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Effect of ketogenic diet on nucleotide hydrolysis and hepatic enzymes in blood serum of rats in a lithium-pilocarpine-induced status epilepticus

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Abstract

The ketogenic diet (KD) is a high-fat and low-carbohydrate diet, used for treating refractory epilepsy in children. We have previously shown alterations in nucleotidase activities from the central nervous system and blood serum of rats submitted to different models of epilepsy. In this study we investigated the effect of KD on nucleotidase activities in the blood serum, as well if KD has any influence in the activity of liver enzymes such as alkaline phosphatase, aspartate aminotransferase, and alanine aminotransferase activities in Wistar rats submitted to the lithium–pilocarpine model of epilepsy. At 21 days of age, rats received an injection of lithium chloride and, 18–19 h later, they received an injection of pilocarpine hydrochloride for status epilepticus induction. The results reported herein show that seizures induced by lithium–pilocarpine elicit a significant increase in ATP hydrolysis and alkaline phosphatase activity, as well as a decrease in ADP hydrolysis and aspartate aminotransferase activity. The KD is a rigorous regimen that can be associated with hepatic damage, as shown herein by the elevated activities of liver enzymes and 5′-nucleotidase in blood serum. Further studies are necessary to investigate the mechanism of inhibition of lithium on nucleotidases in blood serum.

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References

  • Ballaban-Gil K, Callahan C, O’Dell C, Pappo M, Moshé S, Shinnar S (1998) Complications of the ketogenic diet. Epilepsia 39(7):744–748

    Article  CAS  PubMed  Google Scholar 

  • Barth RC, Steven AS, Robert WS (1979) Clinical internal medicine. Little Brown, England, pp 211–214

    Google Scholar 

  • Bonan CD, Walz R, Pereira GS, Worm PV, Battastini AM, Cavalheiro EA, Izquierdo I, Sarkis JJ (2000) Changes in synaptosomal ectonucleotidase activities in two rat models of temporal lobe epilepsy. Epilepsy Res 39(3):229–238

    Article  CAS  PubMed  Google Scholar 

  • Bradford MM (1976) A rapid and sensitive method for the quantification of microgram quantities of protein utilizing the principle of protein–dye binding. Anal Biochem 72:218–254

    Article  Google Scholar 

  • Bruno AN, Oses JP, Bonan CD, Walz R, Battastini AM, Sarkis JJ (2002) Increase of nucleotidase activities in rat blood serum after a single convulsive injection of pentylenetetrazol. Neurosci Res 43(3):283–288

    Article  CAS  PubMed  Google Scholar 

  • Bruno AN, Oses JP, Amaral O, Coitinho A, Bonan CD, Battastini AM, Sarkis JJ (2003) Changes in nucleotide hydrolysis in rat blood serum induced by pentylenetetrazol-kindling. Brain Res: Mol Brain Res 114(2):140–145

    Article  Google Scholar 

  • Cavalheiro EA (1995) The pilocarpine model of epilepsy. Ital J Neurol Sci 16:33–37

    Article  CAS  PubMed  Google Scholar 

  • Cavalheiro EA, Delrio FS, Turski WA, Calderazzo-Filho LS, Bortolotto ZA, Turski L (1987) The susceptibility of rats to pilocarpine-induced seizures is age-dependent. Brain Res 26:32–47

    Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Chen W, Guidotti G (2001) The metal coordination of sCD39 during ATP hydrolysis. BMC Biochem 2:9

    Article  CAS  PubMed  Google Scholar 

  • Dixon TF, Purdom M (1954) Serum 5′-nucleotidase. J Clin Pathol 7:341–343

    Article  CAS  PubMed  Google Scholar 

  • Dubé C, da Silva Fernandes MJ, Nehlig A (2001a) Age-dependent consequences of seizures and the development of temporal lobe epilepsy in the rat. Dev Neurosci 23:219–223

    Article  PubMed  Google Scholar 

  • Dubé C, Boyet S, Marescaux C, Nehlig A (2001b) Relationship between neuronal loss and interictal glucose metabolism during the chronic phase of the lithium–pilocarpine model of epilepsy in the immature and adult rat. Exp Neurol 167:227–241

    Article  PubMed  Google Scholar 

  • Dubyak GR (2000) Purinergic signaling at immunological synapses. J Auton Nerv Syst 81(1–3):64–68

    Article  CAS  PubMed  Google Scholar 

  • Giannini E, Risso D, Botta F, Chiarbonello B, Fasoli A, Malfatti F, Romagnoli P, Testa E, Ceppa P, Testa R (2003) Validity and clinical utility of the aspartate aminotransferase-alanine aminotransferase ratio in assessing disease severity and prognosis in patients with hepatitis C virus-related chronic liver disease. Arch Int Med 163(2):218–224

    Article  Google Scholar 

  • Goldberg DM (1973) 5′nucleotidase: recent advances in cell biology, methodology and clinical significance. Digestion 8:87–99

    Article  CAS  PubMed  Google Scholar 

  • Gutman AB (1959) Serum alkaline phosphatase activity in diseases of the skeletal and hepatobiliary systems. A consideration of the current status. Am J Med 27:875–901

    Article  CAS  PubMed  Google Scholar 

  • Hill PG, Sammons HG (1967) An assessment of 5′nucleotidase as a liver function test. Q J Med 36:457–468

    CAS  PubMed  Google Scholar 

  • Honchar MP, Olney JW, Sherman WR (1983) Systemic cholinergic agents induce seizures and brain damage in lithium-treated rats. Science 220:323–325

    Article  CAS  PubMed  Google Scholar 

  • Janigro D (1999) Blood–brain barrier, ion homeostatis and epilepsy: possible implications towards the understanding of ketogenic diet mechanisms. Epilepsy Res 37:223–232

    Article  CAS  PubMed  Google Scholar 

  • Leite JP, Garcia-Cairasco N, Cavalheiro EA (2002) New insights from the use of pilocarpine and kainate models. Epilepsy Res 50:93–103

    Article  CAS  PubMed  Google Scholar 

  • Ludwig S, Kaplowitz N (1980) Effect of pyridoxine deficiency on serum and liver transaminases in experimental liver injury in the rat. Gastroenterology 79(3):545–549

    CAS  PubMed  Google Scholar 

  • Kang HC, Chung DE, Kim DW, Kim HD (2004) Early- and late-onset complications of the ketogenic diet for intractable epilepsy. Epilepsia 45(9):1116–1123

    Article  PubMed  Google Scholar 

  • Masino SA, Geiger JD (2008) Are purines mediators of the anticonvulsivant/neuroprotective effects of ketogenic diet? Trends Neurosci 31(6):273–278

    Article  CAS  PubMed  Google Scholar 

  • Masino SA, Geiger JD (2009) The ketogenic diet and epilepsy: is adenosine the missing link? Epilepsia 50(2):332–333

    Article  PubMed  Google Scholar 

  • Morrisett RA, Jope RS, Snead OC (1987a) Effects of drugs on the initiation and maintenance of status epilepticus induced by administration of pilocarpine to lithium-pretreated rats. Exp Neurol 97:193–200

    Article  CAS  PubMed  Google Scholar 

  • Morrisett RA, Jope RS, Snead OC (1987b) Status epilepticus is produced by administration of cholinergic agonists to lithium-treated rats: comparison with kainic acid. Exp Neurol 98(3):594–605

    Article  CAS  PubMed  Google Scholar 

  • Neuschwander-Tetri BA, Nicholson C, Tracy WLD, Jr TF (1996) Cholestatic liver injury down-regulates hepatic glutathione synthesis. J Surg Res 63(2):447–451

    Article  CAS  PubMed  Google Scholar 

  • Oses JP, Cardoso CM, Germano RA, Kirst IB, Rücker B, Fürstenau CR, Wink MR, Bonan CD, Battastini AM, Sarkis JJF (2004) Soluble NTPDase: an additional system of nucleotide hydrolysis in rat blood serum. Life Sci 74(26):3275–3284

    Article  PubMed  Google Scholar 

  • Oses JP, Viola GG, de Paula CG, Júnior VH, Hansel G, Böhmer AE, Leke R, Bruno AN, Bonan CD, Bogo MR, Portela LV, Souza DO, Sarkis JJ (2007) Pentylenetetrazol kindling alters adenine and guanine nucleotide catabolism in rat hippocampal slices and cerebrospinal fluid. Epilepsy Res 75(2–3):104–111

    Article  CAS  PubMed  Google Scholar 

  • Pagani F, Panteghini M (2001) 5′-nucleotidase in the detection of increased activity of the liver form of alkaline phosphatase in serum. Clin Chem 47(11):2046–2048

    CAS  PubMed  Google Scholar 

  • Reichling J, Kaplan M (1988) Clinical use of serum enzymes in liver disease. Dig Dis Sci 33(12):1601–1614

    Article  CAS  PubMed  Google Scholar 

  • Reitman S, Frankel SA (1957) Colorimetric method for the determination of serum glutamic oxaloacetic and glutamic pyruvic transaminases. Am J Clin Pathol 28:56–63

    CAS  PubMed  Google Scholar 

  • Rigoulot MA, Koning E, Ferrandon A, Nehlig A (2004) Neuroprotective properties of topiramate in the lithium–pilocarpine model of epilepsy. J Pharmacol Exp Ther 308(2):787–795

    Article  CAS  PubMed  Google Scholar 

  • Roberts WM (1930) Variations in the phosphatase activity in the blood in disease. Br J Exp Pathol 11:90–95

    CAS  Google Scholar 

  • Roy AV (1970) Rapid method for determining alkaline phosphatase activity in serum with thymolphthalein monophosphate. Clin Chem 16(5):431–436

    CAS  PubMed  Google Scholar 

  • Schwartzkroin PA (1999) Mechanisms underlying the anti-epileptic efficacy of the ketogenic diet. Epilepsy Res 37:171–180

    Article  CAS  PubMed  Google Scholar 

  • Song CS, Kappas A, Bodansky O (1969) 5′nucleotidase of plasma membranes of the rat liver: studies and subcellular distribution. Ann N Y Acad Sci 166:565–573

    Article  CAS  PubMed  Google Scholar 

  • Stafstrom CE (2004) Dietary approaches to epilepsy treatment: old and new options on the menu. Epilepsy Curr 4(6):215–222

    Article  PubMed  Google Scholar 

  • Thompson MD, Killoran A, Percy ME, Nezarati M, David EC, Cole DEC, Hwang PA (2006) Hyperphosphatasia with neurologic deficit: a pyridoxine-responsive seizure disorder. Pediatr Neurol 34(4):303–307

    Article  PubMed  Google Scholar 

  • Todorov LD, Mihaylova-Todorova S, Westfall TD, Sneddon P, Kennedy C, Bjur RA, Westfall DP (1997) Neuronal release of soluble nucleotidases and their role in neurotransmitter inactivation. Nature 387:76–79

    Article  CAS  PubMed  Google Scholar 

  • Turski WA (2000) Pilocarpine-induced seizures in rodents-17 years on. Polish J Pharmacol 52:63–65

    CAS  Google Scholar 

  • Turski L, Ikonomidou C, Turski WA, Bortolotto ZA, Cavalheiro EA (1989) Review: cholinergic mechanisms and epileptogenesis. The seizures induced by pilocarpine: a novel experimental model of intractable epilepsy. Synapse 3:154–171

    Article  CAS  PubMed  Google Scholar 

  • Walton NY, Nagy AK, Treiman DM (1998) Altered residual ATP content in rat braincortex subcellular fractions following status epilepticus induced by lithium and pilocarpine. J Mol Neurosci 11(3):233–242

    Article  CAS  PubMed  Google Scholar 

  • Wilder RM (1921) The effects of ketonemia on the course of epilepsy. Mayo Clin Proc 2:307–308

    Google Scholar 

  • Yegutkin GG (1997) Kinetic analysis of enzymatic hydrolysis of ATP in human and rat blood serum. Biochemistry-Moscow 62:724–728

    Google Scholar 

  • Yegutkin GG, Bodin P, Burnstock G (2000) Effect of shear stress on the release of soluble ecto-enzymes ATPase and 5′-nucleotidase along with endogenous ATP from vascular endothelial cells. Brit J Pharmacol 129(5):921–926

    Article  CAS  Google Scholar 

  • Zhao Q, Stafstrom CE, Fu DD, Hu Y, Holmes GL (2004) Detrimental effects of the ketogenic diet on cognitive function in rats. Pediatr Res 5(3):498–506

    Article  Google Scholar 

  • Zhou SL, Gordon RE, Bradbury M, Stump D, Kiang CL, Berk PD (1998) Ethanol up-regulates fatty acid uptake and plasma membrane expression and export of mitochondrial aspartate aminotransferase in HepG2 cells. Hepatology 27(4):1064–1074

    Article  CAS  PubMed  Google Scholar 

  • Zimmermann H (2001) Ectonucleotidases: some recent developments and a note on nomenclature. Drug Dev Res 52:44–56

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). Vanessa Gass da Silveira was recipient of a CNPq fellowship. We thank Jean Pierre Oses for the critical reading of the manuscript.

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Authors and Affiliations

  1. Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600, Anexo, 90035-003, Porto Alegre, RS, Brazil

    Vanessa Gass da Silveira, Giana de Paula Cognato, Alexandre Pastoris Müller, Fabrício Figueiró, Marcos L. Santos Perry & Ana Maria Oliveira Battastini

  2. Departamento de Biologia Celular e Molecular, Faculdade de Biociências, Pontifícia Universidade Católica do Rio Grande do Sul, Avenida Ipiranga, 6681, Caixa Postal 1429, 90619-900, Porto Alegre, RS, Brazil

    Carla Denise Bonan

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  1. Vanessa Gass da Silveira
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  2. Giana de Paula Cognato
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  3. Alexandre Pastoris Müller
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Correspondence to Ana Maria Oliveira Battastini.

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da Silveira, V.G., de Paula Cognato, G., Müller, A.P. et al. Effect of ketogenic diet on nucleotide hydrolysis and hepatic enzymes in blood serum of rats in a lithium-pilocarpine-induced status epilepticus. Metab Brain Dis 25, 211–217 (2010). https://doi.org/10.1007/s11011-010-9198-6

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