title: Protective effects of BAY 73-6691, a selective inhibitor of phosphodiesterase 9, on amyloid-β peptides-induced oxidative stress in in-vivo and in-vitro models of Alzheimer's disease.
abstract: Alzheimer's disease (AD) is accompanied by enhanced oxidative stress and excess free radicals. Phosphodiesterase 9 inhibitors (PDE-9Is) showed memory improving effects in many pharmacological deficit models. However, whether BAY 73-6691 (a selective PDE-9I) may attenuate the oxidative stress during the development of AD is still unclear. For this purpose, primary cultures of SH-SY5Y cells were incubated with 20μM beta-amyloid25-35 (Aβ25-35), followed by exposure to different concentrations (50, 100, 150 and 200μg/ml) of BAY 73-6691. Furthermore, the antioxidant effect of BAY 73-6691 was evaluated in mice subjected to intracerebroventricular injection of Aβ25-35 (day 0) and treatment with BAY 73-6691 by intraperitoneal injection once daily (days 1-10). Our results elucidated that treatment with BAY 73-6691 attenuated the Aβ25-35-induced cytotoxicity and oxidative stress in SH-SY5Y cells. In vivo, BAY 73-6691 protected Aβ25-35-induced oxidative damage in hippocampus, associated with the attenuation of impairments in hippocampal neurons. Administration of BAY 73-6691 improved learning and memory in the Morris water maze test, and restored several hippocampal memory-associated proteins. Our study identified a neuroprotective role for BAY 73-6691 against Aβ25-35-induced oxidative stress in vivo and in vitro, harboring therapeutic potential for the treatment of AD by alleviating the impairments in spatial memory and hippocampal neurons.
authors.affiliation: Department of Neurology, the First Affiliated Hospital of Liaoning Medical College, Jinzhou 121001, China. Electronic address: lijian070505@163.com.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Liaoning Medical College, Jinzhou 121001, China.
authors.forename: Chun-Na
authors.initials: CN
authors.lastname: Liu
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States; Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, United States.
authors.forename: Ning
authors.initials: N
authors.lastname: Wei
authors.affiliation: Department of Neurology, the First Affiliated Hospital of Liaoning Medical College, Jinzhou 121001, China.
authors.forename: Xi-Dong
authors.initials: XD
authors.lastname: Li
authors.affiliation: Department of Neurology, the First Affiliated Hospital of Liaoning Medical College, Jinzhou 121001, China.
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Liu
authors.affiliation: Department of Neurology, the First Affiliated Hospital of Liaoning Medical College, Jinzhou 121001, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Yang
authors.affiliation: Department of Neurology, the First Affiliated Hospital of Liaoning Medical College, Jinzhou 121001, China.
authors.forename: Yu-Jie
authors.initials: YJ
authors.lastname: Jia
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008813:Mice, Inbred ICR; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D018384:Oxidative Stress / Q000187:drug effects*; D010446:Peptide Fragments / Q000633:toxicity*; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage*; D011720:Pyrazoles / Q000008:administration & dosage*; D011743:Pyrimidines / Q000008:administration & dosage*; D065852:Spatial Memory / Q000187:drug effects
chemical_list: D016229:Amyloid beta-Peptides; C507056:BAY 73-6691; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D010726:Phosphodiesterase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C074636:amyloid beta-protein (25-35)
keywords: Beta-amyloid(25–35); Hippocampal neurogenesis; Oxidative stress; Phosphodiesterase 9 inhibitors; Spatial memory deficit