Interplay of free radicals and mitochondrial dysfunction in multiple sclerosis
My research line is focused on the identification of molecular pathways underlying impaired mitochondrial metabolism and reactive oxygen species (ROS) production in MS and to examine the potential of antioxidant protection to counteract oxidative stress and improve mitochondrial function (figure). The approach we use is to assemble information obtained from neuropathological examination of MS brain tissue and translate these findings into an experimental setting using a variety of molecular and in vitro techniques to study molecular pathways involved in excessive ROS formation and mitochondrial dysfunction in MS pathology. Moreover, we investigate the potential therapeutic effects of antioxidant strategies to counteract oxidative injury and associated cellular damage. The observation that oxidative damage is widespread in MS lesions suggests that during neuroinflammation the antioxidant response may be insufficient to reduce ROS-induced cellular injury. Hence, increasing the levels of endogenous antioxidants represents an attractive approach to counteract oxidative stress and ROS-mediated cellular injury in MS. Indeed, our recent data indicate that the induction of antioxidant enzyme production protect CNS cells from ROS-induced cell death and limits MS-associated pathology. Our approach, varying from analysis of MS brain tissue to in vitro models and experimental animal models, will enhance our understanding of processes involved in free radical formation and detoxification and may ultimately lead to the identification of novel targets for future treatment strategies in MS.
M.E. Witte, P.G. Nijland, J.A. Drexhage, W. Gerritsen, D. Geerts, B. van het Hof, A. Reijerkerk, H.E. de Vries, P. van der Valk, J. van Horssen. Reduced
expression of PGC-1? partly underlies mitochondrial changes and correlates with neuronal loss in multiple sclerosis cortex. Acta Neuropathol . 2012.
H. Lassmann, J. van Horssen, D. Mahad. Progressive multiple sclerosis: Pathology and mechanisms of tissue injury. Nature Rev. Neurol . 2012.
M.T. Fischer, R. Sharma, J.L. Lim, L. Haider, J.M. Frischer, D. Mahad, M. Bradl, J. van Horssen and H. Lassmann. NADPH Oxidase Expression in Active Multiple Sclerosis Lesions in Relation to Oxidative Tissue Damage and Mitochondrial Injury. Brain 2012.
M.E. Witte, L. Bo, R. Rodenburg, J.A. Belien, R. Musters, T. Hazes, L. Wintjes, J.A. Smeitink, J.Geurts, H.E de Vries, P. van der Valk, J. van Horssen. Enhanced number and activity of mitochondria in multiple sclerosis lesions. J. Pathol. 2009
J. van Horssen, G. Schreibelt, J. Drexhage, T. Hazes, C.D. Dijkstra, P. van der Valk, H.E. de Vries. Severe oxidative damage in multiple sclerosis lesions coincides with enhanced antioxidant enzyme expression. Free Radic Biol Med . 2008
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