Oxidative stress and reduced glutamine synthetase activity in the cortex of a murine model of multiple sclerosis

The role of oxidative stress in neurodegeneration and the temporal relationship between oxidative stress and inflammation have been investigated in murine experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). To address these issues and identify specific targets of protein oxidation we have employed a proteomic approach coupled to quantitative determination of key metabolites in cortex tissues from mice with clinical signs of EAE. Our results show a decrease in endogenous antioxidant levels and a specific increase of glutamine synthetase (GS) oxidation with little or no evidence of immune/inflammatory cell invasion. The reduction in enzyme activity associated to GS oxidation leads to an increase of glutamate/ glutamine ratio and paralleled disease severity in EAE mice. The possibility that GS oxidation 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.