Uced effective effects in EAE consistently pointed to reduction of proinflammatory cytokines which include IL-17A, IFN-, TNF-, IL-6, and IL-1b, and increase of anti-inflammatory cytokines for instance IL-4, IL-10 and TGF- (Nichols et al. 2020; Al-Ghezi et al. 2019a, b; Elliott et al. 2018; Giacoppo et al. 2017; Giacoppo et al. 2015; Rahimi et al. 2015; Duchi et al. 2013; Zhou et al. 2019), at the same time as to induction of immunosuppressive MDSC (Al-Ghezi et al. 2019a; Elliott et al. 2018). Very couple of research addressed the challenge of target receptors involved in the effects of CBD (Moreno-Martet et al. 2015; Al-Ghezi et al. 2019b).One particular study (Gallily and Yekhtin 2019) compared CBD to the anti-MS drug glatiramer displaying that they had been helpful towards the identical extent in reducing EAE. Preclinical investigation of CBD in EAE also incorporated seven studies performed in ex vivo/in vitro models of encephalitogenic lymphocytes (Table 3), all determined by T cells from lymph nodes or spleen of mice with (MOG355)-induced EAE, except for one which employed astrocytes from TMEVIDD SJL/J mice (Mecha et al. 2013). CBD was always used at concentrations ranging from 0,1 to ten M, commonly resulting in decreased proliferation and elevated apoptosis of cells, too as in inhibition of proinflammatory and activation of antiinflammatory pathways. Only handful of studies investigated the molecular targets mediating CBD effects. Kozela et al. NF-κB Activator Compound excluded the contribution of either CB1, CB2, 5-HT1A, TRPV1 or PPAR in CBD-dependent reduction of IL-17 secretion from T cells (Kozela et al. 2013), or of CB1 or CB2 in CBD-dependent inhibition of T cell proliferation (Kozela et al. 2011). No involvement of GPR55, CB1, or CB2 receptors was reported also by Gonz ez-Garc et al. (2017), who studied CBD-induced inhibition of MOG355/IL-12-induced IL-6 secretion and improved apoptosis in mouse encephalitogenic spleen cells, whilst Mecha et al. (2013) recommended a contribution by A2A receptors in CBD-induced reduced of CCL2 secretion from mouse astrocytes.Clinical StudiesOur search provided a total of six studies performed in MS patients and/or on immune cells obtained from patientsTable three Treatment Primary findings Mechanisms/biological target RefEffect of CBD in preclinical models of MSExperimental modelIn vivo (MOG355)-induced EAE in C57BL/6J mice CBD (75 mg/kg/day by oral gavage) 24 h soon after EAE induction and subsequently for 5 days(MOG355)-induced EAE in C57BL/6J miceJ Neuroimmune Pharmacol (2021) 16:251(MOG355)-induced EAE in C57BL/6J miceReduction of clinical score at day 18 in No modify in percentage of Treg Nichols et al. serious but not in mild EAE isolated in the lymph nodes and (2020) spleen, or of MDSC from spleen Reduction of neuroinflammation and T In ex vivo splenocytes restimulated cell infiltration in white matter tracts with MOG355 for 48 h, CBD decreased percentage of IFN- of brain and spinal cord making CD8+ T cells but did not affect IL-17-producing CD8+ T cells In ex vivo splenocytes and lymphocytes from lymph nodes restimulated with MOG355 for 48 h, CBD didn’t have an effect on IFN- and IL-17A production on day three and 10, but enhanced IFN- production on day 18 CBD (10 mg/kg/day i.p.) or 9-THC+ 9-THC+CBD (but not CBD alone) NPY Y1 receptor Agonist medchemexpress Lowered IL-17A and IFN- Al-Ghezi et al. CBD (10 mg/kg/day i.p.) from day decreased clinical symptoms, brain production in iLN cell supernatants (2019b) ten after EAE induction till day infiltration of MNCs, CD3+ T cells Modifications in the expression in brain CD4 15/27 and CD3+CD4+ T cells, an.