Oxidative stress and reduced glutamine synthetase activity in the absence of inflammation in the cortex of mice with experimental allergic encephalomyelitis

Castegna, Alessandra; Palmieri, Luigi; Spera, Iolanda; Porcelli, Vito; Palmieri, F.; Fabis-Pedrini, Marzena J.; Kean, Rhonda; Barkhouse, Darryll A.; Curtis, Mark; Hooper, D. Craig

doi:10.1016/j.neuroscience.2011.04.041

Cited by 60 publications

(48 citation statements)

References 51 publications

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“…This would indicate that oxidative stress precedes the inflammatory response, thus providing indirect support for the hypothesis that oxidative stress [8,26,27]: i) modifies the permeability of the blood-brain barrier; and ii) stimulates the adhesion of monocytes to the vascular endothelium.…”

Section: Discussionmentioning

confidence: 84%

Peripheral oxidative stress in relapsing–remitting multiple sclerosis

Tasset

Agüera

Sánchez-López

et al. 2012

Clinical Biochemistry

104

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Section: Discussionmentioning

confidence: 84%

Peripheral oxidative stress in relapsing–remitting multiple sclerosis

Tasset

Agüera

Sánchez-López

et al. 2012

Clinical Biochemistry

104

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“…Indeed, increased glutamate levels were observed in the cerebrospinal fluid and in normal appearing white matter (NAWM) of MS patients [10–13]. In search of the culprit for these elevated glutamate levels, glutamate-metabolizing enzymes (glutamine synthetase and glutamate dehydrogenase) [14–17] as well as glutamate receptors [18–23] and EAATs [24–28] have been extensively investigated in the brain tissue of MS patients and animal models, such as the experimental autoimmune encephalomyelitis (EAE) mouse model of inflammatory demyelination [29] and the Theiler’s murine encephalomyelitis virus-induced demyelination model [30]. …”

Section: Introductionmentioning

confidence: 99%

Absence of system xc − on immune cells invading the central nervous system alleviates experimental autoimmune encephalitis

Merckx

Albertini

Paterka

et al. 2017

J Neuroinflammation

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BackgroundMultiple sclerosis (MS) is an autoimmune demyelinating disease that affects the central nervous system (CNS), leading to neurodegeneration and chronic disability. Accumulating evidence points to a key role for neuroinflammation, oxidative stress, and excitotoxicity in this degenerative process. System xc − or the cystine/glutamate antiporter could tie these pathological mechanisms together: its activity is enhanced by reactive oxygen species and inflammatory stimuli, and its enhancement might lead to the release of toxic amounts of glutamate, thereby triggering excitotoxicity and neurodegeneration.MethodsSemi-quantitative Western blotting served to study protein expression of xCT, the specific subunit of system xc −, as well as of regulators of xCT transcription, in the normal appearing white matter (NAWM) of MS patients and in the CNS and spleen of mice exposed to experimental autoimmune encephalomyelitis (EAE), an accepted mouse model of MS. We next compared the clinical course of the EAE disease, the extent of demyelination, the infiltration of immune cells and microglial activation in xCT-knockout (xCT−/−) mice and irradiated mice reconstituted in xCT−/− bone marrow (BM), to their proper wild type (xCT+/+) controls.ResultsxCT protein expression levels were upregulated in the NAWM of MS patients and in the brain, spinal cord, and spleen of EAE mice. The pathways involved in this upregulation in NAWM of MS patients remain unresolved. Compared to xCT+/+ mice, xCT−/− mice were equally susceptible to EAE, whereas mice transplanted with xCT−/− BM, and as such only exhibiting loss of xCT in their immune cells, were less susceptible to EAE. In none of the above-described conditions, demyelination, microglial activation, or infiltration of immune cells were affected.ConclusionsOur findings demonstrate enhancement of xCT protein expression in MS pathology and suggest that system xc − on immune cells invading the CNS participates to EAE. Since a total loss of system xc − had no net beneficial effects, these results have important implications for targeting system xc − for treatment of MS.

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“…It is found mostly in young adults in the western world [1, 2]. The main pathological features of the disease include focal CNS inflammation with axonal demyelination and neuronal death [3]. The common clinical strategy for therapy of acute relapses in MS is either by high dose, short-term pulse therapy with glucocorticoid [4] or by immunomodulatory treatments such as interferon beta [5], glatiramer acetate [6], and mitoxantrone [7].…”

Section: Introductionmentioning

confidence: 99%

Astragalosides from Radix Astragali benefits experimental autoimmune encephalomyelitis in C57BL /6 mice at multiple levels

Shi

et al. 2014

BMC Complement Altern Med

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BackgroundRadix Astragali is famous for its beneficial effect on inflammation associated diseases. This study was to assess the efficacy of astragalosides (AST) extracted from Radix Astragali, on the progression of experimental autoimmune encephalomyelitis (EAE), and explore its possible underlying molecular mechanisms.MethodsEAE was induced by subcutaneous immunization of MOG35–55. Infiltration of inflammatory cells was examined by HE staining. ROS level was detected by measuring infiltrated hydroethidine. Leakage of blood brain barrier (BBB) was assessed using Evan’s blue dye extravasation method. Levels of inflammatory cytokines were measured using ELISA kits. Activities of total-SOD, GSH-Px, and iNOS and MDA concentration were measured using biochemical analytic kits. Gene expression was detected using real-time PCR method. Protein expression was assayed using western blotting approach.ResultsAST administration attenuated the progression of EAE in mice remarkably. Further studies manifested that AST treatment inhibited infiltration of inflammatory cells, lessened ROS production and decreased BBB leakage. In peripheral immune-systems, AST up-regulated mRNA expression of transcriptional factors T-bet and Foxp3 but decreased that of RORγt to modulate T cell differentiation. In CNS, AST stopped BBB leakage, reduced ROS production by up-regulation of T-SOD, and reduced neuroinflammation by inhibition of iNOS and other inflammatory cytokines. Moreover, AST inhibited production of p53 and phosphorylation of tau by modulation of the Bcl-2/Bax ratio.ConclusionsAST orchestrated multiple pathways, including immuno-regulation, anti-oxidative stress, anti-neuroinflammation and anti-neuroapoptosis involved in the MS pathogenesis, to prevent the deterioration of EAE, which paves the way for the application of it in clinical prevention/therapy of MS.

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Oxidative stress and reduced glutamine synthetase activity in the absence of inflammation in the cortex of mice with experimental allergic encephalomyelitis

Cited by 60 publications

References 51 publications

Peripheral oxidative stress in relapsing–remitting multiple sclerosis

Peripheral oxidative stress in relapsing–remitting multiple sclerosis

Absence of system xc − on immune cells invading the central nervous system alleviates experimental autoimmune encephalitis

Astragalosides from Radix Astragali benefits experimental autoimmune encephalomyelitis in C57BL /6 mice at multiple levels

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