ABSTRACT Using the rat model Experimental Autoimmune Encephalomyelitis (EAE), we have investigated the cytokinetical and cellular events of axonal degeneration and demyelination following treatment with 5 mg/kg/24h R(+)WIN55,212-2 or 10 mg/kg/24h R(+)WIN55,212-2, which have immunosuppressive effects. EAE was induced using MOG(1-125) in Dark Agouti rats and treatment was initiated at symptom debut and continued until first relapse culminated. The central nervous system (CNS) cell death including caspase and calpain activation, axonal degeneration and demyelination as well as a wide range of immunological parameters were quantified. We found a significant reduction in axonal degeneration associated with reduced calpain 1 following treatment with 5 mg/kg/24h R(+)WIN55,212-2. Treatment with 10 mg/kg/24h resulted furthermore in an improved clinical performance and a reduction in inflammatory activity and demyelination. Furthermore, the cytokines IL-2, IL-6, IL-10, RANTES, and TGF-ß were significantly reduced as were the cellular infiltration with regulatory T cells. We suggest that cannabinoids in low doses are neuroprotective through a reduction in calpain 1 expression. Our study implies that long-term low-dose cannabinoid administration to multiple sclerosis (MS) patients could result in some degree of neuroprotection, and thereby slow down the atrophy associated with this disease.