IFNc and IL-1b in the spinal cord of VCE-003 EAE-treated mice in the mRNA transcripts encoding the adhesion molecule ICAM-1 and iNOS. In addition, direct evidence that microglial cells are targets for VCE-003 was confirmed when it was shown to reverse the increase in iNOS protein in activated murine BV2 microglial cells through a mechanism that involves PPARc and CB2 receptors, supporting our findings on disease severity scores. Myelin-specific CD4 + Th1 and Th17 cells with the contribution of CD8 + T cells, is one of the major driving forces in the pathological process of EAE. Here, we show that there were fewer CD4 + T cells in the spinal cord of EAE mice after VCE-003 administration and thus, the improvement in spinal cord damage may be associated with decreased CD4 + T cell infiltration from peripheral tissues. In this sense, we have shown that VCE003 inhibits peripheral primary T cell activation and proliferation, as well as the release of Th1 and Th17 Everolimus cytokines or chemokines. Although the lipophilic nature of VCE-003, like other pCBs, predicts it will penetrate into the CNS, it is possible that VCE-003 may also exert its effects at the level of the peripheral immune response. Accordingly, it is noteworthy that VCE-003 inhibits IL17-mediated production of pro-inflammatory cytokines in macrophages and perhaps, the migration of pro-inflammatory macrophages to the CNS. Preclinical and clinical data have shown that Th17 cells are associated with several autoimmune diseases, such as MS, arthritis, psoriasis and lupus. In the present study, IL-17 mRNA expression was reduced in the spinal cord of EAE mice administered VCE-003. In vitro approaches indicated that VCE003 was capable of reducing the transcription of IL-17, and it was more effective in inhibiting TNFa release than TNFa-gene promoter activity. On this basis, VCE-003 possibly inhibits Trichostatin A cytokine release at both the transcriptional and post-transcriptional level. Since we found that VCE-003 inhibited IL-17 signaling in macrophages we cannot rule out the 
possibility that a similar situation may also occur also in primary T cells. If this were the case, IL-17 released in CD3/CD28-stimulated T cells could act in an autocrine manner, increasing the stability of other CD3/CD28induced cytokine mRNAs, an activity that could also be inhibited by VCE-003. Although PPARc and CB2 are the more relevant targets for VCE-003 we cannot discard that other mechanism of action are also involved in the immunosuppressive activity of VCE-003. In this sense it is also possible that the effect of VCE-003 on cytokine expression is reflecting inhibition of T cell proliferation mediated by targeting downstream signal pathways other than PPARc and CB2, which prevent proliferation and subsequently cytokine production. We are currently performing experiments to identify the exact mechanism of action of VCE-003 in TCR-induced and IL-17R-induced signaling pathways. The CNS has several protective antioxidant mechanisms that are regulated through the nuclear factor–E2-related factor transcription factor and the antioxidant response element. In MS, Nrf2/ARE expression is enhanced and this is indicative of a response to oxidative stress. Moreover, disruption of Nrf2 gene expression in mice exacerbates the clinical and pathological symptoms of EAE. Here, we found that VCE003 activates the Nrf2 pathway in several neuronal cell lines.