title: Ginkgolide B revamps neuroprotective role of apurinic/apyrimidinic endonuclease 1 and mitochondrial oxidative phosphorylation against Aβ25-35 -induced neurotoxicity in human neuroblastoma cells.
abstract: Accumulating evidence points to roles for oxidative stress, amyloid beta (Aβ), and mitochondrial dysfunction in the pathogenesis of Alzheimer's disease (AD). In neurons, the base excision repair pathway is the predominant DNA repair (BER) pathway for repairing oxidized base lesions. Apurinic/apyrimidinic endonuclease 1 (APE1), a multifunctional enzyme with DNA repair and reduction-oxidation activities, has been shown to enhance neuronal survival after oxidative stress. This study seeks to determine 1) the effect of Aβ25-35 on reactive oxygen species (ROS)/reactive nitrogen species (RNS) levels, 2) the activities of respiratory complexes (I, III, and IV), 3) the role of APE1 by ectopic expression, and 4) the neuromodulatory role of ginkgolide B (GB; from the leaves of Ginkgo biloba). The pro-oxidant Aβ25-35 peptide treatment increased the levels of ROS/RNS in human neuroblastoma IMR-32 and SH-SY5Y cells, which were decreased after pretreatment with GB. Furthermore, the mitochondrial APE1 level was found to be decreased after treatment with Aβ25-35 up to 48 hr, and the level was increased significantly in cells pretreated with GB. The oxidative phosphorylation (OXPHOS; activities of complexes I, III, and IV) indicated that Aβ25-35 treatment decreased activities of complexes I and IV, and pretreatment with GB and ectopic APE1 expression enhanced these activities significantly compared with Aβ25-35 treatment. Our results indicate that ectopic expression of APE1 potentiates neuronal cells to overcome the oxidative damage caused by Aβ25-35 . In addition, GB has been shown to modulate the mitochondrial OXPHOS against Aβ25-35 -induced oxidative stress and also to regulate the levels of ROS/RNS in the presence of ectopic APE1. This study presents findings from a new point of view to improve therapeutic potential for AD via the synergistic neuroprotective role played by APE1 in combination with the phytochemical GB.
authors: Centre for Biosciences, School of Basic and Applied Sciences, Central University of Punjab, Bathinda, Punjab, India.
authors: Navrattan
authors: N
authors: Kaur
authors: Monisha
authors: M
authors: Dhiman
authors: J Regino
authors: JR
authors: Perez-Polo
authors: Anil K
authors: AK
authors: Mantha
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity*; D045744:Cell Line, Tumor; D015252:Deoxyribonucleases, Type II Site-Specific / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D046934:Ginkgolides / Q000494:pharmacology*; D006801:Humans; D007783:Lactones / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects*; D009097:Multienzyme Complexes / Q000378:metabolism; D009447:Neuroblastoma / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010085:Oxidative Phosphorylation / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D010446:Peptide Fragments / Q000633:toxicity*; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D014162:Transfection
chemical_list: D016229:Amyloid beta-Peptides; D046934:Ginkgolides; D007783:Lactones; D009097:Multienzyme Complexes; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; C074636:amyloid beta-protein (25-35); C045856:ginkgolide B; C046545:CCWGG-specific type II deoxyribonucleases; D015252:Deoxyribonucleases, Type II Site-Specific
keywords: APE1; Alzheimer's disease; Aβ25-35; OXPHOS; Ref-1; amyloid beta; ginkgolide B