Combination of Imipramine, a sphingomyelinase inhibitor, and β-caryophyllene improve their therapeutic effects on experimental autoimmune encephalomyelitis (EAE)

[Display omitted] •BCP low dose improves the clinical and pathological manifestations of EAE.•IMP improves the clinical and pathological manifestations of EAE.•Combination of BCP and IMP improves the clinical and pathological manifestations of EAE.•Combination of BCP and IMP provides synergistic anti-inflammatory effects, in vitro. Multiple Sclerosis (MS) is one of the most common inflammatory diseases with the essential role of immune system in the demyelination, damage and inflammation of the central nervous system neurons (CNS). β-Caryophyllene (BCP), a natural and selective CB2 agonist, possesses several protective effects. In the present study, we evaluated the protective effects of low dose of BCP (5 mg/kg), sphingomyelinase (SMase) inhibitor imipramine (IMP, 10 mg/kg), and the combination of BCP (2.5 and 5 mg/kg) with IMP in the treatment of experimental autoimmune encephalomyelitis (EAE) mice as a known model of chronic MS. These effects were assessed on the levels of pro- or anti-inflammatory cytokines as well as the polarization of spleen lymphocytes and microglia, in EAE mice. Our results indicated that low dose of BCP, IMP and BCP combined with a SMase inhibitor IMP exert protective effects in treatment of EAE mice. We also found that they reduced the clinical and pathological defects in EAE mice through modulation of both local (microglia) and systemic (lymphocytes and blood) immunity from inflammatory (Th1/Th17/M1) towards anti-inflammatory (Th2/Treg/M2) phenotypes. Therefore, it can be suggested that a low dose of BCP alone or combined with IMP as a known SMase inhibitor deserve a therapeutic position for treatment of MS.