Clinical implications of a possible role of vitamin D in multiple sclerosis

Hypovitaminosis D is currently one of the most studied environmental risk factors for multiple sclerosis (MS) and is potentially the most promising in terms of new clinical implications. These practical consequences, which could be applied to MS patients without further delay, constitute the main purpose of this review. Vitamin D is involved in a number of important general actions, which were not even suspected until quite recently. In particular, this vitamin could play an immunomodulatory role in the central nervous system. Many and varied arguments support a significant role for vitamin D in MS. In animal studies, vitamin D prevents and improves experimental autoimmune encephalomyelitis. Epidemiologically, latitude, past exposure to sun and the serum level of vitamin D influence the risk of MS, with, furthermore, significant links existing between these different factors. Clinically, most MS patients have low serum levels of vitamin D and are in a state of insufficiency or even deficiency compared to the international norm, which has been established on a metabolic basis. Large therapeutic trials using vitamin D are still lacking but the first results of phase I/II studies are promising. In the meantime, while awaiting the results of future therapeutic trials, it can no longer be ignored that many MS patients have a lack of vitamin D, which could be detected by a serum titration and corrected using an appropriate vitamin D supplementation in order to restore their serum level to within the normal range. From a purely medical point of view, vitamin D supplementation appears in this light to be unavoidable in order to improve the general state of these patients. Furthermore, it cannot currently be ruled out that this supplementation could also be neurologically beneficial

Synergism between sirolimus and 1,25-dihydroxyvitamin D-3 in vitro and in vivo

The active form of vitamin D, 1 alpha,25-(OH)(2)D-3, displays immunomodulatory effects in vitro and in vivo at pharmacological levels. We evaluated the dose-effect relationship of 1,25(OH)(2)D-3 and sirolimus (rapamycin, RAP) in vitro, on the inhibition of PHA-srimulated PBMC proliferation, by using the median effect analysis. Pharmacological concentrations of 1,25(OH)(2)D-3 (between 10(-9) and 3 x 10(-6) M) interacted synergistically with RAP (combination index value of 0.01 for 50% suppression of PBMC proliferation). In vivo, the effect of 1,25(OH),D, and RAP combinations on the evolution of experimental allergic encephalomyelitis in SJL mice was analyzed. 1,25(OH)(2)D-3, given ip, in monotherapy, at a dose of 2 mu g/kg every two days, from day -3 until day +19 after disease induction, or RAP, injected daily at a dose of 0.3 mg/kg for the same period, decreased EAE incidence (paralysis in 70 and 55% of the animals, respectively, versus 98% in the placebo treated group, p < 0.001). The combination treatment using the two drugs in these subtherapeutical doses provided near-total clinical (8% paralysis, p < 0.001 compared to monotherapy with 1,25(OH),D, or RAP) and histological protection, comparable to that obtained with RAP in monotherapy at a threefold higher dose (1 mg/kg/d). When the two drugs were given using an alternate day administration schedule (RAP at 0.6 mg/kg and 1,25(OH)(2)D-3 at 2 mu g/kg. each given on alternate days from day -3 to 19), near total protection was again obtained (13% paralysis, p < 0.001 versus control). These in vitro and in vivo data support the existence of synergistic interactions between 1,25(OH)(2)D-3 and RAP. Considering the narrow therapeutic windows of both RAP and vitamin D-related compounds in autoimmune disease models, combinations of these drugs could find clinical application in reducing their individual therapeutically efficient doses to non-toxic levels. (C) 1997 Elsevier Science B.V

D-myo-inositol derivatives alter liposomal membrane fluidity

We investigated the effect on membrane fluidity induced by D-myo-inositol derivatives (IP3, IP4, IP5, IP6). Fluidity was determined as the anisotropy of fluorescence polarisation fi om liposome model membranes labelled with DPH (1,6-diphenyl-1,3,5 hexatriene). IP3 (10(-10) to 10(-5) M) increased the membrane fluidity with a maximum effect at 10(-5) M. For IP4, IP5 and IP6, at concentrations less than 10(-6) M these derivatives increased the membrane viscosity (i.e. reduced fluidity). This effect was enhanced when the derivatives were incorporated in the vesicles, rather than added to the vesicle suspension. In this case IP5 and IP6 increased viscosity over the reference values. We conclude that inositol derivatives directly modified membrane fluidity which could play a role in their effects in biological systems, beside the one mediated by binding to specific receptors