Steroids, Volume 156, April 2020,
Background: The nuclear factor erythroid2-related factor2 (Nrf2), a chief transcriptional regulator of antioxidant response element (ARE), is considered a promising target for the prevention of Alzheimer's disease (AD). Vitamin D has been recognized to have a crucial role in improving AD cognitive functions. The present study was conducted to evaluate the effects of active vitamin D analogue, Maxacalcitol, on Keap1-Nrf2 signaling pathway in experimental Alzheimer's disease in rats. Materials and methods: The study was conducted on thirty female white albino rats divided equally into 3 groups: control group, Alzheimer group induced by Lipopolysaccharide and Alzheimer group treated with active vitamin D3 analogue, Maxacalcitol. The following parameters were assessed in rat brain tissues: Gene expression of Nrf2, Keap1 and MAF by RT-PCR, protein levels of phosphorylated MAPK-38p and ERK1/2 by Western Blot Technique, estimation of HO-1, Amyloid β, p-Tau levels and serum levels of TNFα, IL-10 and total 25-hydroxyvitamin D, serum calcium levels, GSH and MDA levels were also estimated in addition to cognitive function tests and histo-pathological examination of rat brain tissues. Results: In Alzheimer group, there was a significant deficit in cognition along with down-regulation of gene expression of Nrf2 and the protein levels of its downstream antioxidant effectors (HO-1 and GSH) with increased levels of the lipid peroxidation biomarker MDA. Also, there was increased neuro-inflammation as evidenced by increased levels of TNFα and decreased levels of IL-10. Moreover, there were increased amyloid β load and enhanced levels of phosphorylation of MAPK-38 and ERK1/2 leading to hyperphosphorylation of Tau protein. In addition, there were decreased serum levels of both total 25-hydroxyvitamin D and calcium. Treatment with vitamin D3 analogue, Maxacalcitol significantly improved cognitive dysfunction and histopathological picture of the brains of Alzheimer rats. Also, Vitamin D analogue significantly increased expression of Nrf2 and its downstream effectors (HO-1 and GSH), improved serum levels of total 25-hydroxyvitamin D and calcium, decreased neuro-inflammation and Amyloid β load as well as hyperphosphorylation of MAPK-38, ERK1/2 and tau proteins were also observed. Therefore, these data suggest that vitamin D analogue, Maxacalcitol could be used as a therapeutic agent in treatment of Alzheimer disease.
22 Oxacalcitriol; 25 Hydroxyvitamin D; 3,4 Methylenedioxyamphetamine; Active Vitamin D Analogue (Maxacalcitol); Adult; Alzheimer Disease; Alzheimer's Disease; Amyloid Beta Protein; Animal; Animal Experiment; Animal Model; Animal Tissue; Animals; Article; Behavior Assessment; Brain Tissue; Calcitriol; Calcium; Calcium Blood Level; Cognition; Cognitive Defect; Cognitive Function Test; Controlled Study; Down Regulation; Drug Effect; Enzyme Phosphorylation; Experimental Rat; Extracellular Signal-Regulated MAP Kinases; Female; Gene Expression; Glutathione; Heme Oxygenase 1; Hippocampus; Histopathology; Injections, Intraperitoneal; Interleukin 10; Intraperitoneal Drug Administration; KEAP1 Protein, Rat; Keap1–Nrf2 Pathway; Kelch Like ECH Associated Protein 1; Kelch-Like ECH-Associated Protein 1; Lipid Peroxidation; Lipopolysaccharide; Lipopolysaccharides; Maxacalcitol; Metabolism; Mitogen Activated Protein Kinase; Mitogen Activated Protein Kinase 3; Mitogen Activated Protein Kinase P38; NF-E2-Related Factor 2; Nfe2l2 Protein, Rat; Nonhuman; P38 Mitogen-Activated Protein Kinases; Rat; Rats; Real Time Polymerase Chain Reaction; Signal Transduction; Tau Protein; Transcription Factor Nrf2; Tumor Necrosis Factor; Western Blotting; Global