title: Protective effects of 3-alkyl luteolin derivatives are mediated by Nrf2 transcriptional activity and decreased oxidative stress in Huntington's disease mouse striatal cells.
abstract: Huntington's disease (HD) is a polyglutamine-expansion neurodegenerative disorder caused by increased number of CAG repeats in the HTT gene, encoding for the huntingtin protein. The mutation is linked to several intracellular mechanisms, including oxidative stress. Flavones are compounds with a protective role in neurodegenerative pathologies. In the present study we analyzed the protective effect of luteolin (Lut, 3',4',5,7-tetrahydroxyflavone) and four luteolin derivatives bearing 3-alkyl chains of 1, 4, 6 and 10 carbons (Lut-C1, Lut-C4, Lut-C6, Lut-C10) in striatal cells derived from HD knock-in mice expressing mutant Htt (STHdh(Q111/Q111)) versus wild-type striatal cells (STHdh(Q7/Q7)). HD cells showed increased caspase-3-like activity and intracellular reactive oxygen species (ROS), which were significantly decreased following treatment with Lut-C4 and Lut-C6 under concentrations that enhanced cell viability. Interestingly, Lut-C4 and Lut-C6 rose the nuclear levels of phospho(Ser40)-nuclear factor (erythroid-derived-2)-like 2 (Nrf2) and Nrf2/ARE transcriptional activity. Concordantly with increased Nrf2/ARE transcription, Lut-C6 enhanced superoxide dismutase 1 (SOD1) mRNA and SOD activity and glutamate-cysteine ligase catalytic subunit (GCLc) mRNA and protein levels, while Lut-C4 induced mRNA levels of GCLc only in mutant striatal cells. Data suggest that Lut-C6 luteolin derivative (in particular) might be relevant for the development of antioxidant strategies in HD.
authors.affiliation: Chemistry Department & QOPNA, University of Aveiro, 3810-193 Aveiro, Portugal; CNC-Center for Neuroscience and Cell Biology, University of Coimbra - Pólo I, 3004-504 Coimbra, Portugal.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Oliveira
authors.affiliation: Chemistry Department & QOPNA, University of Aveiro, 3810-193 Aveiro, Portugal; CERNAS, Coimbra College of Agriculture, Polytechnic Institute of Coimbra, 3045-601 Coimbra, Portugal.
authors.forename: Susana M
authors.initials: SM
authors.lastname: Cardoso
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra - Pólo I, 3004-504 Coimbra, Portugal.
authors.forename: Márcio
authors.initials: M
authors.lastname: Ribeiro
authors.affiliation: Chemistry Department & QOPNA, University of Aveiro, 3810-193 Aveiro, Portugal.
authors.forename: Raquel S G R
authors.initials: RS
authors.lastname: Seixas
authors.affiliation: Chemistry Department & QOPNA, University of Aveiro, 3810-193 Aveiro, Portugal.
authors.forename: Artur M S
authors.initials: AM
authors.lastname: Silva
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra - Pólo I, 3004-504 Coimbra, Portugal; Faculty of Medicine, University of Coimbra - Pólo III, 3000-354 Coimbra, Portugal. Electronic address: a.cristina.rego@gmail.com.
authors.forename: A Cristina
authors.initials: AC
authors.lastname: Rego
mesh_terms: D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D055879:Gene Knock-In Techniques; D005721:Glutamate-Cysteine Ligase / Q000378:metabolism; D006816:Huntington Disease / Q000188:drug therapy*; D047311:Luteolin / Q000494:pharmacology*; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000096:biosynthesis / Q000235:genetics*; D017072:Neostriatum / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics; D013482:Superoxide Dismutase / Q000378:metabolism; D000072105:Superoxide Dismutase-1
chemical_list: D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; C495636:Nfe2l2 protein, mouse; D017382:Reactive Oxygen Species; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C505409:Casp3 protein, mouse; D053148:Caspase 3; D005721:Glutamate-Cysteine Ligase; D047311:Luteolin
keywords: Glutamate-cysteine ligase catalytic subunit; Huntington's disease; Luteolin; Nuclear factor (erythroid-derived-2)-like 2; Oxidative stress; Superoxide dismutase