title: Both creatine and its product phosphocreatine reduce oxidative stress and afford neuroprotection in an in vitro Parkinson's model.
abstract: Creatine is the substrate for creatine kinase in the synthesis of phosphocreatine (PCr). This energetic system is endowed of antioxidant and neuroprotective properties and plays a pivotal role in brain energy homeostasis. The purpose of this study was to investigate the neuroprotective effect of creatine and PCr against 6-hydroxydopamine (6-OHDA)-induced mitochondrial dysfunction and cell death in rat striatal slices, used as an in vitro Parkinson's model. The possible involvement of the signaling pathway mediated by phosphatidylinositol-3 kinase (PI3K), protein kinase B (Akt), and glycogen synthase kinase-3β (GSK3β) was also evaluated. Exposure of striatal slices to 6-OHDA caused a significant disruption of the cellular homeostasis measured as 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide reduction, lactate dehydrogenase release, and tyrosine hydroxylase levels. 6-OHDA exposure increased the levels of reactive oxygen species and thiobarbituric acid reactive substances production and decreased mitochondrial membrane potential in rat striatal slices. Furthermore, 6-OHDA decreased the phosphorylation of Akt (Serine(473)) and GSK3β (Serine(9)). Coincubation with 6-OHDA and creatine or PCr reduced the effects of 6-OHDA toxicity. The protective effect afforded by creatine or PCr against 6-OHDA-induced toxicity was reversed by the PI3K inhibitor LY294002. In conclusion, creatine and PCr minimize oxidative stress in striatum to afford neuroprotection of dopaminergic neurons.
authors.affiliation: Facultad de Medicina, Instituto Teófilo Hernando, Universidad Autónoma de Madrid, Spain Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Spain Departamento de Bioquímica, Universidade Federal de Santa Catarina, Centro de Ciências Biológicas, Florianópolis, SC, Brazil mauricio.personal@gmail.com.
authors.forename: Mauricio Peña
authors.initials: MP
authors.lastname: Cunha
authors.affiliation: Facultad de Medicina, Instituto Teófilo Hernando, Universidad Autónoma de Madrid, Spain Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Spain Department of Physiology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Maria D
authors.initials: MD
authors.lastname: Martín-de-Saavedra
authors.affiliation: Facultad de Medicina, Instituto Teófilo Hernando, Universidad Autónoma de Madrid, Spain Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Spain Departamento de Toxicología y Farmacología, Facultad de Veterinaria, Universidad Complutense de Madrid, Spain.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Romero
authors.affiliation: Facultad de Medicina, Instituto Teófilo Hernando, Universidad Autónoma de Madrid, Spain Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Spain Instituto de Investigación Sanitaria Hospital de la Princesa, Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Egea
authors.affiliation: Departamento de Bioquímica, Universidade Federal de Santa Catarina, Centro de Ciências Biológicas, Florianópolis, SC, Brazil Department of Pharmacy, Universidade do Contestado, Canoinhas, SC, Brazil.
authors.forename: Fabiana K
authors.initials: FK
authors.lastname: Ludka
authors.affiliation: Facultad de Medicina, Instituto Teófilo Hernando, Universidad Autónoma de Madrid, Spain.
authors.forename: Carla I
authors.initials: CI
authors.lastname: Tasca
authors.affiliation: Departamento de Bioquímica, Universidade Federal de Santa Catarina, Centro de Ciências Biológicas, Florianópolis, SC, Brazil.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Farina
authors.affiliation: Departamento de Bioquímica, Universidade Federal de Santa Catarina, Centro de Ciências Biológicas, Florianópolis, SC, Brazil.
authors.forename: Ana Lúcia S
authors.initials: AL
authors.lastname: Rodrigues
authors.affiliation: Facultad de Medicina, Instituto Teófilo Hernando, Universidad Autónoma de Madrid, Spain Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Spain.
authors.forename: Manuela G
authors.initials: MG
authors.lastname: López
mesh_terms: D018663:Adrenergic Agents / Q000494:pharmacology; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects*; D003401:Creatine / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D016627:Oxidopamine / Q000494:pharmacology; D058539:Phosphatidylinositol 3-Kinase; D010725:Phosphocreatine / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D018663:Adrenergic Agents; D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D018696:Neuroprotective Agents; D010725:Phosphocreatine; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D016627:Oxidopamine; D007770:L-Lactate Dehydrogenase; D058539:Phosphatidylinositol 3-Kinase; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D003401:Creatine
keywords: 6-OHDA; PI3K; creatine; neuroprotective; oxidative stress; phosphocreatine