Uncontrolled or excessive oxidative stress may increase the Regorafenib inquirer expression of Nrf2 mRNA, as observed in EAE mice, probably as a primary mechanism to suppress aberrant oxidative stress responses and to promote protection from inflammatory disease. However, it should be noted that VCE-003-treated EAE mice showed reduced Nrf2 transcripts and no changes in Nrf2dependent gene expression Hmox-1. The discrepancies between the in vitro and in vivo results may be due to the fact that Nrf2 expression was assessed at the end of treatment, when the clinical scores of the mice that received VCE-003 were less than 1 and therefore, these EAE mice showed a clear clinical improvement. BBB integrity is critical to regulate the infiltration of migrating cells into the CNS. ICAM-1 was expressed strongly in acute MS Z-VAD-FMK lesions and comparable levels were also detected in chronic-active MS lesions, whereas the expression of VCAM-1 was greatly increased in chronic-active MS lesions compared to in acute MS. In the EAE model, many studies have demonstrated changes in adhesion molecules that reflect alterations to the BBB. We have recently shown that VCAM-1 is reduced in the spinal cord of TMEV-infected mice that were administered VCE003. In keeping with the fact that VCAM-1 expression is critical to allow lymphocyte trafficking from the periphery to the CNS, we showed a decrease in spinal cord infiltrates and specifically, decreased CD4 + T cells. Collectively these data may explain why immunized mice that receive VCE-003 display a notable alteration in disease onset and severity, in terms of reduced symptomatology and inflammation. Remarkably, VCE-003 treated mice develop significantly less paralysis and histological signs of EAE, and concordantly, they display weaker expression of the canonical Th1 cytokine IFNc and the Th17 cytokine, IL-17A. As VCE-003 acts as an agonist of both CB2 and PPARc receptors, and 
the activation of these receptors has been linked with antiinflammatory effects in EAE, we showed that the blockade of these receptors significantly attenuated the anti-inflammatory effects of VCE-003 in microglia. Although more work is needed to determine the cellular and molecular targets of VCE-003, and to clearly establish the signaling pathways involved in its actions, the unique capacity of VCE-003 to simultaneously repress IL-17 expression, microglial activity and CNS infiltrates suggests that it may be useful to manage MS. This CBG derivative appears to be a novel compound for inflammatory diseases. Nicotinic acetylcholine receptors are ligand-gated ion channels that are ubiquitously expressed throughout the central and peripheral nervous systems as well as in non neuronal tissues. These channels are composed of five individual subunits that assemble around a central pore and open to allow the passage of ions across the plasma membrane when activated by an agonist. There are seventeen nAChR genes that code for the different nAChR subunits and include ten a, four b, and one d, e, and c subunits; receptors composed of a1b1de/c have only been found at the neuromuscular junction. These subunits combine in various combinations to form different receptor subtypes each having unique biophysical properties including permeability to calcium and sensitivity to ligands. Many of these receptor subtypes have been implicated in human conditions.