Location of Repository

Urate and Its Transgenic Depletion Modulate Neuronal Vulnerability in a Cellular Model of Parkinson's Disease

By Sara Cipriani, Cody A. Desjardins, Thomas C. Burdett, Yuehang Xu, Kui Xu and Michael A. Schwarzschild

Abstract

Urate is a major antioxidant as well as the enzymatic end product of purine metabolism in humans. Higher levels correlate with a reduced risk of developing Parkinson's disease (PD) and with a slower rate of PD progression. In this study we investigated the effects of modulating intracellular urate concentration on 1-methyl-4-phenyl-pyridinium (MPP+)-induced degeneration of dopaminergic neurons in cultures of mouse ventral mesencephalon prepared to contain low (neuron-enriched cultures) or high (neuron-glial cultures) percentage of astrocytes. Urate, added to the cultures 24 hours before and during treatment with MPP+, attenuated the loss of dopaminergic neurons in neuron-enriched cultures and fully prevented their loss and atrophy in neuron-astrocyte cultures. Exogenous urate was found to increase intracellular urate content in cortical neuronal cultures. To assess the effect of reducing cellular urate content on MPP+-induced toxicity, mesencephalic neurons were prepared from mice over-expressing urate oxidase (UOx). Transgenic UOx expression decreased endogenous urate content both in neurons and astrocytes. Dopaminergic neurons expressing UOx were more susceptible to MPP+ in mesencephalic neuron-enriched cultures and to a greater extent in mesencephalic neuron-astrocyte cultures. Our findings correlate intracellular urate content in dopaminergic neurons with their toxin resistance in a cellular model of PD and suggest a facilitative role for astrocytes in the neuroprotective effect of urate

Topics: Research Article
Publisher: Public Library of Science
OAI identifier: oai:pubmedcentral.nih.gov:3351394
Provided by: PubMed Central
Download PDF:
Sorry, we are unable to provide the full text but you may find it at the following location(s):
  • http://www.pubmedcentral.nih.g... (external link)
  • Suggested articles

    Preview

    Citations

    1. (1997). 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) decreases glutamate uptake in cultured astrocytes.
    2. (2003). 1-methyl-4-phenylpyridinium (MPP+)-induced apoptosis and mitochondrial oxidant generation: Role of transferrin-receptor-dependent iron and hydrogen peroxide.
    3. (2002). A reassessment of the peroxynitrite scavenging activity of uric acid.
    4. (2009). Anti-nociceptive properties of the xanthine oxidase inhibitor allopurinol in mice: Role of A1 adenosine receptors.
    5. (2007). Ascherio A
    6. (2006). Ascorbate transport and recycling by SH-SY5Y neuroblastoma cells: Response to glutamate toxicity.
    7. (2006). Ascorbic acid protects SH-SY5Y neuroblastoma cells from apoptosis and death induced by beta-amyloid.
    8. (2007). Astrogliamediated effects of uric acid to protect spinal cord neurons from glutamate toxicity.
    9. (2011). Caffeine and uric acid mediate glutathione synthesis for neuroprotection.
    10. (1991). Characteristics of ascorbic acid uptake by isolated ox neurohypophyseal nerve terminals and the influence of glucocorticoid and tri-iodothyronine on uptake.
    11. (1983). Chronic parkinsonism in humans due to a product of meperidine-analog synthesis.
    12. (2002). Dietary folate deficiency and elevated homocysteine levels endanger dopaminergic neurons in models of parkinson’s disease.
    13. (2002). Differential effect of catecholamines and MPP(+) on membrane permeability in brain mitochondria and cell viability in PC12 cells.
    14. (2005). Free radical scavenging, DNA protection, and inhibition of lipid peroxidation mediated by uric acid.
    15. (2001). Glutamate is not involved in the MPP+-induced dopamine overflow in the striatum of freely moving C57BL/6 mice.
    16. (1994). Hyperuricemia and urate nephropathy in urate oxidase-deficient mice.
    17. (1987). Inhibition of ATP synthesis by 1-methyl-4-phenylpyridinium ion (MPP+) in isolated mitochondria from mouse brains.
    18. (2011). Iron mediates neuritic tree collapse in mesencephalic neurons treated with 1-methyl-4-phenylpyridinium (MPP+).
    19. (2011). Iron regulates the uptake of ascorbic acid and the expression of sodium-dependent vitamin C transporter 1 (SVCT1) in human intestinal caco-2 cells.
    20. (1992). Irreversible inhibition of mitochondrial complex I by 1-methyl-4-phenylpyridinium: Evidence for free radical involvement.
    21. (2002). Loss of urate oxidase activity in hominoids and its evolutionary implications.
    22. (1991). Molecular evolution of the urate oxidase-encoding gene in hominoid primates: Nonsense mutations.
    23. (2002). Molecular identification of a renal urate anion exchanger that regulates blood urate levels.
    24. (2005). MPP+-induced COX-2 activation and subsequent dopaminergic neurodegeneration.
    25. (2003). N-methylated betacarbolines protect PC12 cells from cytotoxic effect of MPP+ by attenuation of mitochondrial membrane permeability change.
    26. (1996). Observations on serum uric acid levels and the risk of idiopathic parkinson’s disease.
    27. (1955). Origin of man.
    28. (1992). Possible mechanism of inhibition of nitrite-induced oxidation of oxyhemoglobin by ergothioneine and uric acid.
    29. (1986). Prevention of the nigrostriatal toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine by inhibitors of 3,4-dihydroxyphenylethylamine transport.
    30. (2009). Protection of midbrain dopaminergic neurons by the end-product of purine Cellular Urate and MPP+
    31. (2011). Protective effects of urate against 6-OHDA-induced cell injury in PC12 cells through antioxidant action.
    32. (2010). Protective effects of uric acid on nigrostriatal system injury induced by 6-hydroxydopamine in rats.
    33. (1994). Reactive oxygen species inhibit high-affinity glutamate uptake: Molecular mechanism and neuropathological implications.
    34. (1986). Reduced susceptibility to lipid peroxidation in cold ischemic rabbit kidneys after addition of desferrioxamine, mannitol, or uric acid to the flush solution.
    35. (2011). Serum urate and probability of dopaminergic deficit in early ‘‘parkinson’s disease’’.
    36. (2008). Serum urate as a predictor of clinical and radiographic progression in parkinson disease.
    37. (2005). Serum uric acid levels and the risk of parkinson disease.
    38. (2009). Serum uric acid levels in patients with parkinson’s disease: Their relationship to treatment and disease duration.
    39. (1970). Similar functions of uric acid and ascorbate in man?
    40. (2011). Sodiumdependent vitamin C transporter 2 (SVCT2) expression and activity in brain capillary endothelial cells after transient ischemia in mice.
    41. (2007). Soluble neuroprotective antioxidant uric acid analogs ameliorate ischemic brain injury in mice.
    42. (1999). Stadlin A
    43. (2003). Targeting programmed cell death in neurodegenerative diseases.
    44. (1992). The glutamate antagonist, MK-801, does not prevent dopaminergic cell death induced by the 1-methyl-4-phenylpyridinium ion (MPP+) in rat dissociated mesencephalic cultures.
    45. (1955). The origin of man.
    46. (1992). Toxicity of the 1-methyl-4-phenyl2,3-dihydropyridinium and 1-methyl-4-phenylpyridinium species in primary cultures of mouse astrocytes.
    47. (1992). Two independent mutational events in the loss of urate oxidase during hominoid evolution.
    48. (2009). Urate as a predictor of the rate of clinical decline in parkinson disease.
    49. (1989). Urate oxidase: Primary structure and evolutionary implications.
    50. (1994). Uric acid is reduced in the substantia nigra in parkinson’s disease: Effect on dopamine oxidation.
    51. (2010). Uric acid promotes an acute inflammatory response to sterile cell death in mice.
    52. (2005). Uric acid protects against secondary damage after spinal cord injury.
    53. (1981). Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: A hypothesis.
    54. (1986). Uric acidiron ion complexes. A new aspect of the antioxidant functions of uric acid.
    55. (1933). Uricase and its action: Distribution in various animals.
    56. (2006). Valproate protects dopaminergic neurons in midbrain neuron/glia cultures by stimulating the release of neurotrophic factors from astrocytes.

    To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.