title: The metabolic enhancer piracetam attenuates mitochondrion-specific endonuclease G translocation and oxidative DNA fragmentation.
abstract: This study was performed to investigate the involvement of mitochondrion-specific endonuclease G in piracetam (P)-induced protective mechanisms. Studies have shown the antiapoptotic effects of piracetam but the mechanism of action of piracetam is still an enigma. To assess the involvement of endonuclease G in piracetam-induced protective effects, astrocyte glial cells were treated with lipopolysaccharide (LPS) and piracetam. LPS treatment caused significantly decreased viability, mitochondrial activity, oxidative stress, chromatin condensation, and DNA fragmentation, which were attenuated by piracetam cotreatment. Cotreatment of astrocytes with piracetam showed its significantly time-dependent absorption as observed with high-performance liquid chromatography. Astrocytes treated with piracetam alone showed enhanced mitochondrial membrane potential (MMP) in comparison to control astrocytes. However, in LPS-treated cells no significant alteration in MMP was observed in comparison to control cells. Protein and mRNA levels of the terminal executor of the caspase-mediated pathway, caspase-3, were not altered significantly in LPS or LPS + piracetam-treated astrocytes, whereas endonuclease G was significantly translocated to the nucleus in LPS-treated astrocytes. Piracetam cotreatment attenuated the LPS-induced endonuclease G translocation. In conclusion this study indicates that LPS treatment of astrocytes caused decreased viability, oxidative stress, mitochondrial dysfunction, chromatin condensation, DNA damage, and translocation of endonuclease G to the nucleus, which was inhibited by piracetam cotreatment, confirming that the mitochondrion-specific endonuclease G is one of the factors involved in piracetam-induced protective mechanisms.
authors.affiliation: Toxicology Division, CSIR-Central Drug Research Institute, Lucknow 226031, Uttar Pradesh, India.
authors.forename: Sonam
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Toxicology Division, CSIR-Central Drug Research Institute, Lucknow 226031, Uttar Pradesh, India.
authors.forename: Dinesh Kumar
authors.initials: DK
authors.lastname: Verma
authors.affiliation: Toxicology Division, CSIR-Central Drug Research Institute, Lucknow 226031, Uttar Pradesh, India.
authors.forename: Joyshree
authors.initials: J
authors.lastname: Biswas
authors.affiliation: Pharmacokinetics & Metabolism Division, CSIR-Central Drug Research Institute, Lucknow 226031, Uttar Pradesh, India.
authors.forename: K Siva
authors.initials: KS
authors.lastname: Rama Raju
authors.affiliation: Center for Gene Regulation in Health and Disease, Department of Biological Sciences, Cleveland State University, Cleveland, Ohio, USA.
authors.forename: Neeraj
authors.initials: N
authors.lastname: Joshi
authors.affiliation: Pharmacokinetics & Metabolism Division, CSIR-Central Drug Research Institute, Lucknow 226031, Uttar Pradesh, India.
authors.lastname: Wahajuddin
authors.affiliation: Toxicology Division, CSIR-Central Drug Research Institute, Lucknow 226031, Uttar Pradesh, India. Electronic address: sarika_singh@cdri.res.in.
authors.forename: Sarika
authors.initials: S
authors.lastname: Singh
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism*; D053148:Caspase 3 / Q000235:genetics; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects*; D004706:Endodeoxyribonucleases / Q000378:metabolism*; D008070:Lipopolysaccharides; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000235:genetics; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D010088:Oxidoreductases / Q000378:metabolism; D010889:Piracetam / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; D018696:Neuroprotective Agents; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D010088:Oxidoreductases; D004706:Endodeoxyribonucleases; C052391:endonuclease G; D053148:Caspase 3; D010889:Piracetam
keywords: Astrocytes; DNA damage; Endonuclease-G; Free radicals; Lipopolysaccharide; Piracetam