Skip to main content
Log in

Role of antioxidants on Na+,K+-ATPase activity and gene expression in cerebral cortex of hyperprolinemic rats

  • Original Paper
  • Published:
Metabolic Brain Disease Aims and scope Submit manuscript

Abstract

Considering that Na+,K+-ATPase is an embedded-membrane enzyme and that experimental chronic hyperprolinemia decreases the activity of this enzyme in brain synaptic plasma membranes, the present study investigated the effect of chronic proline administration on thiobarbituric acid-reactive substances, as well as the influence of antioxidant vitamins E plus C on the effects mediated by proline on Na+,K+-ATPase activity in cerebral cortex of rats. The expression of Na+,K+-ATPase catalytic subunits was also evaluated. Results showed that proline increased thiobarbituric acid-reactive substances, suggesting an increase of lipid peroxidation. Furthermore, concomitant administration of vitamins E plus C significantly prevented the increase of lipid peroxidation, as well as the inhibition of Na+,K+-ATPase activity caused by proline. We did not observe any change in levels of Na+,K+-ATPase mRNA transcripts after chronic exposure to proline and vitamins E plus C. These findings provide insights into the mechanisms through which proline exerts its effects on brain function and suggest that treatment with antioxidants may be beneficial to treat neurological dysfunctions present in hyperprolinemic patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Aperia A (2007) New roles for an old enzyme: Na+, K+ -ATPase emerges as an interesting drug target. J Intern Med 261:44–52

    Article  PubMed  CAS  Google Scholar 

  • Ben J, Soares FM, Cechetti F, Vuaden FC, Bonan CD, Netto CA, Wyse ATS (2009) Exercise effects on activities of Na+, K+ -ATPase, acetylcholinesterase and adenine nucleotides hydrolysis in ovariectomized rats. Brain Res 1302:248–255

    Article  PubMed  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

    PubMed  CAS  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  PubMed  CAS  Google Scholar 

  • Chan KM, Delfert D, Junger KD (1986) A direct colorimetric assay for Ca2+ -stimulated ATPase activity. Anal Biochem 157:375–380

    Article  PubMed  CAS  Google Scholar 

  • de Vasconcellos AP, Zugno AI, dos Santos AH, Nietto FB, Crema LM, Goncalves M, Franzon R, Wyse ATS, da Rocha ER, Dalmaz C (2005) Na+, K+-ATPase activity is reduced in hippocampus of rats submitted to an experimental model of depression: effect of chronic lithium treatment and possible involvement in learning deficits. Neurobiol Learn Mem 84:102–110

    Article  PubMed  Google Scholar 

  • Delwing D, Bavaresco CS, Wannmacher CM, Wajner M, Dutra-Filho CS, Wyse ATS (2003) Proline induces oxidative stress in cerebral cortex of rats. Int J Dev Neurosci 21:105–110

    Article  PubMed  CAS  Google Scholar 

  • Delwing D, Chiarani F, Bavaresco CS, Wannmacher CM, Wajner M, Dutra-Filho CS, Wyse AT (2005) Protective effect of antioxidants on brain oxidative damage caused by proline administration. Neurosci Res 52:69–74

    Article  PubMed  CAS  Google Scholar 

  • Delwing D, Tagliari B, Chiarani F, Wannmacher CM, Wajner M, Wyse AT (2006) Alpha-tocopherol and ascorbic acid administration prevents the impairment of brain energy metabolism of hyperargininemic rats. Cell Mol Neurobiol 26:177–189

    Article  PubMed  CAS  Google Scholar 

  • Delwing D, Chiarani F, Kurek AG, Wyse AT (2007) Proline reduces brain cytochrome c oxidase: prevention by antioxidants. Int J Dev Neurosci 25:17–22

    Article  PubMed  CAS  Google Scholar 

  • Dempski RE, Friedrich T, Bamberg E (2009) Voltage clamp fluorometry: combining fluorescence and electrophysiological methods to examine the structure-function of the Na+, K+-ATPase. Biochim Biophys Acta 1787:714–720

    Article  PubMed  CAS  Google Scholar 

  • Dencher NA, Frenzel M, Reifschneider NH, Sugawa M, Krause F (2007) Proteome alterations in rat mitochondria caused by aging. Ann NY Acad Sci 1100:291–298

    Article  PubMed  CAS  Google Scholar 

  • Farrant RD, Walker V, Mills GA, Mellor JM, Langley GJ (2001) Pyridoxal phosphate de-activation by pyrroline-5-carboxylic acid. Increased risk of vitamin B6 deficiency and seizures in hyperprolinemia type II. J Biol Chem 276:15107–15116

    Article  PubMed  CAS  Google Scholar 

  • Ferreira AGK, Lima DD, Delwing D, Mackedanz V, Tagliari B, Kolling J, Schuck PF, Wajner M, Wyse ATS (2010) Proline impairs energy metabolism in cerebral cortex of young rats. Metab Brain Dis 25:161–168

    Article  PubMed  CAS  Google Scholar 

  • Fighera MR, Queiroz CM, Stracke MP, Brauer MC, Gonzalez-Rodriguez LL, Frussa-Filho R, Wajner M, de Mello CF (1999) Ascorbic acid and alpha-tocopherol attenuate methylmalonic acid-induced convulsions. Neuroreport 10:2039–2043

    Article  PubMed  CAS  Google Scholar 

  • Flynn MP, Martin MC, Moore PT, Stafford JA, Fleming GA, Phang JM (1989) Type II hyperprolinaemia in a pedigree of Irish travellers (nomads). Arch Dis Child 64:1699–1707

    Article  PubMed  CAS  Google Scholar 

  • Gamaro GD, Streck EL, Matte C, Prediger ME, Wyse ATS, 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  PubMed  CAS  Google Scholar 

  • Geering K (2001) The functional role of beta subunits in oligomeric P-type ATPases. J Bioenerg Biomembr 33:425–438

    Article  PubMed  CAS  Google Scholar 

  • Grisar T, Guillaume D, Delgado-Escueta AV (1992) Contribution of Na+, K+-ATPase to focal epilepsy: a brief review. Epilepsy Res 12:141–149

    Article  PubMed  CAS  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. Neurosci Lett 254:141–144

    Article  PubMed  CAS  Google Scholar 

  • Jones DH, Matus AI (1974) Isolation of synaptic plasma membrane from brain by combined flotation-sedimentation density gradient centrifugation. Biochim Biophys Acta 356:276–287

    Article  PubMed  CAS  Google Scholar 

  • Jorgensen PL, Hakansson KO, Karlish SJ (2003) Structure and mechanism of Na+, K+-ATPase: functional sites and their interactions. Annu Rev Physiol 65:817–849

    Article  PubMed  CAS  Google Scholar 

  • Kaplan JH (2002) Biochemistry of Na+, K+-ATPase. Annu Rev Biochem 71:511–535

    Article  PubMed  CAS  Google Scholar 

  • Kessler A, Costabeber E, Dutra-Filho CS, Wyse AT, Wajner M, Wannmacher CM (2003) Proline reduces creatine kinase activity in the brain cortex of rats. Neurochem Res 28:1175–1180

    Article  PubMed  CAS  Google Scholar 

  • Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275

    PubMed  CAS  Google Scholar 

  • Mobasheri A, Avila J, Cozar-Castellano I, Brownleader MD, Trevan M, Francis MJ, Lamb JF, Martin-Vasallo P (2000) Na+, K+-ATPase isozyme diversity; comparative biochemistry and physiological implications of novel functional interactions. Biosci Rep 20:51–91

    Article  PubMed  CAS  Google Scholar 

  • Monteiro SC, Matte C, Delwing D, Wyse ATS (2005) Ovariectomy increases Na+, K+-ATPase, acetylcholine sterase and catalase in rat hippocampus. Mol Cell Endocrinol 236:9–16

    Article  PubMed  CAS  Google Scholar 

  • Monteiro SC, Mattos CB, Scherer EB, Wyse ATS (2007) Supplementation with vitamins E plus C or soy isoflavones in ovariectomized rats: effect on the activities of Na+, K+-ATPase and cholinesterases. Metab Brain Dis 22:156–171

    Article  PubMed  CAS  Google Scholar 

  • Moreira JC, Wannmacher CM, Costa SM, Wajner M (1989) Effect of proline administration on rat behavior in aversive and nonaversive tasks. Pharmacol Biochem Behav 32:885–890

    Article  PubMed  CAS  Google Scholar 

  • Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351–358

    Article  PubMed  CAS  Google Scholar 

  • Pari L, Murugavel P (2007) Diallyl tetrasulfide improves cadmium induced alterations of acetylcholinesterase, ATPases and oxidative stress in brain of rats. Toxicology 234:44–50

    Article  PubMed  CAS  Google Scholar 

  • Phang JM, Hu CA, Valle D (2001) Disorders of proline and hydroxyproline metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular bases of inherited disease, vol 3. McGraw-Hill, New York, pp 1821–1838

    Google Scholar 

  • Pontes ZE, Oliveira LS, Bavaresco CS, Streck EL, Dutra-Filho CS, Wajner M, Wannmacher CM, Wyse AT (1999) Proline administration decreases Na+, K+-ATPase activity in the synaptic plasma membrane from cerebral cortex of rats. Metab Brain Dis 14:265–272

    Article  PubMed  CAS  Google Scholar 

  • Pontes ZL, Oliveira LS, Franzon R, Wajner M, Wannmacher CM, Wyse AT (2001) Inhibition of Na+, K+-ATPase activity from rat hippocampus by proline. Neurochem Res 26:1321–1326

    Article  PubMed  CAS  Google Scholar 

  • Potts MB, Koh SE, Whetstone WD, Walker BA, Yoneyama T, Claus CP, Manvelyan HM, Noble-Haeusslein LJ (2006) Traumatic injury to the immature brain: inflammation, oxidative injury, and iron-mediated damage as potential therapeutic targets. NeuroRx 3:143–153

    Article  PubMed  CAS  Google Scholar 

  • Rose AM, Valdes R Jr (1994) Understanding the sodium pump and its relevance to disease. Clin Chem 40:1674–1685

    PubMed  CAS  Google Scholar 

  • Serluca FC, Sidow A, Mably JD, Fishman MC (2001) Partitioning of tissue expression accompanies multiple duplications of the Na+, K+-ATPase alpha subunit gene. Genome Res 11:1625–1631

    Article  PubMed  CAS  Google Scholar 

  • Siems WG, Hapner SJ, van Kuijk FJ (1996) 4-hydroxynonenal inhibits Na+, K+-ATPase. Free Radic Biol Med 20:215–223

    Article  PubMed  CAS  Google Scholar 

  • Stefanello FM, Chiarani F, Kurek AG, Wannmacher CM, Wajner M, Wyse ATS (2005) Methionine alters Na+, K+-ATPase activity, lipid peroxidation and nonenzymatic antioxidant defenses in rat hippocampus. Int J Dev Neurosci 23:651–656

    Article  PubMed  CAS  Google Scholar 

  • Streck EL, Zugno AI, Tagliari B, Sarkis JJ, Wajner M, Wannmacher CM, Wyse AT (2002) On the mechanism of the inhibition of Na+, K+-ATPase activity caused by homocysteine. Int J Dev Neurosci 20:77–81

    Article  PubMed  CAS  Google Scholar 

  • Therien AG, Blostein R (2000) Mechanisms of sodium pump regulation. Am J Physiol Cell Physiol 279:C541–C566

    PubMed  CAS  Google Scholar 

  • Tsakiris S, Deliconstantinos G (1984) Influence of phosphatidylserine on (Na+, K+)-stimulated ATPase and acetylcholinesterase activities of dog brain synaptosomal plasma membranes. Biochem J 220:301–307

    PubMed  CAS  Google Scholar 

  • Wetzel RK, Arystarkhova E, Sweadner KJ (1999) Cellular and subcellular specification of Na+, K+-ATPase alpha and beta isoforms in the postnatal development of mouse retina. J Neurosci 19:9878–9889

    PubMed  CAS  Google Scholar 

  • Wyse ATS, Bolognesi G, Brusque AM, Wajner M, Wannmacher CMD (1995) Na+,K+-ATPase activity in the synaptic plasma membrane from the cerebral cortex of rats subjected to chemically induced phenylketonuria. Med Sci Res 23:261–263

    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, Bavaresco CS, Bandinelli C, Streck EL, Franzon R, Dutra-Filho CS, Wajner M (2001) Nitric oxide synthase inhibition by L-NAME prevents the decrease of Na+, K+-ATPase activity in midbrain of rats subjected to arginine administration. Neurochem Res 26:515–520

    Article  PubMed  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  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported in part by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq - Brazil) and Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS).

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Angela T. S. Wyse.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ferreira, A.G.K., Stefanello, F.M., Cunha, A.A. et al. Role of antioxidants on Na+,K+-ATPase activity and gene expression in cerebral cortex of hyperprolinemic rats. Metab Brain Dis 26, 141–147 (2011). https://doi.org/10.1007/s11011-011-9243-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11011-011-9243-0

Keywords

Navigation