In addition, LQ treatment reverses ongoing motor deficit as measured using standard EAE clinical scoring and rotorod motor performance. While many reports focus on the prevention or inhibition of early EAE symptoms using LQ, ours is the first study to show distinct improvement in axon myelination, axon conduction, and motor function as a result of LQ treatment in pre (day 0), early post (day 8), and peak (~day 21) EAE mice. We took advantage of PLP_EGFP and Thy1-YFP transgenic mice to study the direct effects Inhibitors,research,lifescience,medical of LQ treatment
on neurodegeneration and demyelination in EAE. LQ treatment significantly attenuated the loss of GFP fluorescence in neurons, axons, and OLs of the CNS. Most remarkable was the increased axon remyelination, axon conduction, and Inhibitors,research,lifescience,medical the significant recovery in proliferating and mature OL numbers of EAE animals
treated with LQ after peak disease. This recovery correlated with LQ-mediated suppression of cytokine production and reduction in infiltrating immune cells in the CNS. Previous studies have also shown LQ-induced neuroprotection in EAE CNS (Ruffini et al. 2012), which correlates with suppression of cytokine production and reduction in infiltrating immune cells (Yang et al. 2004; Wegner et al. 2010; Aharoni et al. 2012; Bruck et al. 2012). In the present study, peripheral Inhibitors,research,lifescience,medical cytokine PI3K inhibitor levels determined after post-immunization day 30 of EAE following 25 mg/kg LQ treatment were similar to levels observed at day 13 (i.e., downregulation of pro-inflammatory cytokines IL-13, Inhibitors,research,lifescience,medical IL-17, IFN-γ, and TNF-α (Wegner et al. 2010). In addition, there was a significant decrease in IL-4, IL-5, and IL-6 cytokines. Our findings of LQ-induced reduction in IL-10 levels in EAE mice are similar to Wegner et al. (2010) and contrast the increase in IL-10 levels reported by Yang et al. (2004). MMP have a crucial function in the migration of peripheral inflammatory cells into the CNS and levels of MMP-9 are elevated in MS and EAE.
Inhibitors,research,lifescience,medical The 25 mg/kg LQ treatment during pre-EAE and peak EAE significantly decreased MMP-9 levels. Taken together, our findings suggest that LQ protects myelin and axons by decreasing pro-inflammatory cytokines and Suplatast tosilate impairing the migratory capacity of inflammatory cells. Reactive astrogliosis is a prominent feature of the chronic and widespread adaptive immune inflammation of the CNS that occurs during EAE and MS (Eng 1985). Reactive astrocytes are responsible for the production of pro-inflammatory molecules (e.g., cytokines, chemokines, growth factors, nitric oxide), growth-inhibitory molecules, and increased production of NFκB-dependent pro-inflammatory molecules. These molecules are detrimental to oligodendrocyte survival, remyelination, and functional recovery (Brambilla et al. 2009; Chang et al. 2012).