allopurinol and Parkinson-Disease

In this review, we report on new findings regarding associations of uric acid with kidney health. We discuss kidney stones, effects of uric acid in chronic kidney disease (CKD), and management of gout in CKD. Recent studies on neuroprotective effects of raising uric acid provide interesting data regarding nephrolithiasis.. Elevated urate levels have been implicated in the progression of chronic kidney disease (CKD), but the results from PERL and CKD-FIX studies did not demonstrate that allopurinol slowed CKD progression. The SURE-PD3 sought to determine if increasing uric acid would slow the progression of Parkinson's disease. Results ultimately did not support this hypothesis, but high urinary uric acid levels caused uric acid stones, not calcium stones. Low urinary pH remains the key to the formation of uric acid stones. Thiazolidinediones improve insulin resistance, which is associated with an increase in urine pH. The most recent research has not supported the hypothesis that lowering serum uric acid levels will slow the progression of CKD or provide neuroprotection in Parkinson's disease. It is still unclear as to why uric acid stone formers have a high net acid excretion. The STOP-GOUT trial demonstrates that there was a lack of significant adverse events with higher urate-lowering dosages of allopurinol and febuxostat, despite patients' kidney function. This may push other studies to administer higher dosages per ACR guidelines. Future studies could then demonstrate decreased progression of CKD.

Topics: Allopurinol; Female; Gout; Gout Suppressants; Humans; Kidney; Male; Parkinson Disease; Renal Insufficiency, Chronic; Uric Acid

Topics: Aged; Allopurinol; Cohort Studies; Female; Gout; Humans; Incidence; Middle Aged; Parkinson Disease; Retrospective Studies; Risk Factors

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). Oxidative stress has been hypothesized to play a major role in the development of PD in various studies. This study assessed to investigate oxidative and anti-oxidative status in PD patients. We evaluated oxidant/antioxidant status by measuring serum malondialdehyde (MDA) levels, xanthine oxidase (XO) activities, and activities of antioxidant enzymes, namely, glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD). The study included 29 patients with PD and 32 healthy subjects as controls. Comparison of oxidative parameters in the patient and control groups revealed significantly higher GSH-Px and XO activities in the patient group. Serum MDA and SOD activities in PD patients were not significantly different from the controls. MDA was negatively correlated with duration of the PD and positively with age of onset. There was a negative correlation between SOD and Hoehn and Yahr (H&Y) stage. According to these results, we suggest that oxidative stress may contribute to the development of PD.

Topics: Aged; Antioxidants; Female; Glutathione Peroxidase; Humans; Male; Malondialdehyde; Middle Aged; Oxidants; Oxidation-Reduction; Oxidative Stress; Parkinson Disease; Superoxide Dismutase; Xanthine Oxidase

Robust epidemiological data link higher levels of the antioxidant urate to a reduced risk of developing Parkinson׳s disease (PD) and to a slower rate of its progression. Allopurinol, an inhibitor of xanthine oxidoreductase (XOR), blocks the oxidation of xanthine to urate. The present study sought to determine whether lowering levels of urate using allopurinol results in exacerbated neurotoxicity in a dual pesticide mouse model of PD. Although oral allopurinol reduced serum and striatal urate levels 4-fold and 1.3-fold, respectively, it did not alter the multiple motor deficits induced by chronic (7 week) intermittent (biweekly) exposure to intraperitoneal Paraquat (PQ) plus Maneb (MB). However, striatal dopamine content, which was unaffected after either allopurinol or chronic pesticide exposure alone, was significantly reduced by 22% in mice exposed to the combination. Stereological assessment showed that the numbers of dopaminergic nigral neurons were significantly reduced by 29% and the tyrosine hydroxylase (TH) negative neurons unaffected after PQ+MB treatments. This reduction in TH-positive neurons was not affected by allopurinol treatment. Of note, despite the expectation of exacerbated oxidative damage due to the reduction in urate, protein carbonyl levels, a marker of oxidative damage, were actually reduced in the presence of allopurinol. Overall, allopurinol lowered urate levels but did not exacerbate dopaminergic neuron degeneration, findings suggesting that basal levels of urate in mice do not appreciably protect against oxidative damage and neurotoxicity in the PQ+MB model of PD, and/or that allopurinol produces an antioxidant benefit offsetting its detrimental urate-lowering effect.

Topics: Allopurinol; Animals; Corpus Striatum; Disease Models, Animal; Dopamine; Dopaminergic Neurons; Enzyme Inhibitors; Male; Maneb; Mice; Mice, Inbred C57BL; Motor Activity; Paraquat; Parkinson Disease; Pesticides; Uric Acid

Plasma uric acid (UA) levels decrease following clinical progression and stage development of Parkinson's disease (PD). However, the molecular mechanisms underlying decreases in plasma UA levels remain unclear, and the potential to apply mutagenesis to a PD model has not previously been discovered. We identified a unique mutant of the silkworm Bombyx mori (B.mori) op. Initially, we investigated the causality of the phenotypic "op" by microarray analysis using our constructed KAIKO functional annotation pipeline. Consequently, we found a novel UA synthesis-modulating pathway, from DJ-1 to xanthine oxidase, and established methods for large-scale analysis of gene expression in B. mori. We found that the mRNA levels of genes in this pathway were significantly lower in B. mori op mutants, indicating that downstream events in the signal transduction cascade might be prevented. Additionally, levels of B.mori tyrosine hydroxylase (TH) and DJ-1 mRNA were significantly lower in the brain of B. mori op mutants. UA content was significantly lower in the B. mori op mutant tissues and hemolymph. The possibility that the B. mori op mutant might be due to loss of DJ-1 function was supported by the observed vulnerability to oxidative stress. These results suggest that UA synthesis, transport, elimination and accumulation are decreased by environmental oxidative stress in the B. mori op mutant. In the case of B. mori op mutants, the relatively low availability of UA appears to be due both to the oxidation of DJ-1 and to its expenditure to mitigate the effects of environmental oxidative stress. Our findings are expected to provide information needed to elucidate the molecular mechanism of decreased plasma UA levels in the clinical stage progression of PD.

Topics: Animals; Bombyx; Disease Models, Animal; Mutation; Oxidative Stress; Parkinson Disease; Signal Transduction; Tyrosine 3-Monooxygenase; Uric Acid; Xanthine Oxidase

The available scientific data indicate that the pathomechanism of Parkinson's disease (PD) involves the accumulation of endogenous and exogenous toxic substances. The disruption of the proper functioning of certain transporters in the blood-brain barrier and in the blood-cerebrospinal fluid barrier in PD would accompany to that accumulation. Although there is an emerging role of the dysfunction of multidrug resistance-associated proteins (MRPs), members of ATP-b nding cassette (ABC) transporter superfamily, in neurodegenerative disorders, there is only a few available data as regards PD. So the aim of our study was the assessment of the role of certain MRPs (1 ,2, 4 and 5) in neurotoxicity induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Following the intraperitoneal administration of silymarin (with MRP1, 2, 4 and 5 inhibitory effects), naringenin (with MRP1, 2 and 4 stimulatory effects), sulfinpyrazone (with MRP1, 4 and 5 inhibitory and MRP2 stimulatory effects) and allopurinol (with MRP4 stimulatory effect in doses of 100 mg/kg, 100 mg/kg, 100 mg/kg and 60 mg/kg, respectively, for one week before and after the administration of MPTP in C57B/6 mice in acute dosing regimen the striatal concentrations of dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic acid has been measured using high-performance liquid chromatography.. Although the results of these experiments showed that neither of these substances exerted significant influence on MPTP-induced striatal depletion of dopamine and its metabolites, naringenin exerted a slight prevention of dopamine decrease, while allopurinol considerably enhanced the MPTP-induced lethality in mice. The explanation of these findings would be that the stimulation of MRP1- and MRP2-mediated transport of glutathione conjugates of toxic substances may have slight beneficial effects, while stimulation of MRP4-mediated efflux of brain urate, which has an important antioxidant potency, may worsen the effects of oxidative stress.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 3,4-Dihydroxyphenylacetic Acid; Allopurinol; Animals; Brain; Chromatography, High Pressure Liquid; Corpus Striatum; Dopamine; Dopamine Agents; Drug Administration Schedule; Flavanones; Homovanillic Acid; Infusions, Parenteral; Male; Mice; Mice, Inbred C57BL; Multidrug Resistance-Associated Protein 2; Multidrug Resistance-Associated Proteins; Neurotoxins; Oxidative Stress; Parkinson Disease; Silymarin; Sulfinpyrazone; Uric Acid

A series of C7-O- and C20-O-amidated 2,3-dehydrosilybin (DHS) derivatives ((+/-)-1a-f and (+/-)-2), as well as a set of alkenylated DHS analogues ((+/-)-4a-f), were designed and de novo synthesized. A diesteric derivative of DHS ((+/-)-3) and two C23 esterified DHS analogues ((+/-)-5a and (+/-)-5b) were also prepared for comparison. The cell viability of PC12 cells, Fe(2+) chelation, lipid peroxidation (LPO), free radical scavenging, and xanthine oxidase inhibition models were utilized to evaluate their antioxidative and neuron protective properties. The study revealed that the diether at C7-OH and C20-OH as well as the monoether at C7-OH, which possess aliphatic substituted acetamides, demonstrated more potent LPO inhibition and Fe(2+) chelation compared to DHS and quercetin. Conversely, the diallyl ether at C7-OH and C20-OH was more potent in protection of PC12 cells against H(2)O(2)-induced injury than DHS and quercetin. Overall, the more lipophilic alkenylated DHS analogues were better performing neuroprotective agents than the acetamidated derivatives. The results in this study would be beneficial for optimizing the therapeutic potential of lignoflavonoids, especially in neurodegenerative disorders such as Alzheimer's and Parkinson's disease.

Topics: Alkenes; Alzheimer Disease; Amides; Animals; Drug Design; Free Radical Scavengers; Humans; Iron Chelating Agents; Lipid Peroxidation; Liver; Male; Models, Molecular; Molecular Conformation; Neurons; Neuroprotective Agents; Parkinson Disease; PC12 Cells; Rats; Silymarin; Structure-Activity Relationship; Xanthine Oxidase

It is anticipated that further understanding of the protective mechanism induced by ischemic preconditioning will improve prognosis for patients of ischemic injury. It is not known whether preconditioning exerts beneficial actions in neurodegenerative diseases, in which ischemic injury plays a causative role. Here we show that transient activation of ATP-sensitive potassium channels, a trigger in ischemic preconditioning signaling, confers protection in PC12 cells and SH-SY5Y cells against neurotoxic effect of rotenone and MPTP, mitochondrial complex I inhibitors that have been implicated in the pathogenesis of Parkinson's disease. The degree of protection is in proportion to the bouts of exposure to an ATP-sensitive potassium channel opener, a feature reminiscent of ischemic tolerance in vivo. Protection is sensitive to a protein synthesis inhibitor, indicating the involvement of de novo protein synthesis in the protective processes. Pretreatment of PC12 cells with preconditioning stimuli FeSO(4) or xanthine/xanthine oxidase also confers protection against rotenone-induced cell death. Our results demonstrate for the first time the protective role of ATP-sensitive potassium channels in a dopaminergic neuronal cell line against rotenone-induced neurotoxicity and conceptually support the view that ischemic preconditioning-derived therapeutic strategies may have potential and feasibility in therapy for Parkinson's disease.

Topics: Adenosine Triphosphate; Animals; Cell Death; Dose-Response Relationship, Drug; Electron Transport Complex I; Ferrous Compounds; Glyburide; Ischemic Preconditioning; Mitochondria; NADH, NADPH Oxidoreductases; Neurons; Parkinson Disease; Parkinson Disease, Secondary; PC12 Cells; Pinacidil; Potassium Channel Blockers; Potassium Channels; Protein Synthesis Inhibitors; Rats; Rotenone; Uncoupling Agents; Vasodilator Agents; Xanthine; Xanthine Oxidase

We examined the effect of N(G)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor, on extracellular potassium ion concentration ([K(+)](o))-enhanced hydroxyl radical (.OH) generation due to 1-methyl-4-phenylpyridinium ion (MPP(+)) was examined in the rat striatum. Rats were anesthetized, and sodium salicylate in Ringer's solution (0.5 nmol/microl per min) was infused through a microdialysis probe to detect the generation of.OH as reflected by the non-enzymatic formation of 2,3-dihydroxybenzoic acid (DHBA) in the striatum. Induction of KCl (20, 70 and 140 mM) increased MPP(+)-induced.OH formation trapped as 2,3-dihydroxybenzoic acid (DHBA) in a concentration dependent manner. However, the application of L-NAME (5 mg/kg i.v.) abolished the [K(+)](o) depolarization-induced.OH formation with MPP(+). Dopamine (DA; 10 microM) also increased the levels of DHBA due to MPP(+). However, the effect of DA after application of L-NAME did not change the levels of DHBA. On the other hand, the application of allopurinol (20 mg/kg i.v., 30 min prior to study), a xanthine oxidase (XO) inhibitor was abolished the both [K(+)](o)- and DA-induced.OH generation. Moreover, when iron(II) was administered to MPP(+) then [K(+)](o) (70 mM)-pretreated animals, a marked increase in the level of DHBA. However, when corresponding experiments were performed with L-NAME-pretreated animals, the same results were obtained. Therefore, NOS activation may be no relation to Fenton-type reaction via [K(+)](o) depolarization-induced.OH generation. The present results suggest that [K(+)](o)-induced depolarization augmented MPP(+)-induced.OH formation by enhancing NO synthesis.

Topics: 1-Methyl-4-phenylpyridinium; Allopurinol; Animals; Dopamine; Enzyme Inhibitors; Extracellular Space; Herbicides; Hydroxybenzoates; Hydroxyl Radical; Iron; Iron Chelating Agents; Male; Membrane Potentials; Microdialysis; Neostriatum; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Oxidative Stress; Parkinson Disease; Potassium; Rats; Rats, Wistar

We recently demonstrated that para-nonylphenol, an environmental estrogen-like chemical, enhances hydroxyl radical (*OH) generation in the rat striatum. In the present study we have examined whether para-nonylphenol enhanced 1-methyl-4-phenylpyridinium ion (MPP(+))-induced *OH generation in the rat striatum using a microdialysis technique. Para-nonylphenol significantly enhanced MPP(+)-induced *OH generation. Further, we studied the effect of allopurinol, a xanthine oxidase inhibitor, on para-nonylphenol and MPP(+)-induced *OH generation. Allopurinol significantly suppressed para-nonylphenol and MPP(+)-induced *OH generation. The results indicate that para-nonylphenol enhanced *OH generation based on superoxide anion production, and allopurinol may have preventive effect on para-nonylphenol and MPP(+)-induced *OH generation.

Topics: 1-Methyl-4-phenylpyridinium; Allopurinol; Animals; Dose-Response Relationship, Drug; Drug Interactions; Free Radical Scavengers; Hazardous Substances; Hydroxyl Radical; Male; Microdialysis; Neostriatum; Nerve Degeneration; Parkinson Disease; Parkinson Disease, Secondary; Phenols; Rats; Rats, Wistar