The Vitamin D, Ionised Calcium and Parathyroid Hormone Axis of Cerebral Capillary Function: Therapeutic Considerations for Vascular-Based Neurodegenerative Disorders

Abstract

Blood-brain barrier dysfunction characterised by brain parenchymal extravasation of plasma proteins may contribute to risk of neurodegenerative disorders, however the mechanisms for increased capillary permeability are not understood. Increasing evidence suggests vitamin D confers central nervous system benefits and there is increasing demand for vitamin D supplementation. Vitamin D may influence the CNS via modulation of capillary function, however such effects may be indirect as it has a central role in maintaining calcium homeostasis, in concert with calcium regulatory hormones. This study utilised an integrated approach and investigated the effects of vitamin D supplementation, parathyroid tissue ablation (PTX), or exogenous infusion of parathyroid hormone (PTH) on cerebral capillary integrity. Parenchymal extravasation of immunoglobulin G (IgG) was used as a marker of cerebral capillary permeability. In C57BL/6J mice and Sprague Dawley rats, dietary vitamin D was associated with exaggerated abundance of IgG within cerebral cortex (CTX) and hippocampal formation (HPF). Vitamin D was also associated with increased plasma ionised calcium (iCa) and decreased PTH. A response to dose was suggested and parenchymal effects persisted for up to 24 weeks. Ablation of parathyroid glands increased CTX- and HPF-IgG abundance concomitant with a reduction in plasma iCa. With the provision of PTH, iCa levels increased, however the PTH treated animals did not show increased cerebral permeability. Vitamin D supplemented groups and rats with PTH-tissue ablation showed modestly increased parenchymal abundance of glial-fibrillary acidic protein (GFAP), a marker of astroglial activation. PTH infusion attenuated GFAP abundance. The findings suggest that vitamin D can compromise capillary integrity via a mechanism that is independent of calcium homeostasis. The effects of exogenous vitamin D supplementation on capillary function and in the context of prevention of vascular neurodegenerative conditions should be considered in the context of synergistic effects with calcium modulating hormones.

Vitamin D supplementation of initially vitamin D-deficient mice diminishes lung inflammation with limited effects on pulmonary epithelial integrity

“…Active 1,25(OH) 2 D and expression of the VDR can improve airway barrier function, and reduce lung disease and injury in mice (Liu et al 2013;Lam et al 2015). Treatment of BALB/c mice with active 1,25(OH) 2 D (100 ng intraperitoneal injection) altered the expression of zona occludens-1 (ZO-1) and E-cadherin in airway epithelial cells, and reduced signs of asthma induced by dermal sensitization and respiratory challenge with toluene di-isocyanate .…”

Genetic, environmental and biomarker considerations delineating the regulatory effects of vitamin D on central nervous system function

“…BBB dysfunction is characterised by compromised cerebrovascular integrity leading to unregulated extravasation of serum constituents into the brain parenchyma. An increasing number of studies suggest that impairment of cerebral capillaries at the endothelial cell may be a major risk factor prior to the progression of clinical cognitive dysfunction (24,144,148) . Recent experimental and clinical studies have shown therapeutic benefit in attenuating progression of neurodegeneration/cognitive decline if cerebrovascular disturbances are attenuated (149,150) .…”

“…However, the putative effects of vit-D deficiency and by extension vit-D supplementation on CNS function are contradictory. An emerging body of pre-clinical and clinical studies suggests an inverse U-shaped association with low and greater abundance of serum vit-D both correlated with neurocognitive deficits (14,24,26) . Whilst the mechanisms for the latter are presently not established, preclinical studies suggest that chronically heightened levels of serum vit-D may compromise cognitive performance through a cerebrovascular axis.…”

“…Whilst the mechanisms for the latter are presently not established, preclinical studies suggest that chronically heightened levels of serum vit-D may compromise cognitive performance through a cerebrovascular axis. In two rodent species, dietary-induced hypervitaminosis-D increased cerebral capillary permeability, resulting in inappropriate kinetics of plasma proteins from blood into brain parenchyme and neurovascular inflammation (24) , whilst genetically engineered mice with hypervitaminosis-D show an accelerated ageing phenotype (26,27) . trends showing increased self-prescribed use of supplementary vit-D nutraceuticals and clinical trials with interventions of up to 7500 μg of vit-D 3 per dose (28)(29)(30)(31)(32) .…”

Biostatistical analysis of quantitative immunofluorescence microscopy images

“…Following a single week holding phase, animals were supplied ad libitum access to water and their respective diets. The control group was given a low fat maintenance diet (Glen Forrest Stock Feeds; AIN-93G), while the treatment group was supplied a modified control diet to induce capillary permeability (Lam et al, 2015), formulated to deliver 40 000 IU of vitamin D3 per kg of diet consumed [daily ingested dose of approximately 600 international units (IU) vs. 15 IU for control animals].…”