D +T cells of quite a few miRNAs demyelination involved in Th polarization and cell cycle arrest/apoptosis Upregulation of genes for FoxP3, STAT5, IL-10 and IL-4 and downregulation of genes for Tbet-1, IFN-, STAT3 and IL-17A in brain MNCs Elevated production by brain MNCs of IL-10 and TGF- and lowered production IL-17A, IFN-, TNF-, IL-6, and IL-1b In brain MNCs mTORC1 Activator Compound improved apoptosis and decreased cell frequency in G0/G1 phase and improved frequency in G2/M phase Doable involvement of CB1 and CB2 receptors, based on outcomes in CB1-/- CB2-/- animals 9-THC+CBD (1:1 ratio) (10+ Decreased EAE severity, such as Increased spleen MDSC and reduced Al-Ghezi et al. 10 mg/kg/day i.p.) from day ten soon after lowered cell infiltration and tissue pro-inflammatory cytokines (2019a) EAE induction till day 15/18 damage in the brain (IL-17A and IFN-) and increased anti-inflammatory cytokines (TGF- and IL-10) in serum and spleen cells supernatantsTable three (continued) Therapy Major findings Mechanisms/biological target RefExperimental modelJ Neuroimmune Pharmacol (2021) 16:251(MOG355)-induced EAE in C57BL/6J mice(MOG355)-induced EAE in C57BL/6J mice(MOG355)-induced EAE in C57BL/6J mice(MOG355)-induced EAE in C57BL/6J miceReduced abundance of Akkermansia muciniphila (A. muc) and decreased LPS biosynthesis inside the gut Improved levels of SCFAs for example butyric, isovaleric, and valeric acids CBD (20 mg/kg/day i.p.) from day 9 to Delayed onset and attenuated clinical Lowered MNCs inside the spinal cord and Elliott et al. 25 post-EAE induction signs of EAE lowered CD3+CD4+ and CD3+ (2018) CD8+ T cells in the CNS Reduced IFN- and IL-17 in serum Lowered gene expression of T-bet and ROR- and enhanced gene expression of IL-10 in splenic CD4+ T cells In ex vivo splenocytes restimulated with MOG355, reduced production of IFN- and IL-17, and improved production of IL-10 Induction of highly immunosuppressive CD11b+Gr-1+ MDSCs which lowered clinical scores of EAE and cellular infiltration in the CNS MDSC depletion reversed CBD effects CBD (10 mg/kg/day i.p.) from day 14 Enhanced EAE clinical and histological Suppressed IFN- and IL-17 staining Giacoppo et al. until day 28 immediately after EAE induction score with decreased infiltration of and enhanced BDNF and PPAR (2017) inflammatory cells within the white staining in spinal cord sections matter of spinal cord Upregulation of the PI3K/Akt/mTOR pathway and lowered expression of JNK and p-p38 inside the MAPK pathway in the spinal cord 9-THC-BDS+CBD-BDS All therapies delayed symptoms onset Activation of CB1 receptors, but not of Moreno-Martet (30.8 mg/kg/day i.p., equivalent to but only 9-THC-BDS+CBD-BDS PPAR- et al. (2015) about ten mg/kg/day of pure also enhanced illness progression 9-THC+10 mg/kg/day of pure CBD) or CBD-BDS alone (20 mg/kg/day i.p., equivalent to about 13 mg/kg/day of pure CBD) at days 101 post MOG-inoculation CBD cream 1 applied on decrease limbs EAE clinical score improvement and Reduced FoxP3 staining in spinal cord Giacoppo et al. every PPARγ Activator medchemexpress single 24 h as much as 28 days after avoidance of EAE-associated body and lowered CD4 and CD8 (2015) illness onset weight reduction staining in spleen Decreased demyelination and axonal loss Reduced TNF-, IL-6, TGF- and and comprehensive resolution of INF- and improved IL-10 in spinal inflammatory cells infiltration cord Improved response to mechanical Lowered production of nitrotyrosine, stimuli iNOS and PARP, and reducedTable three (continued) Therapy Major findings Mechanisms/biological target RefExperimental model(MOG.