title: RETRACTED: 6-OHDA-induced apoptosis and mitochondrial dysfunction are mediated by early modulation of intracellular signals and interaction of Nrf2 and NF-κB factors.
abstract: 6-Hydroxydopamine (6-OHDA) is a neurotoxin that generates an experimental model of Parkinson's disease in rodents and is commonly employed to induce a lesion in dopaminergic pathways. The characterization of those molecular mechanisms linked to 6-OHDA-induced early toxicity is needed to better understand the cellular events further leading to neurodegeneration. The present work explored how 6-OHDA triggers early downstream signaling pathways that activate neurotoxicity in the rat striatum. Mitochondrial function, caspases-dependent apoptosis, kinases signaling (Akt, ERK 1/2, SAP/JNK and p38) and crosstalk between nuclear factor kappa B (NF-κB) and nuclear factor-erythroid-2-related factor 2 (Nrf2) were evaluated at early times post-lesion. We found that 6-OHDA initiates cell damage via mitochondrial complex I inhibition, cytochrome c and apoptosis-inducing factor (AIF) release, as well as activation of caspases 9 and 3 to induce apoptosis, kinase signaling modulation and NF-κB-mediated inflammatory responses, accompanied by inhibition of antioxidant systems regulated by the Nrf2 pathway. Our results suggest that kinases SAP/JNK and p38 up-regulation may play a role in the early stages of 6-OHDA toxicity to trigger intrinsic pathways for apoptosis and enhanced NF-κB activation. In turn, these cellular events inhibit the activation of cytoprotective mechanisms, thereby leading to a condition of general damage.
authors.affiliation: Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y Neurocirugía - S.S.A., Mexico City, Mexico.
authors.forename: Julio C
authors.initials: JC
authors.lastname: Tobón-Velasco
authors.forename: Jorge H
authors.initials: JH
authors.lastname: Limón-Pacheco
authors.forename: Marisol
authors.initials: M
authors.lastname: Orozco-Ibarra
authors.forename: Marina
authors.initials: M
authors.lastname: Macías-Silva
authors.forename: Genaro
authors.initials: G
authors.lastname: Vázquez-Victorio
authors.forename: Elvis
authors.initials: E
authors.lastname: Cuevas
authors.forename: Syed F
authors.initials: SF
authors.lastname: Ali
authors.forename: Antonio
authors.initials: A
authors.lastname: Cuadrado
authors.forename: José
authors.initials: J
authors.lastname: Pedraza-Chaverrí
authors.forename: Abel
authors.initials: A
authors.lastname: Santamaría
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology; D045304:Cytochromes c / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000473:pathology; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D020258:Neurotoxicity Syndromes / Q000209:etiology / Q000473:pathology; D016627:Oxidopamine / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics
chemical_list: D051033:Apoptosis Inducing Factor; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495637:Nfe2l2 protein, rat; D016627:Oxidopamine; D045304:Cytochromes c; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3; D053453:Caspase 9