Severe Hyperhomocysteinemia Decreases Respiratory Enzyme and Na+-K+ ATPase Activities, and Leads to Mitochondrial Alterations in Rat Amygdala

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• 作者：Janaína Kolling ; Emilene B. S. Scherer ; Cassiana Siebert…
• 关键词：Severe hyperhomocysteinemia ; α1 Subunit of Na+ ; K+ ; ATPase ; Creatine ; Mitochondrial functions
• 刊名：Neurotoxicity Research
• 出版年：2016
• 出版时间：April 2016
• 年：2016
• 卷：29
• 期：3
• 页码：408-418
• 全文大小：668 KB
• 参考文献：Ajith TA, Ranimenon (2015) Homocysteine in ocular diseases. Clin Chim Acta 450:316–321. doi:10.​1016/​j.​cca.​2015.​09.​007 CrossRef PubMed
  Akmaev IG, Kalimullina LB, Sharipova LA (2004) The central nucleus of the amygdaloid body of the brain: cytoarchitectonics, neuronal organization, connections. Neurosci Behav Physiol 34:603–610CrossRef PubMed
  Albers RW, Siegel GJ (2012) Membrane transport. In: Brady ST, Siegel GJ, Albers RW, Price D (eds) Basic neurochemistry: principles of molecular, cellular and medical neurobiology, 8th edn. Elsevier Academic Press, Massachusetts, pp 41–62
  Alcaide P, Krijt J, Ruiz-Sala P, Ješina P, Ugarte M, Kožich V, Merinero B (2014) Enzymatic diagnosis of homocystinuria by determination of cystathionine-ß-synthase activity in plasma using LC-MS/MS. Clin Chim Acta 438:261–265. doi:10.​1016/​j CrossRef PubMed
  Alevizopoulos K, Calogeropoulou T, Lang F, Stournaras C (2014) Na +/K + ATPase inhibitors in cancer. Curr Drug Targets 15:988–1000PubMed
  Allah Yar R, Akbar A, Iqbal F (2015) Creatine monohydrate supplementation for 10 weeks mediates neuroprotection and improves learning/memory following neonatal hypoxia ischemia encephalopathy in female albino mice. Brain Res 1595:92–100. doi:10.​1016/​j.​brainres.​2014.​11.​017 CrossRef PubMed
  Balestrino M, Lensman M, Parodi M, Perasso L, Rebaudo R, Melani R, Polenov S, Cupello A (2002) Role of creatine and phosphocreatine in neuronal protection from anoxic and ischemic damage. Amino Acids 23:221–229CrossRef PubMed
  Bassit RA, Pinheiro CH, Vitzel KF, Sproesser AJ, Silveira LR, Curi R (2010) Effect of short-term creatine supplementation on markers of skeletal muscle damage after strenuous contractile activity. Eur J Appl Physiol 108:945–955. doi:10.​1007/​s00421-009-1305-1 CrossRef PubMed
  Baydas G, Koz ST, Tuzcu M, Etem E, Nedzvetsky VS (2007) Melatonin inhibits oxidative stress and apoptosis in fetal brains of hyperhomocysteinemic rat dams. J Pineal Res 43:225–231CrossRef PubMed
  Beal MF (2011) Neuroprotective effects of creatine. Aminoacids 40:1305–1313
  Belcastro V, Striano P, Gorgone G, Costa C, Ciampa C, Caccamo D, Pisani LR, Oteri G, Marciani MG, Aguglia U, Striano S, Ientile R, Calabresi P, Pisani F (2010) Hyperhomocysteinemia in epileptic patients on new antiepileptic drugs. Epilepsia 5:274–279. doi:10.​1111/​j CrossRef
  Belhadj Slimen I, Najar T, Ghram A, Dabbebi H, Ben Mrad M, Abdrabbah M (2014) Reactive oxygen species, heat stress and oxidative-induced mitochondrial damage. A review. Int J Hyperth 30:513–523. doi:10.​3109/​02656736.​2014.​971446 CrossRef
  Blanco G, Mercer RW (1998) Isozymes of the Na + , K + -ATPase: heterogeneity in structure, diversity in function. Am J Physiol 275:F633–F650PubMed
  Bortoluzzi VT, de Franceschi ID, Rieger E, Wannmacher CM (2014) Co-administration of creatine plus pyruvate prevents the effects of phenylalanine administration to female rats during pregnancy and lactation on enzymes activity of energy metabolism in cerebral cortex and hippocampus of the offspring. Neurochem 39(8):1594–1602. doi:10.​1007/​s11064-014-1353-8 CrossRef
  Bøttger P, Doğanlı C, Lykke-Hartmann K (2012) Migraine- and dystonia-related disease-mutations of Na+/K+-ATPases: relevance of behavioral studies in mice to disease symptoms and neurological manifestations in humans. Neurosci Biobehav Rev 36:855–871. doi:10.​1016/​j.​neubiorev.​2011.​10.​005 CrossRef PubMed
  Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254CrossRef PubMed
  Caretti A, Bianciardi P, Sala G, Terruzzi C, Lucchina F, Samaja M (2011) Supplementation of creatine and ribose prevents apoptosis in ischemic cardiomyocytes. Cell Physiol Biochem 26:831–838. doi:10.​1159/​000323992 CrossRef
  Chan KM, Delfert D, Junger KD (1986) A direct colorimetric assay for Ca+2 -stimulated ATPase activity. Anal Biochem 157:375–380CrossRef PubMed
  Crassous B, Richard-Bulteau H, Deldicque L, Serrurier B, Pasdeloup M, Francaux M, Bigard X, Koulmann N (2009) Lack of effects of creatine on the regeneration of soleus muscle after injury in rats. Med Sci Sports Exerc 41:1761–1769. doi:10.​1249/​MSS.​0b013e31819f75cb​ CrossRef PubMed
  Cunha MP, Martín-de-Saavedra MD, Romero A, Egea J, Ludka FK, Tasca CI, Farina M, Rodrigues AL, López MG (2014) Both creatine and its product phosphocreatine reduce oxidative stress and afford neuroprotection in an in vitro Parkinson’s model. ASN Neuro 6. doi:10.​1177/​1759091414554945​
  de Andrade RB, Gemelli T, Rojas DB, Bonorino NF, Costa BM, Funchal C, Dutra-Filho CS, Wannmacher CM (2015) Creatine and pyruvate prevent the alterations caused by tyrosine on parameters of oxidative stress and enzyme activities of phosphoryl transfer et work in cerebral cortex of Wistar rats. Mol Neurobiol 51:1184–1194. doi:10.​1007/​s12035-014-8791-9 CrossRef PubMed
  de Lores Arnaiz GR, Ordieres MG (2014) Brain Na + , K + -atpase activity in aging and disease. Int J Biomed Sci 10:85–102PubMed PubMedCentral
  Deminice R, Jordao AA (2015) Creatine supplementation decreases plasma lipid peroxidation markers and enhances anaerobic performance in rats. Redox Rep [Epub ahead of print]
  Distelmaier F, Koopman WJ, Testa ER, de Jong AS, Swarts HG, Mayatepek E, Smeitink JA, Willems PH (2008) Life cell quantification of mitochondrial membrane potential at the single organelle level. Cytometry A 73:129–138. doi:10.​1002/​cyto.​a.​20503 CrossRef PubMed
  Esse R, Florindo C, Imbard A, Rocha MS, de Vriese AS, Smulders YM, Teerlink T, Tavares de Almeida I, Castro R, Blom HJ (2013) Global protein and histone arginine methylation are affected in a tissue-specific manner in a rat model of diet-induced hyperhomocysteinemia. Biochim Biophys Acta 1832:1708–1714. doi:10.​1016/​j CrossRef PubMed
  Familtseva A, Kalani A, Chaturvedi P, Tyagi N, Metreveli N, Tyagi SC (2014) Mitochondrial mitophagy in mesenteric artery remodeling inhyperhomocysteinemia. Physiol Rep 2:00283. doi:10.​14814/​phy2.​283 CrossRef
  Ferrante RJ, Andreassen OA, Jenkins BG, Dedeoglu A, Kuemmerle S, Kubilus JK, Kaddurah-Daouk R, Hersch SM, Beal MF (2000) Neuroprotective effects of creatine in a transgenic mouse model of Huntington’s disease. J Neurosci 20:4389–4397PubMed
  Fischer JC, Ruitenbeek W, Berden JA et al (1985) Differential investigation of the capacity of succinate oxidation in human skeletal muscle. Clin Chim Acta 153:23–36CrossRef PubMed
  Fransen JC, Zuhl M, Kerksick CM, Cole N, Altobelli S, Kuethe DO, Schneider S (2015) Impact of creatine on muscle performance and phosphagen stores after immobilization. Eur J Appl Physiol [Epub ahead of print]
  Fudge JL, Tucker T (2009) Amygdala projections to central amygdaloid nucleus subdivisions and transition zones in the primate. Neuroscience 159:819–841CrossRef PubMed PubMedCentral
  Gamaro GD, Streck EL, Matte C, Prediger ME, Wyse AT, Dalmaz C (2003) Reduction of hippocampal Na + , K + -ATPase activity in rats subjected to an experimental model of depression. Neurochem Res 28:1339–1344CrossRef PubMed
  Gualano B, Painelli VS, Roschel H et al (2011) Creatine supplementation does not impair kidney function in type 2 diabetic patients: a randomized, double-blind, placebo-controlled, clinical trial. Eur J Appl Physiol 111:749–756CrossRef PubMed
  Guzun R, Timohhina N, Tepp K et al (2011) Systems bioenergetics of creatine kinase networks: physiological roles of creatine and phosphocreatine in regulation of cardiac cell function. Amino Acids 40:1333–1348CrossRef PubMed
  Hattori N, Kitagawa K, Higashida T, Yagyu K, Shimohama S, Wataya T, Perry G, Smith MA, Inagaki C (1998) CI-ATPase and Na + , K + -ATPase activities in Alzheimer’s disease brains. Neu rosci Lett 254:141–144CrossRef
  Iijima T, Mishima T, Akagawa K, Iwao Y (2006) Neuroprotective effect of propofol on necrosis and apoptosis following oxygen-glucose deprivation–relationship between mitochondrial membrane potential and mode of death. Brain Res 1099:25–32CrossRef PubMed
  Izquierdo I, Medina JH (1997) Memory formation: the sequence of biochemical events in the hippocampus and its connection to activity in other brain structures. Neurobiol Learn Mem 68:285–316CrossRef PubMed
  Keij JF, Bell-Prince C, Steinkamp JA (2000) Staining of mitochondrial membranes with 10-nonyl acridine orange, MitoFluor Green, and MitoTracker Green is affected by mitochondrial membrane potential altering drugs. Cytometry A 39:203–210CrossRef
  Kerkeni M, Tnani M, Chuniaud L, Miled A, Maaroufi K, Trivin F (2006) Comparative study on in vitro effects of homocysteine thiolactone and homocysteine on HUVEC cells: evidence for a stronger proapoptotic and proinflammative homocysteine thiolactone. Mol Cell Biochem 291:119–126CrossRef PubMed
  Khanal G, Chung K, Solis-Wever X, Johnson B, Pappas D (2011) Ischemia/reperfusion injury of primary porcine cardiomyocytes in a low-shear microfluidic culture and analysis device. Analyst 136:3519–3526. doi:10.​1039/​C0AN00845A CrossRef PubMed PubMedCentral
  Klopstock T, Elstner M, Bender A (2011) Creatine in mouse models of neurodegeneration and aging. Amino Acids 40:1297–1303. doi:10.​1007/​s00726-011-0850-1 CrossRef PubMed
  Kolling J, Wyse AT (2010) Creatine prevents the inhibition of energy metabolism and lipid peroxidation in rats subjected to GAA administration. Metab Brain Dis 2:331–338CrossRef
  Kolling J, Scherer EB, Siebert C, Hansen F, Torres FV, Scaini G, Ferreira G, de Andrade RB, Gonçalves CA, Streck EL, Wannmacher CM, Wyse AT (2013) Homocysteine induces energy imbalance in rat skeletal muscle: is creatine a protector? Cell Biochem Funct 31:575–584. doi:10.​1002/​cbf.​2938 PubMed
  Kolling J, Scherer EB, Siebert C, Marques EP, Dos Santos TM, Wyse AT (2014) Creatine prevents the imbalance of redox homeostasis caused by homocysteine in skeletal muscle of rats. Gene 545:72–79. doi:10.​1016/​j.​gene.​2014.​05.​005 CrossRef PubMed
  Koopman WJ, Nijtmans LG, Dieteren CE, Roestenberg P, Valsecchi F, Smeitink JA, Willems PH (2010) Mammalian mitochondrial complex I: biogenesis, regulation, and reactive oxygen species generation. Antioxid Redox Signal 12:1431–1470CrossRef PubMed
  Kurup AR, Kurup PA (2002) Membrane Na + , K + - ATPase mediated cascade in bipolar mood disorder, major depressive disorder, and schizophrenia-relationship to hemispheric domi nance. Int J Neurosci 112:965–982CrossRef PubMed
  Laemmli UK (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227:680–685CrossRef PubMed
  Lawler JM, Barnes WS, Wu G, Song W, Demaree S (2002) Direct antioxidant properties of creatine. Biochem Biophys Res Commun 290:47–52CrossRef PubMed
  Lowry OH, Rosebrough NJ, Farr AL, RandalL RJ (1951) Protein measurement with the folin phenol reagent. J Biol Chem 193:265–267PubMed
  Machado FR, Ferreira AG, da Cunha AA, Tagliari B, Mussulini BH, Wofchuk S, Wyse AT (2011) Homocysteine alters glutamate uptake and Na + , K + -ATPase activity and oxidative status in rats hippocampus: protection by vitamin C. Metab Brain Dis 26:61–67. doi:10.​1007/​s11011-011-9232-3 CrossRef PubMed
  Mahabir M, Tucholka A, Shin LM, Etienne P, Brunet A (2015) Emotional face processing in post-traumatic stress disorder after reconsolidation impairment using propranolol: a pilot fMRI study. J Anxiety Disord 36:127–133. doi:10.​1016/​j.​janxdis.​2015.​10.​004 CrossRef PubMed
  Matté C, Durigon E, Stefanello FM, Cipriani F, Wajner M, Wyse AT (2006) Folic acid pretreatment prevents the reduction of Na(+), K(+)-ATPase and butyrylcholinesterase activities in rats subjected to acute hyperhomocysteinemia. Int J Dev Neurosci 24:3–8CrossRef PubMed
  Matté C, Stefanello FM, Mackedanz V, Pederzolli CD, Lamers ML, Dutra-Filho CS, Dos Santos MF, Wyse AT (2009) Homocysteine induces oxidative stress, inflammatory infiltration, fibrosis and reduces glycogen/glycoprotein content in liver of rats. Int J Dev Neurosci 27:337–344. doi:10.​1016/​j.​ijdevneu.​2009.​03.​005 CrossRef PubMed
  McCully KS (2011) Chemical pathology of homocysteine, V. Thioretinamide, thioretinaco, and cystathionine synthase function in degenerative diseases. Ann Clin Lab Sci 41:301–314PubMed
  Misiak B, Frydecka D, Slezak R, Piotrowski P, Kiejna A (2014) Elevated homocysteine level in first-episode schizophrenia patients–the relevance of family history of schizophrenia and lifetime diagnosis of cannabis abuse. Metab Brain Dis 3:661–670. doi:10.​1007/​s11011-014-9534-3 CrossRef
  Moro MA, Almeida A, Bolaños JP, Lizasoain I (2005) Mitochondrial respiratory chain and free radical generation in stroke. Free Radic Biol Med 39:1291–1304CrossRef PubMed
  Morth JP, Poulsen H, Toustrup-Jensen MS, Schack VR, Egebjerg J, Andersen JP, Vilsen B, Nissen P (2009) The structure of the Na + , K + -ATPase and mapping of isoform differences and disease-related mutations. Philos Trans R Soc Lond B Biol Sci 364:217–227. doi:10.​1098/​rstb.​2008.​0201 CrossRef PubMed PubMedCentral
  Mudd SH, Levy HL, Skovby F (2001) Disorders of transsulfuration. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular basis of inherited disease. McGraw-Hill, New York
  Nicastro H, Gualano B, de Moraes WM, de Salles Painelli V, da Luz CR, dos Santos Costa A, de Salvi Guimarães F, Medeiros A, Brum PC, Lancha AH Jr (2012) Effects of creatine supplementation on muscle wasting and glucose homeostasis in rats treated with dexamethasone. Amino Acids 42:1695–1701. doi:10.​1007/​s00726-011-0871-9 CrossRef PubMed
  Nicholls DG, Budd SL (2000) Mitochondria and neuronal survival. Physiol Rev 80:315–360PubMed
  Packard MG, Wingard JC (2004) Amygdala and “emotional” modulation of the relative use of multiple memory systems. Neurobiol Learn Mem 82:243–252CrossRef PubMed
  Pendergrass W, Wolf N, Poot M (2004) Efficacy of MitoTracker Green (TM) and CMXRosamine to measure changes in mitochondrial membrane potentials in living cells and tissues. Cytometry A 61A:162–169CrossRef
  Perez-de-Arce K, Foncea R, Leighton F (2005) Reactive oxygen species mediates homocysteine-induced mitochondrial biogenesis in human endothelial cells: modulation by antioxidants. Biochem Biophys Res Commun 338:1103–1109CrossRef PubMed
  Puddu P, Puddu GM, Cravero E, De Pascalis S, Muscari A (2009) The emerging role of cardiovascular risk factor-induced mitochondrialdysfunction in atherogenesis. J Biomed Sci 16:112. doi:10.​1186/​1423-0127-16-112 CrossRef PubMed PubMedCentral
  Richard E, Jorge-Finnigan A, Garcia-Villoria J, Merinero B, Desviat LR, Gort L, Briones P, Leal F, Pérez-Cerdá C, Ribes A, Ugarte M, Pérez B (2009) Genetic and cellular studies of oxidative stress in methylmalonic aciduria (MMA) cobalamin deficiency type C (cblC) with homocystinuria (MMACHC). Hum Mutat 30:1558–1566. doi:10.​1002/​humu.​21107 CrossRef PubMed
  Rodriguez-Enriquez S, Kai Y, Maldonado E, Currin RT, Lemasters JJ (2009) Roles of mitophagy and the mitochondrial permeability transition in remodeling of cultured rat hepatocytes. Autophagy 5:1099–1106CrossRef PubMed PubMedCentral
  Rustin P, Chretien D, Bourgeron T, Gérard B, Rötig A, Saudubray JM, Munnich A (1994) Biochemical and molecular investigations in respiratory chain deficiencies. Clin Chim Acta 228:35–51CrossRef PubMed
  Saks VA, Javadov SA, Pozin E, Preobrazhensky AN (1987) Biochemical basis of the protective action of phosphocreatine on the ischemic myocardium. In: Saks VA, Bobkov, Strumia E, eds. Proceedings of the symposium “creatine phosphate-biochemistry, pharmacology and clinical efficiency” Baku, October 1986. Edizioni Minerva Medica, Torino, pp 95–111
  Saraiva AL, Ferreira AP, Silva LF, Hoffmann MS, Dutra FD, Furian AF, Oliveira MS, Fighera MR, Royes LF (2012) Creatine reduces oxidative stress markers but does not protect against seizure susceptibility after severe traumatic brain injury. Brain Res Bull 87:180–186. doi:10.​1016/​j.​brainresbull.​2011.​10.​010 CrossRef PubMed
  Sartini S, Sestili P, Colombo E, Martinelli C, Bartolini F, Ciuffoli S, Lattanzi D, Sisti D, Cuppini R (2012) Creatine affects in vitro electrophysiological maturation of neuroblasts and protects them from oxidative stress. J Neurosci Res 90:435–446CrossRef PubMed
  Scherer EB, Loureiro SO, Vuaden FC, Schmitz F, Kolling J, Siebert C, Savio LE, Schweinberger BM, Bogo MR, Bonan CD, Wyse AT (2013) Mild hyperhomocysteinemia reduces the activity and immunocontent, but does not alter the gene expression, of catalytic α subunits of cerebral Na + , K + -ATPase. Mol Cell Biochem 378:91–97. doi:10.​1007/​s11010-013-1598-6 CrossRef PubMed
  Sestili P, Martinelli C, Bravi G, Piccoli G, Curci R, Battistelli M, Falcieri E, Agostini D, Gioacchini AM, Stocchi V (2006) Creatine supplementation affords cytoprotection in oxidatively injured cultured mammalian cells via direct antioxidant activity. Free Radic Biol Med 40:837–849CrossRef PubMed
  Sestili P, Martinelli C, Colombo E, Barbieri E, Potenza L, Sartini S, Fimognari C (2011) Creatine as an antioxidant. Amino Acids 40:1385–1396. doi:10.​1007/​s00726-011-0875-5 CrossRef PubMed
  Shumyatsky GP, Tsvetkov E, Malleret G, Vronskaya S, Hatton M, Hampton L, Battey JF, Dulac C, Kandel ER, Bolshakov VY (2002) Identification of a signaling network in lateral nucleus of amygdala important for inhibiting memory specifically related to learned fear. Cell 111:905–918CrossRef PubMed
  Sipkens JA, Hahn NE, Blom HJ, Lougheed SM, Stehouwer CD, Rauwerda JA, Krijnen PA, van Hinsbergh VW, Niessen HW (2011) S-adenosylhomocysteine induces apoptosis and phosphatidylserine exposure in endothelial cellsindependent of homocysteine. Atherosclerosis 221:48–54. doi:10.​1016/​j CrossRef PubMed
  Sipkens JA, Hahn N, van den Brand CS, Meischl C, Cillessen SA, Smith DE, Juffermans LJ, Musters RJ, Roos D, Jakobs C, Blom HJ, Smulders YM, Krijnen PA, Stehouwer CD, Rauwerda JA, van Hinsbergh VW, Niessen HW (2013) Homocysteine-induced apoptosis in endothelial cells coincides with nuclear NOX2 and peri-nuclear NOX4 activity. Cell Biochem Biophys 67:341–352. doi:10.​1007/​s12013-011-9297-y CrossRef PubMed PubMedCentral
  Stefanello FM, Chiarani F, Kurek AG, Wannmacher CM, Wajner M, Wyse AT (2005) Methionine alters Na + , K + -ATPase activity, lipid peroxidation and nonenzymatic antioxidant defenses in rat hippocampus. Int J Dev Neurosci 23:651–656CrossRef PubMed
  Streck EL, Matte C, Vieira PS, Rombaldi F, Wannmacher CM, Wajner M, Wyse AT (2002) Reduction of Na + , K + -ATPase activity in hippocampus of rats subjected to chemically induced hyperhomocysteinemia. Neurochem Res 27:1593–1598CrossRef PubMed
  Streck EL, Delwing D, Tagliari B, Matté C, Wannmacher CM, Wajner M, Wyse AT (2003) Brain energy metabolism is compromised by the metabolites accumulating in homocystinuria. Neurochem Int 43:597–602CrossRef PubMed
  Strumia E, Pelliccia F, D’Ambrosio G (2012) Creatine phosphate: pharmacological and clinical perspectives. Adv Ther 29:99–123. doi:10.​1007/​s12325-011-0091-4 CrossRef PubMed
  Veeranki S, Tyagi SC (2013) Defective homocysteine metabolism: potential implications for skeletal muscle malfunction. Int J Mol Sci 14:15074–15091. doi:10.​3390/​ijms140715074 CrossRef PubMed PubMedCentral
  Williams KT, Schalinske KL (2010) Homocysteine metabolism and its relation to health and disease. BioFactors 36:19–24PubMed
  Wyse ATS, Streck EL, Worm P, Wajner A, Ritter F, Netto CA (2000) Preconditioning prevents the inhibition of Na + , K + -ATPase activity after brain ischemia. Neurochem Res 25:971–975CrossRef
  Wyse AT, Zugno AI, Streck EL, Matte C, Calcagnotto T, Wannmacher CM, Wajner M (2002) Inhibition of Na + , K + -ATPase activity in hippocampus of rats subjected to acute administration of homocysteine is prevented by vitamins E and C treatment. Neurochem Res 27:1685–1689CrossRef PubMed
  Wyss M, Schulze A (2002) Health implications of creatine: can oral creatine supplementation protect against neurological and atherosclerotic disease? Neuroscience 112:243–260CrossRef PubMed
  Zugno AI, Valvassori SS, Scherer EB, Mattos C, Matte C, Ferreira CL, Rezin GT, Wyse AT, Quevedo J, Streck EL (2009) Na + , K + -ATPase activity in an animal model of mania. J Neural Transm 116:431–436CrossRef PubMed
  
• 作者单位：Janaína Kolling (1) (2)
  Emilene B. S. Scherer (1) (2)
  Cassiana Siebert (1) (2)
  Aline Longoni (1) (2)
  Samanta Loureiro (1) (2)
  Simone Weis (1) (2)
  Letícia Petenuzzo (1) (2)
  Angela T. S. Wyse (1) (2)
  
  1. Laboratório de Neuroproteção e Doenças Neurometabólicas, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil
  2. 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
  
• 刊物主题：Neurosciences; Neurology; Neurochemistry; Pharmacology/Toxicology; Neurobiology; Cell Biology;
• 出版者：Springer US
• ISSN：1476-3524

文摘

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.