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

Abstract Pathological changes occur in areas of CNS tissue remote from inflammatory lesions in multiple sclerosis (MS) and its animal model experimental allergic encephalomyelitis (EAE). To determine if oxidative stress is a significant contributor to this non-inflammatory pathology, cortex tissues...

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Published in:	Neuroscience Vol. 185; pp. 97 - 105
Main Authors:	Castegna, A, Palmieri, L, Spera, I, Porcelli, V, Palmieri, F, Fabis-Pedrini, M.J, Kean, R.B, Barkhouse, D.A, Curtis, M.T, Hooper, D.C
Format:	Journal Article
Language:	English
Published:	Amsterdam Elsevier Ltd 30-06-2011 Elsevier
Subjects:	Analysis of Variance Animal models Animals Biological and medical sciences Calcium - metabolism Cerebral Cortex - enzymology Cerebrospinal fluid. Meninges. Spinal cord Chromatography, High Pressure Liquid - methods Disease Models, Animal Electrophoresis, Gel, Two-Dimensional Encephalitis - pathology Encephalomyelitis, Autoimmune, Experimental - etiology Encephalomyelitis, Autoimmune, Experimental - pathology Encephalomyelitis, Autoimmune, Experimental - physiopathology experimental allergic encephalomyelitis Female Fundamental and applied biological sciences. Psychology Glutamate-Ammonia Ligase - analysis Glutamate-Ammonia Ligase - metabolism Glutamic Acid - metabolism Glutamine - metabolism glutamine synthetase Glutathione - metabolism Glutathione Disulfide - metabolism Guinea Pigs Medical sciences Mice multiple sclerosis Myelin Basic Protein - adverse effects Myelin Basic Protein - immunology NAD - metabolism NADP - metabolism Nervous system (semeiology, syndromes) Neurology Nitric Oxide Synthase Type II - metabolism oxidative stress Oxidative Stress - physiology Tandem Mass Spectrometry - methods Vertebrates: nervous system and sense organs blood-brain barrier GSSG BBB glutathione disulfide multiple sclerosis glutathione MS EAE Gln myelin basic protein glutamine GS experimental allergic encephalomyelitis Glu glutamine synthetase ROS reactive oxygen species MBP GSH oxidative stress glutamate Oxidative stress Nervous system diseases Carbon-nitrogen ligases Encephalomyelitis Enzyme Rodentia Inflammation Cerebral disorder Vertebrata Mammalia Mouse Ligases Animal Central nervous system disease Spinal cord disease Glutamate-ammonia ligase
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Summary:	Abstract Pathological changes occur in areas of CNS tissue remote from inflammatory lesions in multiple sclerosis (MS) and its animal model experimental allergic encephalomyelitis (EAE). To determine if oxidative stress is a significant contributor to this non-inflammatory pathology, cortex tissues from mice with clinical signs of EAE were examined for evidence of inflammation and oxidative stress. Histology and gene expression analysis showed little evidence of immune/inflammatory cell invasion but reductions in natural antioxidant levels and increased protein oxidation that paralleled disease severity. Two-dimensional oxyblots and mass-spectrometry-based protein fingerprinting identified glutamine synthetase (GS) as a particular target of oxidation. Oxidation of GS was associated with reductions in enzyme activity and increased glutamate/glutamine levels. The possibility that this may cause neurodegeneration through glutamate excitotoxicity is supported by evidence of increasing cortical Ca2+ levels in cortex extracts from animals with greater disease severity. These findings indicate that oxidative stress occurs in brain areas that are not actively undergoing inflammation in EAE and that this can lead to a neurodegenerative process due to the susceptibility of GS to oxidative inactivation.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-1
ISSN:	0306-4522 1873-7544
DOI:	10.1016/j.neuroscience.2011.04.041