title: Oxidizing effects of exogenous stressors in Huntington's disease knock-in striatal cells--protective effect of cystamine and creatine.
abstract: Huntington's disease (HD) is a polyglutamine-expansion disease associated to degeneration of striatal and cortical neurons. Previously, we showed that oxidative stress occurs in HD knock-in striatal cells, but little is known regarding cell antioxidant response against exogenous stimuli. Therefore, in the present study we analyzed cellular antioxidant profile following hydrogen peroxide (H2O2) and staurosporine (STS) exposure and tested the protective effect of cystamine and creatine in striatal cells expressing mutant huntingtin with 111 glutamines (STHdh (Q111/Q111); mutant cells) versus wild-type cells (STHdh (Q7/Q7)). Mutant cells displayed increased mitochondrial reactive oxygen species (ROS) and decreased NADPH oxidase and xanthine oxidase (XO) activities, reflecting lower superoxide cytosolic generation, along with increased superoxide dismutases (SODs) and components of glutathione redox cycle. Exposure to H2O2 and STS enhanced ROS in mutant cells and largely increased XO activity; STS further boosted the generation of mitochondrial ROS and caspase-3 activity. Both stimuli slightly increased SOD1 activity, without affecting SOD2 activity, and decreased glutathione reductase with a consequent rise in oxidized glutathione or glutathione disulfide in mutant cells, whereas H2O2 only increased glutathione peroxidase activity. Additionally, creatine and cystamine increased mutant cells viability and prevented ROS formation in HD cells subjected to H2O2 and STS. These results indicate that elevation of the antioxidant systems accompanies mitochondrial-driven ROS generation in mutant striatal cells and that exposure to noxious stimuli induces a higher susceptibility to oxidative stress by increasing XO activity and lowering the antioxidant response. Furthermore, creatine and cystamine are efficient in preventing H2O2- and STS-evoked ROS formation in HD striatal cells.
authors.affiliation: * CNC-Center for Neuroscience and Cell Biology and.
authors.forename: Márcio
authors.initials: M
authors.lastname: Ribeiro
authors.forename: Ana C
authors.initials: AC
authors.lastname: Silva
authors.forename: Joana
authors.initials: J
authors.lastname: Rodrigues
authors.forename: Luana
authors.initials: L
authors.lastname: Naia
authors.forename: A Cristina
authors.initials: AC
authors.lastname: Rego
mesh_terms: D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D003404:Creatinine / Q000494:pharmacology*; D003538:Cystamine / Q000494:pharmacology*; D004798:Enzymes / Q000378:metabolism; D006801:Humans; D006816:Huntington Disease / Q000378:metabolism* / Q000473:pathology; D006861:Hydrogen Peroxide / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D019311:Staurosporine / Q000633:toxicity*
chemical_list: D004798:Enzymes; D017382:Reactive Oxygen Species; D003404:Creatinine; D006861:Hydrogen Peroxide; D019311:Staurosporine; D003538:Cystamine
keywords: Huntington disease; glutathione cycle; mitochondria; mutant huntingtin; oxidative stress; reactive oxygen species; striatal cells; superoxide dismutases.