| Reactive oxygen species (ROS) contribute to the formation and persistence of multiple sclerosis (MS) lesions by acting on distinct pathological processes. In the initial phase of MS lesion development, locally produced ROS may induce blood-brain barrier (BBB) disruption, enhance leukocyte migration and myelin phagocytosis. In later stages, ROS may contribute to lesion persistence by mediating oligodendroglial damage and axonal injury. Generally, high levels of ROS cause oxidative stress leading to transcription of antioxidant response element (ARE)-regulated genes. These genes encode various endogenous antioxidant enzymes that offer protection against oxidative stress and inflammation. Recently, we observed a striking upregulation of antioxidant enzyme genes in brains of experimental autoimmune encephalomyelitis animals as well as increased protein expression of peroxiredoxin-1 and NAD(P)H:quinone oxidoreductase-1, two prominent antioxidant enzymes, in active demyelinating MS lesions. Based on these findings we speculate that endogenous antioxidant enzymes are induced in the course of MS lesion formation. To test our hypothesis we first wish to study the expression of redox enzymes in various MS lesion stages and identify their cellular source. In parallel, we want to perform in vitro studies on their role in glial cell functioning, transendothelial monocyte migration and myelin phagocytosis. Several compounds specifically induce ARE-driven gene expression, thereby increasing the activity of redox enzymes. We propose that enhancement of endogenous antioxidant enzyme activity using specific enzyme inducers may be beneficial in MS. Enhanced antioxidant enzyme expression and activity may restore and stabilize BBB integrity, reduce leukocyte migration, inhibit myelin phagocytosis and prevent ROS-induced oligodendroglial injury. Our study, conducted in a human setting, will significantly increase our understanding on the involvement of antioxidant enzymes in various mechanisms underlying the pathogenesis of MS. Redox enzymes or compounds that activate endogenous antioxidant gene expression may inhibit MS lesion formation and progression and therefore represent an attractive therapeutic target. |
