Enhanced myelination and oligodendrocyte survival following PPAR activation could occur independent of changes in myelin gene expression. PPAR activation suppresses synthesis of inflammatory cytokines/chemokines and reactive oxygen (ROS) and nitrogen (RNS) species, all of which are toxic to oligodendrocytes (Springer et al., 1997; Zhao et al., 2006; McTigue, 2008). These inflammatory mediators are inhibited by PPAR activation in macrophages and astrocytes (Ricote et al., 1998; Bernardo et al., 2000; Xu et al., 2006). PPARγ activation increases cellular antioxidants, including catalase and copper-zinc superoxide dismutase, both of which are expressed at low levels in oligodendrocyte lineage cells (Juurlink et al., 1998; Bernardo et al., 2009). Treating OPCs with the PPARγ antagonist GW9662 abolished the anti-inflammatory and antioxidant effects of PPAR agonists, demonstrating a direct role for PPAR signaling in these signaling cascades (Bernardo et al., 2009).
