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

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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.

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Abbreviations

ANOVA:

One-way analysis of variance

CβS:

Cystathionine β-synthase

CNS:

Central nervous system

DMSO:

Dimethylsulfoxide

EDTA:

Ethylenediamine tetraacetic acid

HCl:

Hydrochloric acid

HCU:

Homocystinuria

Hcy:

Homocysteine

KCl:

Potassium chloride

MTG:

MitoTracker green

MTR:

MitoTracker red

NaCl:

Sodium chloride

SDH:

Succinate dehydrogenase

TBS:

Tris-buffered saline

References

  • Ajith TA, Ranimenon (2015) Homocysteine in ocular diseases. Clin Chim Acta 450:316–321. doi:10.1016/j.cca.2015.09.007

    Article  CAS  PubMed  Google Scholar 

  • Akmaev IG, Kalimullina LB, Sharipova LA (2004) The central nucleus of the amygdaloid body of the brain: cytoarchitectonics, neuronal organization, connections. Neurosci Behav Physiol 34:603–610

    Article  CAS  PubMed  Google Scholar 

  • 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

    Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • Alevizopoulos K, Calogeropoulou T, Lang F, Stournaras C (2014) Na +/K + ATPase inhibitors in cancer. Curr Drug Targets 15:988–1000

    CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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 23:221–229

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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 43:225–231

    Article  CAS  PubMed  Google Scholar 

  • Beal MF (2011) Neuroprotective effects of creatine. Aminoacids 40:1305–1313

    CAS  Google Scholar 

  • 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

    Article  Google Scholar 

  • 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

    Article  CAS  Google Scholar 

  • Blanco G, Mercer RW (1998) Isozymes of the Na + , K + -ATPase: heterogeneity in structure, diversity in function. Am J Physiol 275:F633–F650

    CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • 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 72:248–254

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  Google Scholar 

  • Chan KM, Delfert D, Junger KD (1986) A direct colorimetric assay for Ca+2 -stimulated ATPase activity. Anal Biochem 157:375–380

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • de Lores Arnaiz GR, Ordieres MG (2014) Brain Na + , K + -atpase activity in aging and disease. Int J Biomed Sci 10:85–102

    PubMed  PubMed Central  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  Google Scholar 

  • 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 20:4389–4397

    CAS  PubMed  Google Scholar 

  • Fischer JC, Ruitenbeek W, Berden JA et al (1985) Differential investigation of the capacity of succinate oxidation in human skeletal muscle. Clin Chim Acta 153:23–36

    Article  CAS  PubMed  Google Scholar 

  • 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 159:819–841

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 28:1339–1344

    Article  CAS  PubMed  Google Scholar 

  • 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 111:749–756

    Article  CAS  PubMed  Google Scholar 

  • 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 40:1333–1348

    Article  CAS  PubMed  Google Scholar 

  • 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 254:141–144

    Article  CAS  Google Scholar 

  • 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 1099:25–32

    Article  CAS  PubMed  Google Scholar 

  • 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 68:285–316

    Article  CAS  PubMed  Google Scholar 

  • 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 39:203–210

    Article  CAS  Google Scholar 

  • 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 291:119–126

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Kolling J, Wyse AT (2010) Creatine prevents the inhibition of energy metabolism and lipid peroxidation in rats subjected to GAA administration. Metab Brain Dis 2:331–338

    Article  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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 12:1431–1470

    Article  CAS  PubMed  Google Scholar 

  • 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 112:965–982

    Article  PubMed  Google Scholar 

  • Laemmli UK (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227:680–685

    Article  CAS  PubMed  Google Scholar 

  • Lawler JM, Barnes WS, Wu G, Song W, Demaree S (2002) Direct antioxidant properties of creatine. Biochem Biophys Res Commun 290:47–52

    Article  CAS  PubMed  Google Scholar 

  • Lowry OH, Rosebrough NJ, Farr AL, RandalL RJ (1951) Protein measurement with the folin phenol reagent. J Biol Chem 193:265–267

    CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • 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 24:3–8

    Article  PubMed  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • McCully KS (2011) Chemical pathology of homocysteine, V. Thioretinamide, thioretinaco, and cystathionine synthase function in degenerative diseases. Ann Clin Lab Sci 41:301–314

    CAS  PubMed  Google Scholar 

  • 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

    Article  Google Scholar 

  • Moro MA, Almeida A, Bolaños JP, Lizasoain I (2005) Mitochondrial respiratory chain and free radical generation in stroke. Free Radic Biol Med 39:1291–1304

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Nicholls DG, Budd SL (2000) Mitochondria and neuronal survival. Physiol Rev 80:315–360

    CAS  PubMed  Google Scholar 

  • Packard MG, Wingard JC (2004) Amygdala and “emotional” modulation of the relative use of multiple memory systems. Neurobiol Learn Mem 82:243–252

    Article  PubMed  Google Scholar 

  • 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:162–169

    Article  Google Scholar 

  • 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 338:1103–1109

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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 5:1099–1106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 228:35–51

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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 90:435–446

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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 40:837–849

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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 111:905–918

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 23:651–656

    Article  CAS  PubMed  Google Scholar 

  • 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 27:1593–1598

    Article  CAS  PubMed  Google Scholar 

  • 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 43:597–602

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed  PubMed Central  Google Scholar 

  • Williams KT, Schalinske KL (2010) Homocysteine metabolism and its relation to health and disease. BioFactors 36:19–24

    CAS  PubMed  Google Scholar 

  • 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 25:971–975

    Article  CAS  Google Scholar 

  • 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 27:1685–1689

    Article  CAS  PubMed  Google Scholar 

  • Wyss M, Schulze A (2002) Health implications of creatine: can oral creatine supplementation protect against neurological and atherosclerotic disease? Neuroscience 112:243–260

    Article  CAS  PubMed  Google Scholar 

  • 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 116:431–436

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by grants from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Brazil) (475262/2011-5).

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Authors and Affiliations

  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

    Janaína Kolling, Emilene B. S. Scherer, Cassiana Siebert, Aline Longoni, Samanta Loureiro, Simone Weis, Letícia Petenuzzo & Angela T. S. Wyse

  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

    Janaína Kolling, Emilene B. S. Scherer, Cassiana Siebert, Aline Longoni, Samanta Loureiro, Simone Weis, Letícia Petenuzzo & Angela T. S. Wyse

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  1. Janaína Kolling
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Correspondence to Angela T. S. Wyse.

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Kolling, J., Scherer, E.B.S., Siebert, C. et al. Severe Hyperhomocysteinemia Decreases Respiratory Enzyme and Na+-K+ ATPase Activities, and Leads to Mitochondrial Alterations in Rat Amygdala. Neurotox Res 29, 408–418 (2016). https://doi.org/10.1007/s12640-015-9587-z

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