Abstract
Homocystinuria is an inborn error of sulphur amino acid metabolism, resulting in accumulation of tissue homocysteine. This disease is characterized predominantly by vascular and nervous system dysfunction. In the present study we investigated the in vitro effects of homocysteine, the main metabolite accumulated in homocystinuria, on platelet Na+,K+-ATPase and serum butyrylcholinesterase (BuChE) activities of young rats. Platelet and serum of 29-day-old Wistar rats were incubated in the absence (control) or presence of homocysteine (0.01–0.5 mM). Results showed that Na+,K+-ATPase and BuChE activities were significantly inhibited by homocysteine. It is proposed that inhibition of Na+,K+-ATPase and BuChE activities might be one useful peripheral marker for the neurotoxic effects of homocysteine.
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Allen, I.C., Grieve, A., and Griffiths, R. (1986). Differential changes in the content of amino acid neurotransmitters in discrete regions of the rat brain prior to the onset and during the course of homocysteine-induced seizures. J. Neurochem. 46:1582-1592.
Bedin, M., Estrella, C.H.G., Duarte, D.V., Ponzi, D., Dutra-Filho, C.S., Wyse, A.T.S., Wajner, M., and Wannmacher, C.M.D. (2000). Platelet Na+,K+-ATPase activity as a possible peripheral marker of neurotoxicity effects of phenylalanine in phenylketonuria. Metab. Brain Dis. 15:115-121.
Bedin, M., Estrella, C.H.G., Ponzi, D., Duarte, D.V., Dutra-Filho, C.S., Wyse, A.T.S., Wajner, M., and Wannmacher, C.M.D. (2001). Reduced Na+,K+-ATPase activity in erythrocyte membranes from patients with phenylketonuria. Pediatr. Res. 50:56-60.
Biegon, A., Weizman, A., Karp, L., Ram, A., Tiano, S., and Wolff, M. (1987). Serotonin 5-HT2 receptor binding on blood platelets—A peripheral marker for depression? Life Sci. 41:2485-2492.
Bradford, M.M. (1976). A rapid and sensitive method for the quantification of microgram quantities of protein utilizing the principle of protein-dye-binding. Anal. Biochem. 72:248-254.
Chan, A.Y., Shinde, R., Chow, C.C., Cockram, C.S., and Swaminathan, R. (2001). Platelet Na,K-adenosine triphosphatase as a tissue marker of hyperthyroidism. Metabolism 50:1393-1396.
Chan, K.M., Delfer, D., and Junger, K.D. (1986). A direct colorimetric assay for Ca2 +-stimulated ATPase activity. Anal. Biochem. 157:375-380.
Chatonnet, A., and Lockridge, O. (1989). Comparison of butyrylcholinesterase and acetylcholinesterase. Biochem. J. 260:625-634.
Cokugras, A.N., and Teczan, F. (1997). Amitriptyline: A potent inhibitor of butyrylcholinesterase from human serum. Gen. Pharmacol. 29:835-838.
Cummings, J.L. (2000). The role of cholinergic agents in the management of behavioral disturbances in Alzheimer's disease. Int. J. Neuropsychopharmacol. 3:21-29.
De Franchis, R., Sperandeo, M.P., Sebastio, G., and Andria, G. (1998). Clinical aspects of cystathionine β-synthase: How wide is the spectrum? Eur. J. Pediatr. 157(Suppl. 2):S67-S70.
Di Luca, M., Colciaghi, F., Pastorino, L., Borroni, B., Padovani, A., and Cattabeni, F. (2000). Platelets as a peripheral district where to study pathogenetic mechanisms of Alzheimer disease: The case of amyloid precursor protein. Eur. J. Pharmacol. 405:277-283.
Dubovy, P. (1991). Histochemical study of non-specific cholinesterase in PNS as a tool for the recognition of relationships between axon and Schwann cells. In Cholinesterases, Structure, Function, Mechanism, Genetics, and Cell Biology, pp. 122.
Dubovy, P., and Haninec, P. (1990). Non-specific cholinesterase activity of the developing peripheral nerves and its possible function in cells in intimate contact with growing axons of chick embryo. Ont. J. Dev. Neurosci. 8:589-602.
Ekholm, M. (2001). Predicting relative binding free energies of substrate and inhibitors of acetylcholin-and butyrylcholinesterases. J. Mol. Struct. 572:25-34.
Ellman, G.L., Courtney, K.D., Andres, V., and Featherstone, R.M. (1961). A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem. Pharmacol. 7:88-95.
El-Mallakh, R.S., and Wyatt, R.J. (1995). The Na+,K+-ATPase hypothesis for bipolar illness. Biol. Psychiatry 37:235-244.
Erecinska, M., and Silver, I.A. (1994). Ions and energy in mammalian brain. Prog. Neurobiol. 16:37-71.
Ferrarese, C., Begni, B., Canevari, C., Zoia, C., Piolti, R., Frigo, M., Appollonio, I., and Frattola, L. (2000). Glutamate uptake is decreased in platelets from Alzheimer's disease patients. Ann. Neurol. 47:641-643.
Fossi, M.C., Leonzio, C., Massi, A., Lari, L., and Casini, S. (1992). Serum esterase inhibition in birds: A nondestructive biomarker to assess organophosphorus and carbamate contamination. Arch. Environ. Contam. Toxicol. 23:99-104.
Fowler, B. (1997). Disorder of homocysteine metabolism. J. Inherit. Metab. Dis. 20:270-285.
Gómez-Ramos, P., and Morán, M.A. (1997). Ultraestructural localization of butyrylcholinesterase in senile plaques in the brains of aged and Alzheimer's disease patients. Mol. Chem. Neuropathol. 30:161-173.
Hantgan, R.R. (1984). A study of the kinetics of ADP-triggered platelet shape change. Blood 64:896-906.
Harel, M., Schalk, I., Ehret-Sabatier, L., Bouet, F., Goeldner, M., Hirth, C., Axelsen, P., Silman, I., and Sussman, J.L. (1993). Quaternary ligand binding to aromatic residues in the active-site gorge of acetylcholinesterase. Proc. Natl. Acad. Sci. U.S.A. 90:9031-9035.
Hattori, N., Kitagawa, K., Higashida, T., Yagyu, K., Shimohama, S., Wataya, T., Perry, G., Smith, M.A., and Inagaki, C. (1998). Cl(-ATPase and Na+/K+-ATPase activities in Alzheimer's disease brains. Neurosci. Lett. 254:141-144.
Jaganathan, L., and Boopathy, R. (2000). Distinct effect of benzalkonium chloride on the esterase and aryl acylamidase activities of butyrylcholinesterase. Bioorg. Chem. 28:242-251.
Karczmar, A. (1998). Anticholinesterase: Dramatic aspects of their use and misuse. Neurochem. Int. 32:401-411.
Kim, W.-K., and Pae, Y.-S. (1996). Involvement of N-methyl-d-aspartate receptor and free radical in homocysteine-mediated toxicity on rat cerebellar granule cells in culture. Neurosci. Lett. 216:117-120.
Kraus, J.P. (1998). Biochemistry and molecular genetics of cystathionine β-synthase deficiency. Eur. J. Pediatr. 157(Suppl. 2):S50-S53.
Kubová, H., Folbergrová, J., and Mares, P. (1995). Seizures induced by homocysteine in rats during ontogenesis. Epilepsia 36:750-756.
Kuhn, W., Roebroek, R., Blom, H., van Oppenraaij, D., Przuntek, H., Kretschmer, A., Buttner, T., Woitalla, D., and Muller, T. (1998). Elevated plasma levels of homocysteine in Parkinson's disease. Eur. Neurol. 40:225-227.
Law, A., Gauthier, S., and Quirion, R. (2001). Say NO Alzheimer's disease: The putative links between nitric oxide and dementia of the Alzheimer's type. Brain Res. Rev. 35:73-96.
Leblhuber, F., Walli, J., Artner-Dworzak, E., Vrecko, K., Widner, B., Reibnegger, G., and Fuchs, D. (2000). Hiperhomocysteinemia in dementia. J. Neural Transm. 107:343-353.
Lees, G.J. (1993). Contributory mechanisms in the causation of neurodegenerative disorders. Neuroscience 54:287-322.
Mack, A., and Robitzki, A. (2000). The key role of butyrylcholinesterase during neurogenesis and neural disorders: An antisense—5'butyrylcholinesterase—DNA study. Prog. Neurobiol. 60:607-628.
Massoulié, J., Pezzementi, L., Bom, S., Krejci, E., and Vallete, F.-M. (1993). Molecular and cellular biology of cholinesterases. Prog. Neurobiol. 41:31-91.
Mattson, M.P., Kruman, I.I., and Duan, W. (2002). Folic acid and homocysteine in age-related disease. Ageing Res. Rev. 1:95-111.
Mcllwain, H., and Poll, J.D. (1985). Interaction between adenosine generated endogenously in neocortical tissues, and homocysteine and its thiolactone. Neurochem. Int. 7:103-105.
Mesulam, M.M., Guillozet, A., Shaw, P., Levey, A., Duysen, E.G., and Lockridge, O. (2001). Preservation of cholinergic systems in AChE knockouts and the role of BChE in acetylcholine hydrolysis. Soc. Neurosci. Abstr. 27:2565.
Mesulam, M.M., Guillozet, A., Shaw, P., Levey, A., Duysen, E.G., and Lockridge, O. (2002). Acetylcholinesterase knockouts establish central cholinergic pathways and can use butyrylcholinesterase to hydrolyze acetylcholine. Neuroscience 110:627-639.
Mudd, S.H., Levy, H.L., and Skovby, F. (2001). Disorders of transsulfuration. In (C.R. Scriver, A.L. Beaudet, W.S. Sly, and D. Valle, eds.), The Metabolic and Molecular Bases of Inherited Disease, Vol. 2, McGraw-Hill, New York, pp. 1279-1327.
Padovani, A., Pastorino, L., Borroni, B., Colciaghi, F., Rozzini, L., Monastero, R., Perez, J., Pettenati, C., Mussi, M., Parrinello, G., Cottini, E., Lenzi, G.L., Trabucchi, M., Cattabeni, F., and Di Luca, M. (2001). Amyloid precursor protein in platelets: A peripheral marker for the diagnosis of sporadic AD. Neurology 57:2243-2248.
Rasmussen, A., Christensen, J., Clemmensen, P.M., Dalsgaard, N.J., Dam, H., Hindberg, I., Lunde, M., Plenge, P., and Mellerup, E. (2003). Platelet serotonin transporter in stroke patients. Acta Neurol. Scand. 107:150-153.
Reis, E.A., Zugno, A.I., Franzon, R., Tagliari, B., Matté, C., Lammers, M.L., Netto, C.A., and Wyse, A.T.S. (2002). Pretreatment with vitamins E and C prevent the impairment of memory caused by homocysteine administration in rats. Metab. Brain Dis. 17:211-217.
Seshadri, S., Beiser, A., Selhub, J., Jacques, P.F., Rosemberg, I.H., D'Agostino, R.B., Wilson, P.W.F., and Wolf, P.A. (2002). Plasma homocysteine as a risk for dementia and Alzheimer's disease. N. Engl. J. Med. 346:476-483.
Signorello, M.G., Pascale, R., and Leoncini, G. (2002). Effect of homocysteine on arachidonic acid release in human platelets. Eur. J. Clin. Invest. 32:279-284.
Stahl, S.M. (1985). Peripheral models for the study of neurotransmitter receptors in man. Psychopharmacol. Bull. 21:663-671.
Stefanello, F.M., Zugno, A.I., Wannmacher, C.M.D., Wajner, M., and Wyse, A.T.S. (in press). Homocysteine inhibits butyrylcholinesterase activity in rat serum. Metab. Brain Dis.
Streck, E.L., Delwing, D., Tagliari, B., Matté, C., Wannmacher, C.M.D., Wajner, M., and Wyse, A.T.S. (2003a). Brain energy metabolism is compromised by the metabolites accumulating in homocystinuria. Neurochem. Int. 43:597-602.
Streck, E.L., Matté, C., Vieira, P.S., Rombaldi, F., Wannmacher, C.M.D., Wajner, M., and Wyse, A.T.S. (2002a). Reduction of Na+,K+-ATPase activity in hippocampus of rats subjected to chemically induced hyperhomocysteinemia. Neurochem. Res. 27:1593-1598.
Streck, E.L., Vieira, P.S., Wannmacher, C.M.D., Dutra-Filho, C.S., Wajner, M., and Wyse, A.T.S. (2003b). In vitro effect of homocysteine on some parameters of oxidative stress in rat hippocampus. Metab. Brain Dis. 18:147-154.
Streck, E.L., Zugno, A.I., Tagliari, B., Franzon, R., Wannmacher, C.M.D., Wajner, M., and Wyse, A.T.S. (2001). Inhibition of rat brain Na+,K+-ATPase activity induced by homocysteine is probably mediated by oxidative stress. Neurochem. Res. 26:1195-1200.
Streck, E.L., Zugno, A.I., Tagliari, B., Wannmacher, C.M.D., Wajner, M., and Wyse, A.T.S. (2002b). Inhibition of Na+,K+-ATPase activity by the metabolites accumulating in homocystinuria. Metab. Brain Dis. 17:83-91.
Szegletes, T., Mallander, W.D., Thomas, P.J., and Rosenberry, T.L. (1999). Substrate binding to the peripheral site of acetylcholinesterase initiates enzymatic catalysis: Substrate inhibition arises as a secondary effect. Biochemistry 38:122-133.
Temple, M.E., Luzier, A.B., and Kaazierad, D.J. (2000). Homocysteine as a risk factor for atherosclerosis. Ann. Pharmacol. 34:57-65.
Tsakiris, S., Angelogianni, P., Schulpis, K.H., and Stavridis, J.C. (2000). Protective effect of l-phenylalanine on rat brain acetylcholinesterase inhibition induced by free radicals. Clin. Biochem. 33:103-106.
Tsakiris, S., and Deliconstantinos, G. (1984). Influence of phosphatidylserine on (Na+ + K+)-stimulated ATPase and acetylcholinesterase activities of dog brain synaptossomal plasma membranes. Biochem. J. 22:301-307.
White, A.R., Huang, X., Jobling, M.F., Barrow, C.J., Beyreuther, K., Masters, C.L., Bush, A.I., and Cappai, R. (2001). Homocysteine potentiates copper-and amyloid #x03B2 peptide-mediated toxicity in primary neuronal cultures: Possible risk factors in the Alzheimer's-type neurodegenerative pathways. J. Neurochem. 76:1509-1520.
Wyse, A.T.S., Streck, E.L., Worm, P., Wajner, A., Ritter, F., and Netto, C.A. (2000). Preconditioning prevents the inhibition of Na+,K+-ATPase activity after brain ischemia. Neurochem. Res. 25:971-975.
Wyse, A.T.S., Zugno, A.I., Streck, E.L., Matté, C., Calcagnotto, T., Wannmacher, C.M.D., and 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.
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Stefanello, F.M., Franzon, R., Wannmacher, C.M.D. et al. In Vitro Homocysteine Inhibits Platelet Na+, K+-ATPase and Serum Butyrylcholinesterase Activities of Young Rats. Metab Brain Dis 18, 273–280 (2003). https://doi.org/10.1023/B:MEBR.0000020189.89585.3b
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DOI: https://doi.org/10.1023/B:MEBR.0000020189.89585.3b