title: Evidence that AKT and GSK-3β pathway are involved in acute hyperhomocysteinemia.
abstract: Homocysteine is a neurotoxic amino acid that accumulates in several disorders including homocystinuria, neurodegenerative and neuroinflammatory diseases. In the present study we evaluated the effect of acute and chronic hyperhomocysteinemia on Akt, NF-κB/p65, GSK-3β, as well as Tau protein in hippocampus of rats. For acute treatment, rats received a single injection of homocysteine (0.6 μmol/g body weight) or saline (control). For chronic treatment, rats received daily subcutaneous injections of homocysteine (0.3-0.6 μmol/g body weight) or saline (control) from the 6th to the 28th days-of-age. One or 12h after the last injection, rats were euthanized, the hippocampus was removed and samples were submitted to electrophoresis followed by Western blotting. Results showed that acute hyperhomocysteinemia increases Akt phosphorylation, cytosolic and nuclear immunocontent of NF-κB/p65 subunit and Tau protein phosphorylation, but reduces GSK-3β phosphorylation at 1h after homocysteine injection. However, 12h after acute hyperhomocysteinemia there is no effect on Akt and GSK-3β phosphorylation. Furthermore, chronic hyperhomocysteinemia did not alter Akt and GSK-3β phosphorylation at 1h and 12h after the last administration of this amino acid. Our data showed that Akt, NF-κB/p65, GSK-3β and Tau protein are activated in hippocampus of rats subjected to acute hyperhomocysteinemia, suggesting that these signaling pathways may be, at least in part, important contributors to the neuroinflammation and/or brain dysfunction observed in some hyperhomocystinuric patients.
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Aline A
authors.initials: AA
authors.lastname: da Cunha
authors.forename: Ana Paula
authors.initials: AP
authors.lastname: Horn
authors.forename: Juliana B
authors.initials: JB
authors.lastname: Hoppe
authors.forename: Patrícia B
authors.initials: PB
authors.lastname: Grudzinski
authors.forename: Samanta O
authors.initials: SO
authors.lastname: Loureiro
authors.forename: Andréa G K
authors.initials: AG
authors.lastname: Ferreira
authors.forename: Maira J
authors.initials: MJ
authors.lastname: da Cunha
authors.forename: Felipe
authors.initials: F
authors.lastname: Schmitz
authors.forename: Christianne G
authors.initials: CG
authors.lastname: Salbego
authors.forename: Angela T S
authors.initials: AT
authors.lastname: Wyse
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006710:Homocysteine / Q000009:adverse effects; D020138:Hyperhomocysteinemia / Q000139:chemically induced / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D016875:tau Proteins; D006710:Homocysteine; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3