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

• 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
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2011.04.041

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.