Peroxynitrite formation within the central nervous system in active multiple sclerosis

Cross, Anne H.; Manning, Pamela T.; Keeling, Richard M.; Schmidt, Robert E.; Misko, Thomas P.

doi:10.1016/s0165-5728(98)00078-2

Cited by 191 publications

(121 citation statements)

References 58 publications

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“…For example, ascorbic acid, another biologically relevant antioxidant, was ϳ15-fold less effective at inhibiting DHR 123 oxidation mediated by ONOO Ϫ elaborated by activated macrophages. More important in the context of nitrotyrosine formation in MS and EAE (1)(2)(3)(4)(5), UA efficiently inhibits ONOO Ϫ -mediated tyrosine nitration in the presence and absence of a source of carbonyl anion. Apart from inactivating ONOO Ϫ , UA does not appear to have any significant effect on in vitro measures of immune and inflammatory cell function relevant to EAE.…”

Section: Discussionmentioning

confidence: 99%

“…C entral nervous system lesions containing activated cells of the monocyte lineage and nitrotyrosine residues, evidence of the local formation of peroxynitrite (ONOO Ϫ ), 4 are pathological hallmarks of multiple sclerosis (MS) and experimental allergic encephalomyelitis (EAE) in conventional mouse models (1)(2)(3)(4)(5). In both cases, inflammatory cells producing NO ⅐ (6, 7) as a consequence of the up-regulation of inducible NO synthase (iNOS) (8 -12) are believed to be the primary source of ONOO Ϫ , which is formed by the rapid reaction of NO ⅐ and superoxide.…”

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confidence: 99%

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The Peroxynitrite Scavenger Uric Acid Prevents Inflammatory Cell Invasion into the Central Nervous System in Experimental Allergic Encephalomyelitis through Maintenance of Blood-Central Nervous System Barrier Integrity

Kean

Spitsin

Mikheeva

et al. 2000

The Journal of Immunology

146

113

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Uric acid (UA), a product of purine metabolism, is a known scavenger of peroxynitrite (ONOO−), which has been implicated in the pathogenesis of multiple sclerosis and experimental allergic encephalomyelitis (EAE). To determine whether the known therapeutic action of UA in EAE is mediated through its capacity to inactivate ONOO− or some other immunoregulatory phenomenon, the effects of UA on Ag presentation, T cell reactivity, Ab production, and evidence of CNS inflammation were assessed. The inclusion of physiological levels of UA in culture effectively inhibited ONOO−-mediated oxidation as well as tyrosine nitration, which has been associated with damage in EAE and multiple sclerosis, but had no inhibitory effect on the T cell-proliferative response to myelin basic protein (MBP) or on APC function. In addition, UA treatment was found to have no notable effect on the development of the immune response to MBP in vivo, as measured by the production of MBP-specific Ab and the induction of MBP-specific T cells. The appearance of cells expressing mRNA for inducible NO synthase in the circulation of MBP-immunized mice was also unaffected by UA treatment. However, in UA-treated animals, the blood-CNS barrier breakdown normally associated with EAE did not occur, and inducible NO synthase-positive cells most often failed to reach CNS tissue. These findings are consistent with the notion that UA is therapeutic in EAE by inactivating ONOO−, or a related molecule, which is produced by activated monocytes and contributes to both enhanced blood-CNS barrier permeability as well as CNS tissue pathology.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

The Peroxynitrite Scavenger Uric Acid Prevents Inflammatory Cell Invasion into the Central Nervous System in Experimental Allergic Encephalomyelitis through Maintenance of Blood-Central Nervous System Barrier Integrity

Kean

Spitsin

Mikheeva

et al. 2000

The Journal of Immunology

146

113

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Section: Autophagy In Glial Cellsmentioning

confidence: 99%

“…mTOR in the astrocyte may play a protective role in ischemia via its downstream kinase S6K1 [81] . mTOR can also regulate the stability of iNOS mRNA in astrocytes, reducing the neurotoxic effect of NO which impairs autophagy by disrupting the BECN1 complex and activates mTORC1 [82][83][84] .OPCs are indispensable during oligodendrocyte differentiation and myelin remyelination; they are activated for remyelination in MS lesions [85,86] . They also play an important role in MS pathogenesis by modulating immune activity in the CNS.…”

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confidence: 99%

Role of autophagy in the pathogenesis of multiple sclerosis

Liang

2015

Neurosci. Bull.

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Autophagy plays an important role in maintaining the cellular homeostasis. One of its functions is to degrade unnecessary organelles and proteins for energy recycling or amino-acids for cell survival. Ablation of autophagy leads to neurodegeneration. Multiple sclerosis (MS), a permanent neurological impairment typical of chronic inflammatory demyelinating disorder, is an auto-immune disease of the central nervous system (CNS). Autophagy is tightly linked to the innate and adaptive immune systems during the autoimmune process, and several studies have shown that autophagy directly participates in the progress of MS or experimental autoimmune encephalomyelitis (EAE, a mouse model of MS). Dysfunction of mitochondria that intensively infl uences the autophagy pathway is one of the important factors in the pathogenesis of MS. Autophagy-related gene (ATG) 5 and immune-related GTPase M (IRGM) 1 are increased, while ATG16L2 is decreased, in T-cells in EAE and active relapsing-remitting MS brains. Administration of rapamycin, an inhibitor of mammalian target of rapamycin ( mTOR), ameliorates relapsing-remitting EAE. Infl ammation and oxidative stress are increased in MS lesions and EAE, but Lamp2 and the LC3-II/LC3-I ratio are decreased. Furthermore, autophagy in various glial cells plays important roles in regulating neuro-infl ammation in the CNS, implying potential roles in MS. In this review, we discuss the role of autophagy in the peripheral immune system and the CNS in neuroinfl ammation associated with the pathogenesis of MS. Keywords: autophagy; multiple sclerosis; neuro-infl ammation ·Review· IntroductionAutophagy, a lysosome-dependent degradation pathway, contributes to maintaining cellular homeostasis. Clearance of long-lived proteins, unnecessary organelles, and aggregate-prone proteins is mainly executed by autophagy for recycling cellular materials [1] . There are three subtypes of autophagy, macroautophagy, chaperone-mediated autophagy (CMA), and mitophagy. Macroautophagy is the major type for selective degradation of protein aggregates or misfolded proteins. The ubiquitin-labeled proteins are recognized by autophagy receptors, such as p62, neighbor of BRCA1 gene 1 (NBR1), and NIP3-like protein X (NIX), to form autophagosomes that then fuse with lysosomes for degradation. Many autophagy-related genes function during this process, such as Unc51-like kinase (ULK1) and autophagy-related gene (ATG) 5. Mammalian target of rapamycin (mTOR) represses autophagy by regulating ULK1 phosphorylation, while AMPK activates this process.CMA mediates the degradation of large molecular-weight proteins containing the KFERQ motif recognized by heat shock cognate protein of 70 kDa (HSC70). The substrate is then escorted to lysosome-associated membrane protein 2 (LAMP2A) for lysosomal degradation. Mitophagy is responsible for the degradation of damaged mitochondria.Parkin and PINK1 play critical roles in this process [2] . More Neurosci Bull August 1, 2015, 31(4): 435-444 436 attention has been paid to autophagy in the path...

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“…The formation of reactive nitrogen species (RNS), including peroxynitrite and nitrogen dioxide (NO 2 ), may be the prime reason in many cases why NO· can contribute to the etiology of inflammatory lung diseases, such as asthma [43]. Detection of 3-nitrotyrosine at inflammatory sites serves as a biochemical marker for peroxynitrite formation [18,44]. Our results indicate that H 2 O 2 and the SIN-1 might produce peroxynitrite, which was detected as 3-nitrotyrosine immunoreactivity.…”

Section: Discussionmentioning

confidence: 99%

Dissociation of DNA damage and mitochondrial injury caused by hydrogen peroxide in SV-40 transformed lung epithelial cells

et al. 2002

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BackgroundSince lung epithelial cells are constantly being exposed to reactive oxygen intermediates (ROIs), the alveolar surface is a major site of oxidative stress, and each cell type may respond differently to oxidative stress. We compared the extent of oxidative DNA damage with that of mitochondrial injury in lung epithelial cells at the single cell level.ResultDNA damage and mitochondrial injury were measured after oxidative stress in the SV-40 transformed lung epithelial cell line challenged with hydrogen peroxide (H2O2). Single cell analysis of DNA damage was determined by assessing the number of 8-oxo-2-deoxyguanosine (8-oxo-dG) positive cells, a marker of DNA modification, and the length of a comet tail. Mitochondrial membrane potential, ΔΨm, was determined using JC-1. A 1 h pulse of H2O2 induced small amounts of apoptosis (3%). 8-oxo-dG-positive cells and the length of the comet tail increased within 1 h of exposure to H2O2. The number of cells with reduced ΔΨm increased after the addition of H2O2 in a concentration-dependent manner. In spite of a continual loss of ΔΨm, DNA fragmentation was reduced 2 h after exposure to H2O2.ConclusionThe data suggest that SV-40 transformed lung epithelial cells are resistant to oxidative stress, showing that DNA damage can be dissociated from mitochondrial injury.

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Peroxynitrite formation within the central nervous system in active multiple sclerosis

Cited by 191 publications

References 58 publications

The Peroxynitrite Scavenger Uric Acid Prevents Inflammatory Cell Invasion into the Central Nervous System in Experimental Allergic Encephalomyelitis through Maintenance of Blood-Central Nervous System Barrier Integrity

The Peroxynitrite Scavenger Uric Acid Prevents Inflammatory Cell Invasion into the Central Nervous System in Experimental Allergic Encephalomyelitis through Maintenance of Blood-Central Nervous System Barrier Integrity

Role of autophagy in the pathogenesis of multiple sclerosis

Dissociation of DNA damage and mitochondrial injury caused by hydrogen peroxide in SV-40 transformed lung epithelial cells

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