Exploring vitamin D and its analogues as a possible therapeutic intervention in targeting inflammatory mediators in neurodegenerative disorders like Parkinsons disease

Abstract

Parkinsons disease characterized by dopaminergic neuronal death has been linked with neuroinflammatory processes which involve self-perpetuating detrimental events leading to prolonged neurodegeneration. Vitamin D has been found to possess neuroprotective and immuno-modulatory effects which might justify elevated inflammation and hypovitaminosis D in PD patients. So, we aimed to find the possible interactions of Vitamin-D and its analogues with inflammatory mediators prevalent in PD to get more insight into Vitamin-Ds role in neuroinflammation by assessing specific interactions between Vitamin-D and its marketed analogues with different inflammatory mediators. Moreover, revealing a possible drug repurposing with Vitamin-D analogues against neuroinflammation and other inflammatory conditions. Molecular docking was conducted with 10 inflammatory markers (p38 MAPK, NF-{kappa}B, iNOS, nNOS, COX-2, TNF, IL6, TNF, IL1{beta}, CRP) with bio-active form of Vitamin-D (calcitriol) and its analogues. Among the studied ligands, calcitriol, calcipotriol, seocalcitol, paricalcitol and falecalcitriol were found to be potential inhibitors of different inflammatory agents. Specific standard drugs or experimental inhibitors were used to compared the binding affinity between protein and ligand. BBB permeability of the tested ligands also checked as well as neurotoxicity. Most of the ligands were found to be BBB permeable possibly interacting with inflammatory mediators within the brain and were also found to be non-neurotoxic. This study sheds light on VD and its analogues being possible candidates against various inflammatory markers. The findings could further be used as stepping stone for new study on repurposing of these analogues in neuroinflammation and other inflammatory disease conditions.