Dietary vitamin D deficiency in rats from middle to old age leads to elevated tyrosine nitration and proteomics changes in levels of key proteins in brain: Implications for low vitamin D-dependent age-related cognitive decline

Abstract

In addition to the well-known effects of vitamin D (VitD) in maintaining bone health, there is increasing appreciation that this vitamin may serve important roles in other organs and tissues, including the brain. Given that VitD deficiency is especially widespread among the elderly, it is important to understand how the range of serum VitD levels that mimic those found in humans (from low to high) affects the brain during aging from middle-age to old-age. To address this issue, twenty-seven male F344 rats were split into three groups and fed isocaloric diets containing low (100 IU/kg food), control (1000 IU/kg food), or high (10000 IU/kg food) VitD beginning at middle-age (12 months) and continued for a period of 4–5 months. We compared the effects of these dietary VitD manipulations on oxidative and nitrosative stress measures in posterior brain cortices. The low VitD group showed global elevation of 3-nitrotyrosine (3-NT) compared to control and high VitD treated groups. Further investigation showed that this elevation may involve dysregulation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway and NF-κB mediated transcription of inducible nitric oxide synthase (iNOS) as indicated by translocation of NF-κB to the nucleus and elevation of iNOS levels. Proteomic techniques were used to provide insights into potential mechanisms underlying these effects. Several brain proteins were found at significantly elevated levels in low VitD group compared to the control and high VitD groups. Three of these proteins, 6-phosphofructokinase, triosephosphate isomerase, and pyruvate kinase, are involved directly in glycolysis. Two others, peroxiredoxin-3 and DJ-1/PARK7, have peroxidase activity and are found in mitochondria. Peptidyl-prolyl cis-trans isomerase A (PPIA or cyclophilin A) has been shown to have multiple roles including protein folding, regulation of protein kinases and phosphatases, immunoregulation, cell signaling, and redox status. Together, these results suggest that dietary VitD deficiency contributes to significant nitrosative stress in brain and may promote cognitive decline in middle-aged and elderly adults.

Vitamin D Deficiency Reduces the Immune Response, Phagocytosis Rate, and Intracellular Killing Rate of Microglial Cells

“…In this instance, it was suggested that vitamin D may promote rather than suppress L. major infection. Conversely, rats on a low-vitamin D diet showed a global elevation of 3-nitrotyrosine in comparison to control and highvitamin D-treated animals, suggesting an increase nitrosative stress in the vitamin D-deficient brain (54).…”

Prednisolone and vitamin D(3) modulate oxidative metabolism and cell death pathways in blood and bone marrow mononuclear cells

“…Oxidative/nitrosative stress associated with increased generation of reactive oxygen and nitrogen species as well as impaired effectiveness of antioxidant defense has recently been recognized as one of the key mechanisms in the pathogenesis of various disorders associated with 25OHD 3 deficiency [10]. To clarify whether alterations of oxidative metabolism are involved in the development of cellular Fig.…”

Vitamin D prevents cognitive decline and enhances hippocampal synaptic function in aging rats

“…*P = 0.01; **P = 0.001. Reported in Table 1 of Keeney et al (35). responsiveness with high VitD3 did not appear to be due to hyperexcitability, because slice survival and integrity were comparable across groups.…”