title: PPARδ agonist GW0742 ameliorates Aβ1-42-induced hippocampal neurotoxicity in mice.
abstract: Amyloid-β deposition is thought to be associated with memory deficits, neuroinflammation, apoptotic responses, and progressive neuronal death manifested in Alzheimer's disease. Peroxisome proliferator-activated receptor δ (PPARδ) is a transcription factor with potent anti-inflammatory effect. In the current study, the effect of GW0742, a selective PPARδ agonist, on Aβ1-42-induced neurotoxicity was investigated in the hippocampus of mice. Intra-hippocampal infusion of aggregated Aβ1-42 oligomer (410pmol/mouse) remarkably damaged learning and memory in the Morris water maze (MWM) and Y-maze tests, accompanied by decreased expression of PPARδ in the hippocampus as confirmed by Western blot. Intra-hippocampal infusion of GW0742 (1.06 mM/mouse) significantly improved Aβ1-42-induced memory deficits in mice, reversed Aβ1-42-induced hippocampal PPARδ down-regulation and repressed Aβ1-42-triggered neuroinflammatory and apoptotic responses, indicated by decreased nuclear NF-κB p65, TNF-α, IL-1β as well as a decrease in cleaved caspase-3 and increased ratio of Bcl-2/Bax in the hippocampus. These results suggest that PPARδ activation ameliorates Aβ1-42-induced hippocampal neurotoxicity, and it might play a crucial role in Alzheimer's disease.
authors: Department of Pharmacology, and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing, 210009, China.
authors: Yun-Qi
authors: YQ
authors: An
authors: Department of Pharmacology, and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing, 210009, China.
authors: Chun Teng
authors: CT
authors: Zhang
authors: Department of Pharmacology, and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing, 210009, China.
authors: Yong
authors: Y
authors: Du
authors: Department of Pharmacology, and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing, 210009, China.
authors: Ming
authors: M
authors: Zhang
authors: Department of Pharmacology, and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing, 210009, China.
authors: Su Su
authors: SS
authors: Tang
authors: Department of Pharmacology, and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing, 210009, China.
authors: Mei
authors: M
authors: Hu
authors: Department of Pharmacology, and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing, 210009, China.
authors: Yan
authors: Y
authors: Long
authors: Department of Pharmacology, and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing, 210009, China.
authors: Hong Bing
authors: HB
authors: Sun
authors: Department of Pharmacology, and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing, 210009, China. honghao@cpu.edu.cn.|Department of Pharmacology, China Pharmaceutical University, Nanjing, 210009, China. honghao@cpu.edu.cn.
authors: Hao
authors: H
authors: Hong
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000187:drug effects*; D008569:Memory Disorders / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D016328:NF-kappa B / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D047494:PPAR delta / Q000819:agonists* / Q000378:metabolism; D010446:Peptide Fragments / Q000633:toxicity*; D013844:Thiazoles / Q000494:pharmacology* / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D010636:Phenols; D013438:Sulfhydryl Compounds
chemical_list: D016229:Amyloid beta-Peptides; D053148:Caspase 3; D053583:Interleukin-1beta; D016328:NF-kappa B; D018696:Neuroprotective Agents; D047494:PPAR delta; D010446:Peptide Fragments; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha; C075222:amyloid beta-protein (1-42); C479979:(4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid; D010636:Phenols; D013438:Sulfhydryl Compounds
keywords: Amyloid-β1–42; Memory; Neurotoxicity; Peroxisome proliferator-activated receptor δ