Skip to main content
SpringerLink
Log in

Effect of hypoxanthine, antioxidants and allopurinol on cholinesterase activities in rats

  • Neurology and Preclinical Neurological Studies - Original Article
  • Published:
Journal of Neural Transmission Aims and scope Submit manuscript

Abstract

In the present study, we investigate the in vitro effect of hypoxanthine on acetylcholinesterase and butyrylcholinesterase activities in the hippocampus, striatum, cerebral cortex and serum of 15-, 30- and 60-day-old rats. Furthermore, we also evaluated the influence of antioxidants, namely α-tocopherol (trolox) and ascorbic acid, and allopurinol to investigate the possible participation of free radicals and uric acid in the effects elicited by hypoxanthine on these parameters. Acetylcholinesterase and butyrylcholinesterase activities were determined according to Ellman et al. (Biochem Pharmacol 7:88–95, 1961), with some modifications. Hypoxanthine (10.0 μM), when added to the incubation medium, enhanced acetylcholinesterase activity in the hippocampus and striatum of 15- and 30-day-old rats and reduced butyrylcholinesterase activity in the serum of 60-day-old rats. The administration of allopurinol and/or antioxidants partially prevented the alterations caused by hypoxanthine in acetylcholinesterase and butyrylcholinesterase activities in the cerebrum and serum of rats. Data indicate that hypoxanthine alters cholinesterase activities, probably through free radicals and uric acid production since the alterations were prevented by the administration of allopurinol and antioxidants. It is presumed that the cholinesterase system may be associated, at least in part, with the neuronal dysfunction observed in patients affected by Lesch–Nyhan disease. In addition, although extrapolation of findings from animal experiments to humans is difficult, it is conceivable that these vitamins and allopurinol might serve as an adjuvant therapy to avoid progression of brain damage in patients affected by this disease.

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

Access this article

Log in via an institution

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
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • Bajgar J (2004) Organophosphates/nerve agent poisoning: mechanism of action, diagnosis, prophylaxis, and treatment. Adv Clin Chem 38:151–216

    Article  CAS  PubMed  Google Scholar 

  • Bavaresco CS, Chiarani F, Matte C, Wajner M, Netto CA, Wyse ATS (2005) Effect of hypoxanthine on Na+, K+-ATPase activity and some parameters of oxidative stress in rat striatum. Brain Res 1041:198–204

    Article  CAS  PubMed  Google Scholar 

  • Bavaresco CS, Chiarani F, Duringon E, Ferro MM, Cunha CD, Netto CA, Wyse ATS (2007a) Intrastriatal injection of hypoxanthine reduces striatal serotonin content and impairs spatial memory performance in rats. Metab Brain Dis 22:67–76

    Article  CAS  PubMed  Google Scholar 

  • Bavaresco CS, Chiarani F, Wannmacher CM, Netto CA, Wyse ATS (2007b) Intrastriatal hypoxanthine reduces Na(+), K (+)-ATPase activity and induces oxidative stress in the rats. Metab Brain Dis 22:1–11

    Article  CAS  PubMed  Google Scholar 

  • Bavaresco CS, Chiarani F, Kolling J, Ramos DB, Cognato GP, Bonan CD, Bogo MR, Sarkis JJ, Netto CA, Wyse AT (2008) Intrastriatal injection of hypoxanthine alters striatal ectonucleotidase activities: a time-dependent effect. Brain Res 1239:198–206

    Article  CAS  PubMed  Google Scholar 

  • Benzi G, Moretti A (1998) Is there a rationale for the use of acetylcholinesterase inhibitors in the therapy of Alzheimer’s disease? Eur J Pharmacol 346:1–13

    Article  CAS  PubMed  Google Scholar 

  • Bradford MM (1976) A rapid and sensitive method for the quantification of micrograms quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254

    Article  CAS  PubMed  Google Scholar 

  • Burton GW, Wronska U, Stone L, Foster DO, Ingold KU (1990) Biokinetics of dietary RRR-α-tocopherol in the male guinea-pig at three dietary levels of vitamin C and two levels of vitamin E. Lipids 25:199–210

    Article  CAS  PubMed  Google Scholar 

  • Darvesh S, Hopkins D, Geula C (2003) Neurobiology of butyrylcholinesterase. Nat Rev Neurobiol 4:131–138

    Article  CAS  Google Scholar 

  • Delwing D, Chiarani F, Delwing D, Bavaresco CS, Wannmacher CMD, Wajner M, Wyse ATS (2003) Proline reduces acetylcholinesterase activity in cerebral cortex of rats. Metab Brain Dis 18:79–86

    Article  CAS  PubMed  Google Scholar 

  • Dubois B, Pillon B (1995) Do cognitive changes of Parkinsons disease result from dopamine depletion? J Neural Transm 45:27–34

    CAS  Google Scholar 

  • Ellman GL, Courtney KD, Andres V Jr, Feather-Stone RM (1961) A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 7:88–95

    Article  CAS  PubMed  Google Scholar 

  • Fujimori S (1996) PRPP synthetase superactivity. Nihon Rinsho 54:3309–3314

    CAS  PubMed  Google Scholar 

  • Garcia-Alloza M, Gil-Bea FJ, Diez-Ariza M, Chen CP, Francis PT, Lasheras B, Ramirez MJ (2005) Cholinergic–serotonergic imbalance contributes to cognitive and behavioral symptoms in Alzheimer’s disease. Neuropsychologia 43:442–449

    Article  CAS  PubMed  Google Scholar 

  • Geula C, Darvesh S (2004) Butyrylcholinesterase, cholinergic neurotransmission and the pathology of Alzheimer’s disease. Drugs Today 40:711–721

    Article  CAS  PubMed  Google Scholar 

  • Geula C, Mesulam MM, Kuo CC, Tokuno H (1995) Postnatal development of cortical acetylcholinesterase-rich neurons in the rat brain: permanent and transient patterns. Exp Neurol 134:157–178

    Article  CAS  PubMed  Google Scholar 

  • Hagan JJ, Alpert JE, Morris RG, Iversen SD (1983) The effects of central catecholamine depletions on spatial learning in rats. Behav Brain Res 9:83–104

    Article  CAS  PubMed  Google Scholar 

  • Halliwell B, Gutteridge JMC (1999) Free radicals in biology and medicine. Oxford University Press, London

    Google Scholar 

  • Harkness RA, McCreanor GM, Watts RW (1988) Lesch–Nyhan syndrome and its pathogenesis: purine concentrations in plasma and in urine with metabolite profiles in CSF. J Inher Metab Dis 11:239–252

    Article  CAS  PubMed  Google Scholar 

  • Henderson JF (1968) Possible functions of hypoxanthine–guanine phosphoribosyltransferase and their relation to the biochemical pathology of the Lesch–Nyhan syndrome. Fed Proc 27:1075–1077

    CAS  PubMed  Google Scholar 

  • Henderson VW, Watt L, Buckwalter JG (1996) Cognitive skills associated with estrogen replacement in women with Alzheimer’s disease. Psychoneuroendocrinology 21:421–430

    Article  CAS  PubMed  Google Scholar 

  • Hong YS, Lee MJ, Kim KH, Lee SH, Lee YH, Kim BG, Jeong B, Yoon HR, Nishio H, Kim JY (2004) The C677 mutation in methylene tetrahydrofolate reductase gene: correlation with uric acid and cardiovascular risk factors in elderly Korean men. J Korean Med Sci 19:209–213

    Article  CAS  PubMed  Google Scholar 

  • Jarasch ED, Grund C, Bruder G, Heid HW, Keenan TW, Franke WW (1981) Localization of xanthine oxidase in mammary-gland epithelium and capillary endothelium. Cell 25:67–82

    Article  CAS  PubMed  Google Scholar 

  • Jinnah HA, Friedmann T (2001) Lesch Nyhan disease and it variants. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular bases of inherited disease. McGraw-Hill, New York, pp 2537–2569

    Google Scholar 

  • Klein AS, Joh JW, Rangan U, Wang D, Bulkley GB (1996) Allopurinol: discrimination of antioxidant from enzyme inhibitory activities. Free radical. Biol Med 21:713–717

    CAS  Google Scholar 

  • Lesch M, Nyhan WL (1964) A familial disorder of uric acid metabolism and central nervous system function. Am J Med 36:561–570

    Article  CAS  PubMed  Google Scholar 

  • Lloyd KG, Hornykiewicz O, Davidson L, Shannak K, Farley I, Goldstein M, Shibuya M, Kelley WN, Fox IH (1981) Biochemical evidence of dysfunction of brain neurotransmitters in the Lesch–Nyhan syndrome. N Engl J Med 305:1106–1111

    Article  CAS  PubMed  Google Scholar 

  • Loewi O (1921) Uberhumerole ubertragbarkeit der herznervenwirkung. I Mitteilung Pflugers Arch 189:239–242

    Article  Google Scholar 

  • Massoulie J, Pezzementi L, Bon S, Krejci E, Vallette FM (1993) Molecular and cellular biology of cholinesterases. Prog Neurobiol 41:31–91

    Article  CAS  PubMed  Google Scholar 

  • Melo JB, Agostinho P, Oliveira CR (2003) Involvement of oxidative stress in the enhancement of acetylcholinesterase activity induced by amyloid beta-peptide. Neurosci Res 45:117–127

    Article  CAS  PubMed  Google Scholar 

  • Mesulam MM, Guillozet A, Shaw P, Levey A, Duysen EG, Lockridge O (2002) Acetylcholinesterase knockouts establish central cholinergic pathways and can use butyrylcholinesterase to hydrolyse acetylcholine. Neuroscience 170:627–639

    Article  Google Scholar 

  • Mura A, Feldon J (2003) Spatial learning in rats is impaired after degeneration of the nigrostriatal dopaminergic system. Mov Disord 18:860–871

    Article  PubMed  Google Scholar 

  • Myhrer T (2000) Neurotransmitter systems involved in learning and memory in the rat: a meta-analysis based on studies of four behavioral tasks. Brain Res Rev 41:268–287

    Article  Google Scholar 

  • Nyhan WL (2005) Inherited hyperuricemic disorders. Contrib Nephrol 147:22–34

    CAS  PubMed  Google Scholar 

  • Nyhan WL, Oliver WJ, Lesch M (1965) A familial disorder or uric acid metabolism and central nervous system function II. J Pediatr 67:439–444

    Google Scholar 

  • O′Brien KK, Saxby BK, Ballard CG, Grace J, Harrington F, Ford GA, O′Brien JT, Swan AG, Fairbairn AF, Wesnes K, del Ser T, Edwardson JA, Morris CM, McKeith IG (2003) Regulation of attention and response to therapy in dementia by butyrylcholinesterase. Pharmacogenetics 13:231–239

    Article  PubMed  Google Scholar 

  • Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E (1999) Mild cognitive impairment: clinical characterization and outcome. Arch Neurol 56:303–308

    Article  CAS  PubMed  Google Scholar 

  • Puig JG, Mateos FA (1993) The biochemical basis of HGPRT deficiency. In: Gresser U (ed) Molecular genetics, biochemistry and clinical aspects of inherited disorders of purine and pyrimidine metabolism. Springer, New York, pp 12–26

    Chapter  Google Scholar 

  • Rijksen G, Staal GEJ, Van der Vlist MJM, Beerner FA, Troost J, Gutensohn W, Van Laarhoven JPRM, De Bruyn CHMM (1981) Partial hypoxanthine-guanine phosphoribosyl transferase deficiency with full expression of the Lesch–Nyhan syndrome. Hum Genet 57:39–47

    Article  CAS  PubMed  Google Scholar 

  • Rosenbloom RM, Henderson JF, Caldwell IC, Kelley WN, Seegmiller JE (1967) Inherited disorder of purine metabolism. JAMA 202:175–177

    Article  CAS  PubMed  Google Scholar 

  • Saito Y, Takashima S (2000) Neurotransmitter changes in the pathophysiology of Lesch–Nyhan syndrome. Brain Dev 22:S122–S131

    Article  PubMed  Google Scholar 

  • Silva CG, Bueno ARF, Schuck PF, Leipnitz G, Ribeiro CA, Rosa RB, Dutra Filho CS, Wyse AT, Wannmacher CM, Wajner M (2004) Inhibition of creatine kinase activity from rat cerebral cortex by D-2-hydroxyglutaric acid in vitro. Neuchem Int 44:45–52

    Google Scholar 

  • Silver A (1974) The biology of cholinesterases. North-Holland, Amsterdam

    Google Scholar 

  • Srivastava T, O’Neill JP, Dasouki M, Simckes AM (2002) Childhood hyperuricemia and acute renal failure resulting from a missense mutation in the HPRT gene. Am J Med Gene 108:219–222

    Article  Google Scholar 

  • Stefanello FM, Monteiro SC, Matté C, Scherer EBS, Netto CS, Wyse ATS (2007) Hypermethioninemia increases cerebral acetylcholinesterase activity and impairs memory in rats. Neurochem Res 32:1868–1874

    Article  CAS  PubMed  Google Scholar 

  • Torres RJ, Puig JG (2007) Hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency: Lesch–Nyhan syndrome. Orphanet J Rare Dis 8:48

    Article  Google Scholar 

  • Tsakiris S, Angelogianni P, Schulpis KH, Stavridis JC (2000) Protective effect of l-phenylalanine on rat brain acetylcholinesterase inhibition induced by free radicals. Clin Biochem 33:103–106

    Article  CAS  PubMed  Google Scholar 

  • Wessler I, Kirkpatrick CJ (2008) Acetylcholine beyond neurons: the non-neuronal cholinergic system in humans. Br J Pharmacol 154:1558–1571

    Article  CAS  PubMed  Google Scholar 

  • Wyse ATS, Zugno AI, Streck EL, Matte C, Calcagnotto T, Wannmacher CMD, 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 

  • Wyse ATS, Stefanello FM, Chiarani F, Delwing D, Wannmacher CMD, Wajner M (2004) Arginine administration decreases cerebral cortex acetylcholinesterase and serum butyrylcholinesterase probably by oxidative stress induction. Neurochem Res 29:385–389

    Article  CAS  PubMed  Google Scholar 

  • Yamamoto T, Moriwaki Y, Takahashi S (2005) Effect of ethanol on metabolism of purine bases (hypoxanthine, xanthine, and uric acid). Clin Chim Acta 356:35–57

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from Universidade Regional de Blumenau and PIBIC/CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico).

Author information

Authors and Affiliations

  1. Departamento de Ciências Naturais, Centro de Ciências Exatas e Naturais, Universidade Regional de Blumenau, Rua Antônio da Veiga, 140, Blumenau, SC, CEP 89012-900, Brazil

    José Geraldo Pereira da Cruz & Débora Delwing-Dal Magro

  2. Departamento de Medicina, Universidade da Região de Joinville (UNIVILLE), Campus Universitário, Bairro Bom Retiro, Joinville, SC, CEP 89201-972, Brazil

    Daniela Delwing-de Lima

  3. Departamento de Medicina, Centro de Ciências da Saúde, Universidade Regional de Blumenau, Rua Antônio da Veiga, 140, Blumenau, SC, CEP 89012-900, Brazil

    Morgahna Nathalie Wamser, Eduardo Fernandes Leite & Vinícius Vialle Ferreira

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

    Angela T. S. Wyse

Authors
  1. Morgahna Nathalie Wamser
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eduardo Fernandes Leite
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Vinícius Vialle Ferreira
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Daniela Delwing-de Lima
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. José Geraldo Pereira da Cruz
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Angela T. S. Wyse
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Débora Delwing-Dal Magro
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Débora Delwing-Dal Magro.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wamser, M.N., Leite, E.F., Ferreira, V.V. et al. Effect of hypoxanthine, antioxidants and allopurinol on cholinesterase activities in rats. J Neural Transm 120, 1359–1367 (2013). https://doi.org/10.1007/s00702-013-0989-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00702-013-0989-x

Keywords

Search

Navigation