Chronic vitamin D₃ treatment protects against neurotoxicity by glutamate in association with upregulation of vitamin D receptor mRNA expression in cultured rat cortical neurons

Abstract

The vitamin D receptor (VDR) is believed to mediate different biologic actions of vitamin D3, an active metabolite of vitamin D, through regulation of gene expression after binding to specific DNA-response element (VDRE) on target genes. To further understand roles of both vitamin D3 and VDR in the central nervous system, we examined VDRE binding in nuclear extracts prepared from discrete rat brain regions and cultured rat cortical neurons by electrophoretic mobility shift assay. The highest activity of VDRE binding was found in the cerebellum among other brain regions examined, but sequence specific by taking into consideration the efficient competition with excess unlabeled VDRE but not with mutated VDRE. On in situ hybridization analysis, cells stained for VDR mRNA were abundant in neuron-enriched areas of cerebral cortex, hippocampus and cerebellar cortex in the mouse brain. Chronic treatment of vitamin D3 increased the expression of microtubule-associated protein-2, growth-associated protein-43 and synapsin-1 in cultured rat cortical neurons, suggesting a trophic role of vitamin D3 in differentiation and maturation of neurons. Neuronal cell death by brief glutamate exposure was significantly protected in cultured cortical neurons chronically treated with vitamin D3. Parallel studies showed that VDR mRNA was significantly upregulated 12-24 hr after brief glutamate exposure in cultured neurons chronically treated with vitamin D3, but not in those with vehicle alone. Our results suggest that vitamin D3 may play a role in mechanisms relevant to protective properties against the neurotoxicity of glutamate through upregulation of VDR expression in cultured rat cortical neurons.

The impact of serum vitamin D concentration on median nerve conduction

“…It was suggested that vitamin D exerts its neuroprotective effect through downregulation of L-type calcium channel expression or upregulation of vitamin D receptor (VDR) expression [11]. Thus, vitamin D deficiency has been identified as a factor associated with increased risk for development of neurological diseases.…”

Changes in the expression of the vitamin D receptor and LVSCC-A1C in the rat hippocampus submitted to single prolonged stress

“…Vitamin D may affect neuronal plasticity processes and increase neurite outgrowth when added to cultured hippocampal cells (28). It has been revealed that vitamin D upregulates the expression of microtubule-associated protein-2 and growth-associated protein-43 in cultured cortical neurons (32). Maternal hypovitaminosis D decreases the expression of proteins involved in cytoskeleton maintenance, including neurofilaments, tubulin, actin and glial fibrillary acidic protein (33,34).…”

“…The detrimental effects of excessive Ca 2+ on memory formation and cognitive functioning are widely acknowledged (46)(47)(48)(49). Administration of vitamin D or its metabolites may decrease neuronal death in rat hippocampal cultures, elicited by Ca 2+ -mediated neurotoxicity through the downregulation of LVSCC and increased VDR levels (26,32).…”

Immune-Glutamatergic Dysfunction as a Central Mechanism of the Autism Spectrum Disorders

“…A variable pattern of VDR staining was seen in the amygdala. Taniura et al [169] demonstrated very high activity for vitamin D specific DNA-response element (VDRE) binding in the cerebellum, an area of the brain most severely affected in autism. They suggest a trophic role for vitamin D3 in the CNS and also noted that the neurohormone significantly protected cultured cortical neurons from glutamate excitotoxicity.…”