Administration of 2-arachidonoylglycerol ameliorates both acute and chronic experimental autoimmune encephalomyelitis

Background and purposeExperimental autoimmune encephalomyelitis (EAE) is a widely used model of multiple sclerosis (MS) and both conditions have been reported to exhibit reduced endocannabinoid activity. The purpose of this study was to address the effect of exogenously administered 2-arachidonoylglycerol (2AG), an endocannabinoid receptor ligand, on acute phase and chronic disability in EAE.Experimental approachAcute and chronic EAE models were induced in susceptible mice and 2AG-treatment was applied for 14 days from day of disease induction.Key results2AG-treatment ameliorated acute phase of disease with delay of disease onset in both EAE models and reduced disease mortality and long-term (70 days post-induction) clinical disability in chronic EAE. Reduced axonal pathology in the chronic EAE- (p < 0.0001) and increased activation and ramification of microglia in the 2AG-treated acute EAE- (p < 0.05) model were noticed. The latter was accompanied by a 2- to 4-fold increase of the M2-macrophages in the perivascular infiltrations (p < 0.001) of the 2AG-treated animals in the acute (day 22), although not the chronic (day 70), EAE model. Expression of cannabinoid receptors 1 (CB1R) and 2 (CB2R) was increased in 2AG-treated animals of acute EAE vs. controls (p < 0.05). In addition, ex vivo viability assays exhibited reduced proliferation of activated lymph node cells when extracted from 2AG-treated EAE animals, whereas a dose-dependent response of activated lymphocytes to 2AG-treatment in vitro was noticed.Conclusion and implicationsOur data indicate for the first time that 2AG treatment may provide direct (via CBRs) and immune (via M2 macrophages) mediated neuroprotection in EAE.

Research Highlights
► Exogenous 2AG-treatment is applied for the first time in PLP- and MOG-induced EAE.
► 2AG delayed disease onset and reduced relapse severity and long-term disability in EAE.
► 2AG inhibited lymphocyte-activation and induced apoptosis.
► 2AG-treatment reduced axonal pathology in the chronic EAE model.
► 2AG-induced neuroprotection may be microglia-related in acute EAE.