Abstract
The main objective of this study was to investigate the effects of a single intrastriatal injection of hypoxanthine, a metabolite accumulated in Lesch Nyhan disease and possibly involved in its neuropathology, on Na+,K+-ATPase activity, as well as on some parameters of oxidative stress, namely chemiluminescence (an index of lipid peroxidation), total radical-trapping antioxidant parameter—TRAP (an index of total antioxidant capacity of the tissue) and total thiol protein membrane content, in striatum, cerebral cortex and hippocampus of rats. Results show that hypoxanthine significantly decreased Na+,K+-ATPase activity and TRAP while increased chemiluminescence in all ipsislateral structures tested. However, no effect on total thiol protein membrane content was detected. We suggest that hypoxanthine induces oxidative stress in all cerebral structures studied (striatum, hippocampus and cerebral cortex) and that the reduction of Na+,K+-ATPase activity was probably mediated by reactive oxygen species.
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Aksenov MY, Markesbery WR (2001) Changes in thiol content and expression of glutathione redox system genes in hippocampus and cerebellum in Alzheimer's disease. Neurosci Lett 302:141–145
Bavaresco CS, Zugno AI, Tagliari B, Wannmacher CMD, Wajner M, Wyse ATS (2004) Inhibition of Na+,K+-ATPase activity in rat striatum by metabolites accumulated in Lesch Nyhan disease. Int J Devl Neurosci 22:11–17
Bavaresco CS, Chiarani F, Matté 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
Behl C (2005) Oxidative stress in Alzheimer's disease: Implications for prevention and therapy. Subcell Biochem 38:65–78
Bradford MM (1976) A rapid and sensitive method for the quantification of microgram quantities of protein utilizing the principle of protein –die binding. Anal Biochem 72:248–254
Calabresi P, De Murtas, M, Pisani A, Stefani A, Sancessario G, Mercuri NB, Bernardi G (1995) Vulnerability of medium spiny striatal neurons to glutamate: role of Na+,K+-ATPase activity. Eur J Neurosci 7:1674–1683
Calandriello L, Curini R, Pennisi EM, Palladini G (1995) Spongy state (status spongiosus) and inhibition of Na+,K+-ATPase: A pathogenetic theory. Med Hypotheses 44:173–178
Chan PH, Schmidley JW, Fishman RA, Longar SM (1984) Brain injury, edema and vascular permeability changes induced by oxygen derived free radicals. Neurology 34:315–320
Chan KM, Delfert D, Junger KD (1986). A direct colorimetric assay for Ca+ -stimulated ATPase activity. Anal Biochem 157:375–380
Dasheiff RM (1980). Benzodiazepinic treatment for Lesch-Nyhan syndrome? Dev Med Child Neurol 22:101–102
Erecinska M, Silver IA (1994). Ions and energy in mammalian brain. Prog Neurobiol 7:21–29
Floyd RA (1999) Antioxidants, oxidative stress and degenerative neurological disorders. Proc Soc Exp Biol Med 222:236–245
Golden WC, Brambrink AM, Traystman RJ, Martin LJ (2001) Failure to sustain recovery of Na+,K+-ATPase function is a possible mechanism for striatal neurodegeneration in hypoxic-ischemic newborn piglets. Brain Res Mol Brain Res 81:94–102
Gonzalez Flecha B, Llesuy S, Boveris A (1991) Hydroperoxide-initiated chemiluminescence: An assay for oxidative stress in biopsies of heart, liver, and muscle. Free Radic Biol Med 10:93–100
Grisar T (1984) Glial and neuronal Na+,K+-pump in epilepsy. Ann Neurol 16 (Suppl.):128–134
Hagberg H, Andersson P, Lacarewicz J, Jacobson I, Butcher S, Sandberg M (1987) Extracellular adenosine, inosine, hypoxanthine and xanthine to tissue nucleotides and purines in rat striatum during transient ischemia. J Neurochem 49:227–231
Halliwell B (1996) Free radicals, proteins and DNA: Oxidative damage versus redox regulation. Biochem Soc Trans 24:1023–1027
Halliwell B (2002) Hypothesis: Proteasomal dysfunction: A primary event in neurogeneration that leads to nitrative and oxidative stress and subsequent cell death. Ann NY Acad Sci 962:182–94
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
Hattori N, Kitagawa K, Higashida T, Yagyu K, Shimohama S, Wataya T, Perry G, Smith MA, Inagaki C (1998) Cl -- ATPase and Na+/K +- ATPase activities in Alzheimer's disease brains. Neurosci Lett 254:141–144
Jamme I, Petit E, Divoux D, Gerbi A, Maixent JM, Nouvelot A (1995) Modulation of mouse cerebral Na+,K+-ATPase activity by oxygen free radicals. Neuroreport 7:333–337
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, eighth ed, McGraw-Hill, New York, pp. 2537–2569
Jinnah HA, Gage FH, Friedmann T (1990) Animal models of Lesch-Nyhan syndrome. Brain Res Bull 25:467–475
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
Kisch SJ, Fox IH, Kapur BM, Lloyd KG, Hornykiewicz O (1985) Brain benzodiazepine receptor binding and purine concentration in Lesch-Nyhan. Brain Res 336:117–123
Lees GJ (1993) Contributory mechanism in the causation of neurodegenerative disorders. Neurosci 54:287–322
Lissi E, Pascual C, Del Castillo MD (1992) Luminol luminescence induced by 2,2′–azo-bis (2-amidinopropane) thermolysis. Free Rad Res Comm 17:299–311
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–267
Ma MHY, Stacey NC, Connolly GP (2001) Hypoxanthine impairs morphogenesis and enhances proliferation of a neuroblastoma model of Lesch Nyhan syndrome. J Neurosci Res 63:500–508
Mahon S, Deniau JM, Charpier S (2004) Corticostriatal plasticity: Life after the depression. Trends Neurosci 27:460–467
Morel P, Faucommeau B, Page G (1998). Inhibitory effect of ascorbic acid on dopamine uptake by rat striatal synaptosomes: Relationship to lipid peroxidation and oxidation of protein sulfhydryl groups. Neurosci Res 32:171–179
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
Palmer GC (1987) Free radicals generated by xanthine oxidase—hypoxanthine damage adenylate cyclase and ATPase in gerbil cerebral cortex. Metab Brain Dis 2:243–257
Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates, second ed. Academic Press, London
Puig JG, Jimenez ML, Mateos FA, Fox IH (1989) Adenine nucleotide turnover in hypoxanthine-guanine phosphoribosyl-transferase: Evidence for an increased contribution of purine biosyntheses de novo. Metabolism 38: 410–418
Renkawek K, Renier WO, de Pont JJ, Vogels OJ, Gabreels FJ (1992) Neonatal status convulsivus, spongioform encephalopathy, and low activity of Na+,K+-ATPase in the brain. Epilepsia 33:58–64
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 Gen 57:39–47
Schmidt H, Siems WG, Grune T, Grauel EL (1995) Concentration of purine compounds in the cerebrospinal fluid of infants suffering from sepsis, convulsions and hydrocephalus. J Perinat Med 23:167–174
Visser JE, Bär PR, Jinnah HA (2000) Lesch-Nyhan disease and the basal ganglia. Brain Res Bull 32:449–475
Visser JE, Smith DW, Moy SS, Breese GR, Friedmann T, Rothstein JD, Jinnah HA (2002) Oxidative stress and dopamine deficiency in a genetic mouse model of Lesch-Nyhan disease. Brain Res Dev Brain Res 133:127–139
Wooten GF, Collins RC (1980) Regional glicose utilization following intrastriatal injection of kainic acid. Brain Res. 201:173–184
Wyse ATS, Noriler ME, Borges LF, Floriano PJ, Silva CG, Wajner M, Wannmacher CMD (1999) Alanine prevents the decrease of Na+,K+-ATPase activity in experimental phenylketonuria. Metab Brain Dis 14:95–101
Wyse ATS, Streck EL, Worm P, Wajner M, Ritter F, Netto CA (2000) Preconditioning prevents the inhibition of Na+,K+-ATPase activity after brain ischemia. Neurochem Res 25:969–973
Xie Z, Kometiani P, Liu J, Li J, Shapiro JI, Askari A (1999) Intracellular reactive oxygen species mediate the linkage of Na+-K+–ATPase to hypertrophy and its marker genes in cardiac myocytes. J Biol Chem 274:19323–19328
Xie Z, Cai T (2003). Na+,K+-ATPase—mediated signal transduction: From protein interaction to cellular function. Molecular Interventions 3:157–168
Xiao AY, Wei L, Xia S, Rothman S, Yu SP (2002) Ionic mechanism of ouabain-induced concurrent apoptosis and necrosis in individual cultured cortical neurons. J Neurosci 22:1350–1362
Yang GY, Chen SF, Kinouchi H, Chan PH, Weinstein PR (1992) Edema, cation content, and ATPase activity after middle cerebral artery occlusion in rats. Stroke 23:1331–1336
Zaczek R, Simonton S, Coyle JT (1980) Local and distant neuronal degeneration following intrastriatal injection of kainic acid. J Neuropathol Exp Neurol 39:245–264
Zarkovic K (2003) 4-hydroxynonenal and neurodegenerative diseases. Mol Aspects Med 24:293–303
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This work was supported in part by grants from CNPq – Brazil.
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Bavaresco, C.S., Chiarani, F., Wannmacher, C.M.D. et al. Intrastriatal Hypoxanthine Reduces Na+,K+-ATPase Activity and Induces Oxidative Stress in the Rats. Metab Brain Dis 22, 1–11 (2007). https://doi.org/10.1007/s11011-006-9037-y
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DOI: https://doi.org/10.1007/s11011-006-9037-y