Uced useful effects in EAE regularly pointed to reduction of proinflammatory cytokines such as IL-17A, IFN-, TNF-, IL-6, and IL-1b, and increase of anti-inflammatory cytokines like 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), also as to induction of immunosuppressive MDSC (Al-Ghezi et al. 2019a; Elliott et al. 2018). Quite few studies addressed the problem of target receptors involved TLR4 Agonist site within the effects of CBD (Moreno-Martet et al. 2015; Al-Ghezi et al. 2019b).1 study (Gallily and Yekhtin 2019) compared CBD for the anti-MS drug glatiramer showing that they had been helpful to the same extent in minimizing EAE. Preclinical investigation of CBD in EAE also integrated seven research performed in ex vivo/in vitro models of encephalitogenic lymphocytes (Table three), all depending on T cells from lymph nodes or spleen of mice with (MOG355)-induced EAE, except for one particular which utilised astrocytes from TMEVIDD SJL/J mice (Mecha et al. 2013). CBD was often utilised at concentrations ranging from 0,1 to 10 M, typically resulting in decreased proliferation and elevated apoptosis of cells, too as in inhibition of proinflammatory and activation of antiinflammatory pathways. Only handful of research investigated the molecular targets mediating CBD effects. Kozela et al. 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, while Mecha et al. (2013) suggested a contribution by A2A receptors in CBD-induced reduced of CCL2 secretion from mouse astrocytes.Clinical StudiesOur search offered a total of six research performed in MS individuals and/or on immune cells obtained from patientsTable 3 Therapy Key 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 just 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. extreme but not in mild EAE mTORC1 Inhibitor Species 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 creating CD8+ T cells but didn’t impact IL-17-producing CD8+ T cells In ex vivo splenocytes and lymphocytes from lymph nodes restimulated with MOG355 for 48 h, CBD did not influence IFN- and IL-17A production on day 3 and ten, but elevated IFN- production on day 18 CBD (ten mg/kg/day i.p.) or 9-THC+ 9-THC+CBD (but not CBD alone) Reduced IL-17A and IFN- Al-Ghezi et al. CBD (ten mg/kg/day i.p.) from day lowered clinical symptoms, brain production in iLN cell supernatants (2019b) ten after EAE induction till day infiltration of MNCs, CD3+ T cells Modifications inside the expression in brain CD4 15/27 and CD3+CD4+ T cells, an.