Mechanisms of oxidative damage in multiple sclerosis and a cell therapy approach to treatment

Abstract

Although significant advances have recently been made in the understanding and treatment of multiple sclerosis, reduction of long-term disability remains a key goal. Evidence suggests that inflammation and oxidative stress within the central nervous system are major causes of ongoing tissue damage in the disease. Invading inflammatory cells, as well as resident central nervous system cells, release a number of reactive oxygen and nitrogen species which cause demyelination and axonal destruction, the pathological hallmarks of multiple sclerosis. Reduction in oxidative damage is an important therapeutic strategy to slow or halt disease processes. Many drugs in clinical practice or currently in trial target this mechanism. Cell-based therapies offer an alternative source of antioxidant capability. Classically thought of as being important for myelin or cell replacement in multiple sclerosis, stem cells may, however, have a more important role as providers of supporting factors or direct attenuators of the disease. In this paper we focus on the antioxidant properties of mesenchymal stem cells and discuss their potential importance as a cell-based therapy for multiple sclerosis.

Figure 1

Cellular detoxification of reactive oxygen and nitrative species. Oxygen is reduced to superoxide (O₂⁻) during inflammation, and nitric oxide (NO⁻) is generated by the action of inflammatory nitric oxide synthase (iNOS) on L-arginine. In the absence of detoxifying enzymes, NO⁻ and O₂⁻ react to produce the highly toxic peroxynitrite (ONOO⁻). Superoxide dismutase (SOD) competes for the superoxide anion and dismutes it to form hydrogen peroxide (H₂O₂) which can then be removed by the enzymes catalase and glutathione peroxidase (GPX).

Figure 2

Human bone-marrow-derived mesenchymal stem cells in culture (scale bar = 100 microns).

Figure 3

Nitric oxide promotes axonal injury to cerebellar neurones in vitro. Immunofluorescent images depicting cerebellar axonal morphology (a) pre- and (b) posttreatment with 0.1 mM NO. Green: axonal marker SMI 312. Blue: DAPI nuclear stain.