1,25-DIHYDROXYVITAMIN D-3 INHIBITS THE EXPRESSION OF INDUCIBLE NITRIC-OXIDE SYNTHASE IN RAT CENTRAL-NERVOUS-SYSTEM DURING EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS

The inducible form of nitric oxide synthase (iNOS) generates nitric ox ide of which the excessive production is associated with central nervo us system (CNS) inflammatory diseases. The investigation of iNOS expre ssion during experimental allergic encephalomyelitis (EAE) of the Lewi s rat demonstrated iNOS immunoreactivity and mRNA both during inflamma tory bursts (days 12 and 23 post-immunization) and during the remissio n phase (day 18). iNOS expression was region-specific and expanded wit h time along a caudo-rostral axis, thus, correlating with the developm ent of inflammatory infiltrates. Whereas cells of the monocyte/macroph age lineage continuously contributed to iNOS expression, astrocytes on ly expressed iNOS immunoreactivity or mRNA during the relapse (day 23) . In order to investigate possible regulatory effects of 1,25-dihydrox yvitamin D-3 (1,25-D-3) on iNOS expression, rats were treated with the hormone after the beginning of clinical signs (days 11, 13, 19, 21 an d 23 post-immunization), and areas of the CNS were examined at day 23. 1,25-D-3 exerted a drastic inhibitory effect on iNOS expression, both at the protein and the mRNA levels. However, this effect was region-s pecific, and was most pronounced in the cerebelium and brainstem, but non-existent in cerebral cortex. iNOS down-regulation occurred in macr ophages, activated microglia and astrocytes. The inhibition of iNOS ex pression in some CNS structures could account for the improvement of c linical signs observed in EAE-rats treated with 1,25-D-3. Since 1,25-D -3 can be synthesized by activated macrophages or microglia, our resul ts support the hypothesis that this hormone might be implicated in the control of the CNS-specific immune responses. 1,25-D-3 or its analogu es could, thus, be of therapeutic value in the management of iNOS-asso ciated diseases of the CNS.