title: Chronic glucocorticoids exposure enhances neurodegeneration in the frontal cortex and hippocampus via NLRP-1 inflammasome activation in male mice.
abstract: Neuroinflammation plays an important role in the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease (AD) and depression. Chronic glucocorticoids (GCs) exposure has deleterious effects on the structure and function of neurons and is associated with development and progression of AD. However, little is known about the proinflammatory effects of chronic GCs exposure on neurodegeneration in brain. Therefore, the aim of this study was to evaluate the effects of chronic dexamethasone (DEX) treatment (5mg/kg, s.c. for 7, 14, 21 and 28 days) on behavior, neurodegeneration and neuroinflammatory parameters of nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 1 (NLRP-1) inflammasome in male mice. The results showed that DEX treatment for 21 and 28 days significantly reduced the spontaneous motor activity and exploratory behavior of the mice. In addition, these mice showed significant neurodegeneration and a decrease of microtubule-associated protein 2 (MAP2) in the frontal cortex and hippocampus CA3. DEX treatment for 7, 14, 21 and 28 days significantly decreased the mRNA and protein expression of glucocorticoid receptor (GR). Moreover, DEX treatment for 21 and 28 days significantly increased the proteins expression of NLRP-1, Caspase-1, Caspase-5, apoptosis associated speck-like protein (ASC), nuclear factor-κB (NF-κB), p-NF-κB, interleukin-1β (IL-1β), IL-18 and IL-6 in the frontal cortex and hippocampus brain tissue. DEX treatment for 28 days also significantly increased the mRNA expression levels of NLRP-1, Caspase-1, ASC and IL-1β. These results suggest that chronic GCs exposure may increase brain inflammation via NLRP-1 inflammasome activation and induce neurodegeneration.
authors.affiliation: Department of Pharmacology, Key Laboratory of Anti-inflammatory and Immunopharmacology, Ministry of Education, Anhui Medical University, Hefei 230032, PR China.
authors.forename: Wen
authors.initials: W
authors.lastname: Hu
authors.affiliation: Department of Pharmacology, Key Laboratory of Anti-inflammatory and Immunopharmacology, Ministry of Education, Anhui Medical University, Hefei 230032, PR China.
authors.forename: Yaodong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Key Laboratory of Anti-inflammatory and Immunopharmacology, Ministry of Education, Anhui Medical University, Hefei 230032, PR China.
authors.forename: Wenning
authors.initials: W
authors.lastname: Wu
authors.affiliation: Department of Pharmacology, Key Laboratory of Anti-inflammatory and Immunopharmacology, Ministry of Education, Anhui Medical University, Hefei 230032, PR China.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Yin
authors.affiliation: Synthetic Laboratory of Basic Medicine College, Anhui Medical University, Hefei 230032, PR China.
authors.forename: Dake
authors.initials: D
authors.lastname: Huang
authors.affiliation: Department of Pharmacology, Key Laboratory of Anti-inflammatory and Immunopharmacology, Ministry of Education, Anhui Medical University, Hefei 230032, PR China.
authors.forename: Yuchan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Key Laboratory of Anti-inflammatory and Immunopharmacology, Ministry of Education, Anhui Medical University, Hefei 230032, PR China.
authors.forename: Weiping
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Key Laboratory of Anti-inflammatory and Immunopharmacology, Ministry of Education, Anhui Medical University, Hefei 230032, PR China. Electronic address: liweizu@126.com.
authors.forename: Weizu
authors.initials: W
authors.lastname: Li
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism; D003907:Dexamethasone / Q000008:administration & dosage* / Q000378:metabolism; D005625:Frontal Lobe / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D058847:Inflammasomes / Q000187:drug effects* / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D016328:NF-kappa B / Q000378:metabolism; D011897:Random Allocation; D011965:Receptors, Glucocorticoid / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D003598:Cytoskeletal Proteins; D058847:Inflammasomes; D007378:Interleukins; C529636:NALP1 protein, mouse; D016328:NF-kappa B; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone; D020170:Caspase 1
keywords: Alzheimer’s disease; Glucocorticoids; Locomotor behavior; NLRP1 inflammasome; Neurodegenerative diseases; Neuroinflammation