Dual antiplasmodial activity of vitamin D3 and its analog, 22-oxacalcitriol, by direct and indirect mechanisms

Abstract

Recent evidence suggests that 1α,25-dihydroxyvitamin D3 (calcitriol, VD3), the active form of vitamin D (VD), can inhibit the proliferation of microorganisms. In the present study, we conducted in vitro experiments and utilized in vivo murine models to investigate the antimalarial activity of VD3 and its analog, 22-oxacalcitriol (22-OCT), which was designed to cause less hypercalcemia than VD3. VD3 and 22-OCT treatments effectively resolved a Plasmodium chabaudi (Pc) infection in wild-type mice. Reduced parasitemia was observed during the acute phase of infection in the presence of VD3 and 22-OCT, followed by a delayed peak during the chronic stage of infection. Some anti-Pc activity was observed in VD receptor knockout (KO) mice. VD3 and 22-OCT also completely inhibited the proliferation of P. falciparum (Pf) in human red blood cells in vitro. Plasma levels of interferon (IFN)-γ in VD3-treated B10 and B6 mice were lower than those in vehicle-treated animals, and VD3 resolved a Pc infection in IFN-γ-KO mice, which greatly improved survival. These data suggest that the protective effects of VD3 are elicited through an IFN-γ-independent mechanism. Effective antiplasmodial doses of VD3 and 22-OCT resulted in a loss of body weight in mice. This loss in body weight occurred concomitantly with the development of hypercalcemia. Zoledronic acid partially attenuated VD3-induced hypercalcemia and abrogated the antiparasitic effects of VD3. This study highlights a potential therapeutic role for VD3 in the treatment of malarial infections and shows that hypercalcemia is excellent indicator of the antiplasmodial activity of VD3.

Efficacy and Safety of 22-Oxa-Calcitriol in Patients with Rheumatoid Arthritis: A Phase II Trial

“…During this trial, calcitriol induced hypercalcemia ( P <0.0001, q=15.2), but 2-oxa-calcitriol did not induce hypercalcemia ( P =0.031, q=3.29). This finding supports other reports that 2-oxa- calcitriol as a good vitamin D supplement that does not induce hypercalcemia [10,27]. With respect to the results of our study, additional trials are required to justify the role of calcitriol in RA patients.…”

“…The other derivative of vitamin D3, i.e., 22-oxa-1 alpha, 25-dihydroxy vitamin D3 (22-oxa-calcitriol) has less hypercalcemic activity than calcitriol and has been reported to be effective for cell-proliferative diseases [10]. These reported effects of vitamin D analogs are irrespective of their activity to induce hypercalcemia in terms of structure [11].…”

Vitamin D in malaria: more hypotheses than clues

“…Achieving a similar result (treated mice survived from 4 to 9 days more than untreated mice), the Authors present it as a protection by Vitamin D against CM, but it should not be overlooked that, regardless of the Vitamin D pretreatment, all the mice developed CM symptoms within 5 days from the infection and then died. It is also worth mentioning the experiment conducted by Yamamoto [5]: he tested the efficacy of Vitamin D and 22-oxacalcitriol (22-OCT); the latter was used because it causes less hypercalcaemia and weight loss than Vitamin D. Using VDR-knockout mice, the Authors suggested that both Vitamin D and 22-OCT perform their alleged antiplasmodial action through direct and indirect mechanisms, both VDR-independent and VDR-mediated. However, the Authors suggested that further studies are needed to explain the physiological mechanisms underlying this antiplasmodial activity.…”

“…Low blood Vitamin D levels have been reported in patients affected by infectious diseases, including those caused by parasites [4]. Among these, the pathogen causing malaria in humans, Plasmodium falciparum , was responsible for the death of almost 365.000 African children under the age of five in 2016 [5, 6]. Even though existing antimalarials are highly-effective, malaria is burdened with high morbidity and mortality [7], which means that the search for additional therapies to administer along with antimalarial treatments is rapidly growing.…”

Calcitriol and Non-Calcemic Vitamin D Analogue, 22-Oxacalcitriol, Attenuate Developmental and Pathological Ocular Angiogenesis Ex Vivo and In Vivo

“…Pure crystalline solid 22-oxacalcitriol (Cayman Chemical, Ann Arbor, MI) was dissolved in ethanol as previously reported to yield a 2 µg/µL stock solution [28,29]. This stock solution was diluted in PBS to working solution, 2 µg/mL 22-oxacalcitriol in 0.1% ethanol-PBS on day of the injection.…”