Calcitriol Prevents Neuroinflammation and Reduces Blood-Brain Barrier Disruption and Local Macrophage/Microglia Activation

Abstract

Multiple sclerosis (MS) is a progressive disease of the central nervous system (CNS) that involves damage to the myelin sheath surrounding axons. MS therapy is based on immunomodulatory drugs that reduce disease recurrence and severity. Vitamin D is a hormone whose immunomodulatory ability has been widely demonstrated, including in experimental autoimmune encephalomyelitis (EAE), which is an animal model of CNS inflammation. In this study, we evaluated the potential of very early intervention with the active form of vitamin D (1,25-dihydroxyvitamin D3) to control neuroinflammation during EAE development. EAE was induced in C57BL/6J mice and 1,25-dihydroxyvitamin D3 administration began 1 day after disease induction. This procedure decreased prevalence, clinical score, inflammation, and demyelination. It also reduced MHCII expression in macrophages and microglia as well as the level of oxidative stress and messenger RNA (mRNA) expression for NLRP3, caspase-1, interleukin (IL)-1b, CX 3 CR1, CCL17, RORc and Tbx21 at the CNS. Otherwise, mRNA expression for ZO-1 increased at the lumbar spinal cord. These effects were accompanied by the stabilization of blood-spinal cord barrier permeability. The results of this study indicate that early intervention with 1,25-dihydroxyvitamin D3 can control the neuroinflammatory process that is the hallmark of EAE and MS immunopathogenesis and should thus be explored as an adjunct therapy for MS patients.

Preclinical Therapy with Vitamin D3 in Experimental Encephalomyelitis: Efficacy and Comparison with Paricalcitol

“…Nonetheless, there is still a consistent controversy about its clinical application in MS [59,60]. Our own experience with VitD in EAE indicates that it is very effective when administered near the disease induction period [32,49,50]. In this context, we asked if VitD would still be effective if administered after the disease induction phase when the priming of myelin-epitope-specific CD4+ T cells has already been established.…”

“…We recently described that an early VitD supplementation beginning 24 h after EAE induction was highly effective in decreasing prevalence, clinical score, inflammation, and demyelination. Of note, VitD administration was able to avoid the characteristic disruption of the BBB permeability that precedes EAE paralysis [32].…”

“…A great deal of attention has been focused on the crucial components that allow transmigration through the BBB in various inflammatory conditions of the CNS and on therapeutic strategies that could block this process [42]. Recently, we demonstrated that VitD and ketotifen were able to reduce BBB disruption significantly controlling the severity of EAE [32,43].…”

“…This combination successfully controlled EAE severity when applied three and 11 days after EAE induction [51]. We recently observed that an early intervention with VitD, delivered 24 hours after experimental encephalomyelitis induction, prevented neurodegeneration by downmodulating both inflammasome and oxidative stress [32]. Nonetheless, VitD intake at supraphysiological doses can lead to hypercalcemia, and therefore to side effects such as cardiac arrhythmias, renal vasoconstriction, and acute kidney injury [52].…”

The Role of Natural Compounds and their Nanocarriers in the Treatment of CNS Inflammation

“…A recent clinical study (phase II trials; IRCT20100407003655N4) demonstrated that vitamin D3 exerted neuroprotective effects in MS patients by upregulating the production and expression of anti-inflammatory cytokines and downregulating pro-inflammatory cytokines [ 135 ]. Another recent study reported that vitamin D3 also prevented BBB disruption and inhibited pyroptosis-mediated neuronal cell death and the expression of T cell transcription factors [ 136 ].…”