Suppression of the experimental autoimmune encephalomyelitis model of multiple sclerosis by calcitonin, vitamin D, and ultraviolet radiation

Although the exact cause of multiple sclerosis (MS) is unknown, one potential environmental factor is decreased exposure to ultraviolet radiation (UVR) and subsequent vitamin D insufficiency. A number of studies have demonstrated that the active form of vitamin D, 1alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3), suppresses clinical signs of disease in the experimental autoimmune encephalomyelitis (EAE) animal model of MS. However, complete prevention of EAE requires 1,25(OH)2D3 doses that cause hypercalcemia, and calcium appears to play a critical role in the mechanism of protection.;These observations led us to explore the effect of the peptide hormone calcitonin (CT), which is released in response to acute hypercalcemia, on disease progression in the EAE model. Continuous treatment with pharmacological doses of CT did not suppress clinical signs of EAE. In contrast, combining CT with a sub-therapeutic dose of 1,25(OH)2D3 significantly suppressed EAE without causing hypercalcemia, although complete disease prevention only occurred using 1,25(OH)2D3 doses that caused hypercalcemia.;Another method we employed to eliminate hypercalcemia was to develop vitamin D analogs which would suppress EAE without elevating serum calcium levels. We tested the therapeutic efficacy of two vitamin D analogs in the EAE model: 2-methylene-19-nor-(20S)-1alpha-hydroxy-bishomopregnacalciferol (2MbisP) and 2-methylene-19-nor-(20S)-1alpha,25-dihyroxyvitamin D3 (2MD). While both analogs suppressed EAE with a reduced calcemic effect, neither analog could completely prevent disease without causing elevations in serum calcium levels.;Despite considerable effort, we were unable to prevent induction of EAE without causing hypercalcemia. However, hypercalcemia does not occur upon exposure to UVR due to a number of factors which limit the endogenous production of vitamin D. This led us to explore the effect of UVR on disease progression in the EAE model. We found that continuous treatment with UVR suppressed EAE with no effect on serum calcium levels and only a slight increase in serum 25-hydroxyvitamin D3 (25(OH)D3) levels. In contrast, administration of 25(OH)D3 independent of UVR was unable to suppress EAE until delivered at doses that caused severe hypercalcemia. Our results suggest that UVR is not simply suppressing EAE by increasing vitamin D production, but is playing an active role in disease suppression independent of vitamin D.