagonist was administered at an early (asymptomatic) stage of EAE.

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