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Ginkgolide B revamps neuroprotective role of apurinic/apyrimidinic endonuclease 1 and mitochondrial oxidative phosphorylation against Aβ 25–35 ‐induced neurotoxicity in human neuroblastoma cells
Author(s) -
Kaur Navrattan,
Dhiman Monisha,
PerezPolo J. Regino,
Mantha Anil K.
Publication year - 2015
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.23565
Subject(s) - oxidative stress , base excision repair , oxidative phosphorylation , ap site , dna (apurinic or apyrimidinic site) lyase , reactive oxygen species , neuroprotection , neurotoxicity , dna damage , dna glycosylase , mitochondrion , biology , dna repair , ectopic expression , microbiology and biotechnology , apoptosis , chemistry , biochemistry , pharmacology , dna , toxicity , organic chemistry , gene
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 Aβ 25–35 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 Aβ 25–35 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 Aβ 25–35 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 Aβ 25–35 treatment decreased activities of complexes I and IV, and pretreatment with GB and ectopic APE1 expression enhanced these activities significantly compared with Aβ 25–35 treatment. Our results indicate that ectopic expression of APE1 potentiates neuronal cells to overcome the oxidative damage caused by Aβ 25–35 . In addition, GB has been shown to modulate the mitochondrial OXPHOS against Aβ 25–35 ‐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. © 2015 Wiley Periodicals, Inc.