title: Severe Hyperhomocysteinemia Decreases Respiratory Enzyme and Na(+)-K(+) ATPase Activities, and Leads to Mitochondrial Alterations in Rat Amygdala.
abstract: Severe hyperhomocysteinemia is caused by increased plasma levels of homocysteine (Hcy), a methionine derivative, and is associated with cerebral disorders. Creatine supplementation has emerged as an adjuvant to protect against neurodegenerative diseases, due to its potential antioxidant role. Here, we examined the effects of severe hyperhomocysteinemia on brain metabolism, and evaluated a possible neuroprotective role of creatine in hyperhomocysteinemia, by concomitant treatment with Hcy and creatine (50 mg/Kg body weight). Hyperhomocysteinemia was induced in young rats (6-day-old) by treatment with homocysteine (0.3-0.6 µmol/g body weight) for 23 days, and then the following parameters of rat amygdala were evaluated: (1) the activity of the respiratory chain complexes succinate dehydrogenase, complex II and cytochrome c oxidase; (2) mitochondrial mass and membrane potential; (3) the levels of necrosis and apoptosis; and (4) the activity and immunocontent of Na(+),K(+)-ATPase. Hcy treatment decreased the activities of succinate dehydrogenase and cytochrome c oxidase, but did not alter complex II activity. Hcy treatment also increased the number of cells with high mitochondrial mass, high mitochondrial membrane potential, and in late apoptosis. Importantly, creatine administration prevented some of the key effects of Hcy administration on the amygdala. We also observed a decrease in the activity and immunocontent of the α1 subunit of the Na(+),K(+)-ATPase in amygdala after Hcy- treatment. Our findings support the notion that Hcy modulates mitochondrial function and bioenergetics in the brain, as well as Na(+),K(+)-ATPase activity, and suggest that creatine might represent an effective adjuvant to protect against the effects of high Hcy plasma levels.
authors.affiliation: Laboratório de Neuroproteção e Doenças Neurometabólicas, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil.|Laboratório de Erros Inatos do Metabolismo, Departamento de Bioquímica, ICBS, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil.
authors.forename: Janaína
authors.initials: J
authors.lastname: Kolling
authors.affiliation: Laboratório de Neuroproteção e Doenças Neurometabólicas, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil.|Laboratório de Erros Inatos do Metabolismo, Departamento de Bioquímica, ICBS, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil.
authors.forename: Emilene B S
authors.initials: EB
authors.lastname: Scherer
authors.affiliation: Laboratório de Neuroproteção e Doenças Neurometabólicas, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil.|Laboratório de Erros Inatos do Metabolismo, Departamento de Bioquímica, ICBS, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil.
authors.forename: Cassiana
authors.initials: C
authors.lastname: Siebert
authors.affiliation: Laboratório de Neuroproteção e Doenças Neurometabólicas, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil.|Laboratório de Erros Inatos do Metabolismo, Departamento de Bioquímica, ICBS, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil.
authors.forename: Aline
authors.initials: A
authors.lastname: Longoni
authors.affiliation: Laboratório de Neuroproteção e Doenças Neurometabólicas, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil.|Laboratório de Erros Inatos do Metabolismo, Departamento de Bioquímica, ICBS, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil.
authors.forename: Samanta
authors.initials: S
authors.lastname: Loureiro
authors.affiliation: Laboratório de Neuroproteção e Doenças Neurometabólicas, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil.|Laboratório de Erros Inatos do Metabolismo, Departamento de Bioquímica, ICBS, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil.
authors.forename: Simone
authors.initials: S
authors.lastname: Weis
authors.affiliation: Laboratório de Neuroproteção e Doenças Neurometabólicas, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil.|Laboratório de Erros Inatos do Metabolismo, Departamento de Bioquímica, ICBS, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil.
authors.forename: Letícia
authors.initials: L
authors.lastname: Petenuzzo
authors.affiliation: Laboratório de Neuroproteção e Doenças Neurometabólicas, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil. wyse@ufrgs.br.|Laboratório de Erros Inatos do Metabolismo, Departamento de Bioquímica, ICBS, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil. wyse@ufrgs.br.
authors.forename: Angela T S
authors.initials: AT
authors.lastname: Wyse
mesh_terms: D000679:Amygdala / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D003401:Creatine / Q000008:administration & dosage*; D045222:Electron Transport Chain Complex Proteins / Q000187:drug effects / Q000378:metabolism*; D003576:Electron Transport Complex IV / Q000378:metabolism; D005260:Female; D006710:Homocysteine / Q000097:blood / Q000633:toxicity; D020138:Hyperhomocysteinemia / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009336:Necrosis / Q000139:chemically induced; D051381:Rats; D017208:Rats, Wistar; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*; D013385:Succinate Dehydrogenase / Q000378:metabolism
chemical_list: D045222:Electron Transport Chain Complex Proteins; D006710:Homocysteine; D013385:Succinate Dehydrogenase; D003576:Electron Transport Complex IV; D000254:Sodium-Potassium-Exchanging ATPase; D003401:Creatine
keywords: Creatine; Mitochondrial functions; Severe hyperhomocysteinemia; α1 Subunit of Na+,K+-ATPase