Article

Uric acid demonstrates neuroprotective effect on Parkinson's disease mice through Nrf2-ARE signaling pathway

October 2017
Biochemical and Biophysical Research Communications 493(4)

DOI:10.1016/j.bbrc.2017.10.004

Authors:

Uric acid has neuroprotective effect on Parkinson's disease (PD) by inhibiting oxidative damage and neuronal cell death. Our previous study has shown that uric acid protected dopaminergic cell line damage through inhibiting accumulation of NF-E2-related factor 2 (Nrf2). This study aimed to investigate its in vivo neuroprotective effect. PD was induced by MPTP intraperitoneally injection for 7 d in male C57BL/6 mice. Mice were treated with either uric acid (intraperitoneally injection 250 mg/kg) or saline for a total of 13 d. We showed that uric acid improved behavioural performances and cognition of PD mice, increased TH-positive dopaminergic neurons and decreased GFAP-positive astrocytes in substantia nigra (SN). Uric acid increased mRNA and protein expressions of Nrf2 and three Nrf2-responsive genes, including γ-glutamate-cysteine ligase catalytic subunit (γ-GCLC), heme oxygenase-1 (HO-1) and NQO1. Uric acid significantly increased superoxide dismutase (SOD), CAT, glutathione (GSH) levels and decreased malondialdehyde (MDA) level in SN regions of MPTP-treated mice. Uric acid inhibited the hippocampal expression of IL-1β and decreased serum and hippocampus levels of interleukin-1β (IL-1β), IL-6 and tumor necrosis factor-α (TNF-α). In conclusion, uric acid demonstrates neuroprotective properties for dopaminergic neurons in PD mice through modulation of neuroinflammation and oxidative stress.

Relationships between Serum Lipid, Uric Acid Levels and Mild Cognitive Impairment in Parkinson's Disease and Multiple System Atrophy

Article

Full-text available

Sep 2024
J INTEGR NEUROSCI

Background Mild cognitive impairment is one of the non-motor symptoms in Parkinson's disease (PD) and multiple system atrophy (MSA). Few studies have previously been conducted on the correlation between serum uric acid (SUA) and lipid levels and mild cognitive impairment in PD and MSA. Methods Participants included 149 patients with PD and 99 patients with MSA. The Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) were used to evaluate cognitive function. Evaluations were conducted on SUA and lipid levels, which included triglyceride, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and total cholesterol (TC). Results Patients with PD and MSA diagnosed with mild cognitive impairment demonstrated multiple cognitive domain impairment when compared with patients with normal cognition. Attentional impairment was more pronounced in patients with MSA when compared with PD (p = 0.001). In PD, the risk of mild cognitive impairment was lower in the highest quartiles and secondary quartile of SUA than in the lowest quartiles (odds ratio [OR] = 0.281, 95% confidence intervals [CI]: 0.097–0.810, p = 0.019; and OR = 0.317, 95% CI: 0.110–0.911, p = 0.033). In MSA, the risk of mild cognitive impairment was lower in the third and highest quartile of SUA than in the lowest quartile (OR = 0.233, 95% CI: 0.063–0.868, p = 0.030; and OR = 0.218, 95% CI: 0.058–0.816, p = 0.024). In patients with PD, the MoCA scores were negatively correlated with TC levels (r = –0.226, p = 0.006) and positively correlated with SUA levels (r = 0.206, p = 0.012). In MSA, the MoCA scores were positively correlated with SUA levels (r = 0.353, p = 0.001). Conclusions Lower SUA levels and higher TC levels are a possible risk factor for the risk and severity of mild cognitive impairment in PD. Lower SUA levels are a possible risk factor for the risk and severity of mild cognitive impairment in MSA.

Evidence for Oxidative Pathways in the Pathogenesis of PD: Are Antioxidants Candidate Drugs to Ameliorate Disease Progression?

Article

Full-text available

Jun 2022
INT J MOL SCI

Parkinson’s disease (PD) is a progressive neurodegenerative disorder that arises due to a complex and variable interplay between elements including age, genetic, and environmental risk factors that manifest as the loss of dopaminergic neurons. Contemporary treatments for PD do not prevent or reverse the extent of neurodegeneration that is characteristic of this disorder and accordingly, there is a strong need to develop new approaches which address the underlying disease process and provide benefit to patients with this debilitating disorder. Mitochondrial dysfunction, oxidative damage, and inflammation have been implicated as pathophysiological mechanisms underlying the selective loss of dopaminergic neurons seen in PD. However, results of studies aiming to inhibit these pathways have shown variable success, and outcomes from large-scale clinical trials are not available or report varying success for the interventions studied. Overall, the available data suggest that further development and testing of novel therapies are required to identify new potential therapies for combating PD. Herein, this review reports on the most recent development of antioxidant and anti-inflammatory approaches that have shown positive benefit in cell and animal models of disease with a focus on supplementation with natural product therapies and selected synthetic drugs.

Serum uric acid and diabetic peripheral neuropathy: a double-edged sword

Article

Full-text available

May 2022

Background and objectives Research suggests that diabetic peripheral neuropathy (DPN) is related to high serum uric acid (SUA) level, although its correlation with low SUA level has not been reported. Here, diabetic patients with hyperuricemia were excluded, and the correlation between low SUA level and DPN was explored. Subjects and methods This prospective observational clinical study enrolled 525 type 2 diabetes mellitus (T2DM) patients without hyperuricemia, who were divided into the diabetes with symptomatic neuropathy (150 cases), diabetes with asymptomatic neuropathy (125 cases) and diabetes with no neuropathy (250 cases) groups. Results The SUA slightly decreased in subjects with asymptomatic DPN compared with those with no neuropathy and greatly decreased in subjects with symptomatic DPN compared with those without ( P < 0.001). The association of the SUA with diabetic neuropathy was independent of the hyperglycemic state and other potential confounders (odds ratio 0.985 [0.981–0.988], P < 0.001). The SUA was closely correlated with the means of motor/sensory nerve amplitude and CV (all P < 0.001). The optimal cut-off point for SUA to distinguish patients with diabetic neuropathy from those without was 324 umol/L, with a sensitivity of 76.0% and a specificity of 79.2% (AUC = 0.806). Conclusions The low SUA level is closely associated with DPN. Future studies are warranted to clarify the relationship.

White matter integrity mediated the effect of plasma uric acid levels on cognitive function in ALS patients

Article

Full-text available

Mar 2025
BRAIN IMAGING BEHAV

Objective To investigate the association between plasma uric acid levels and white matter microstructural alterations in amyotrophic lateral sclerosis (ALS) patients and to explore the potential mediating role of white matter microstructural alterations in the protective effect of plasma uric acid on cognitive function in ALS patients. Methods 73 right-handed ALS patients were recruited for this study. Plasma uric acid levels were measured, diffusion tensor imaging scans were performed to assess white matter integrity, and cognition was evaluated using the Edinburgh Cognitive and Behavioral Screen. The relationships among plasma uric acid, white matter integrity, and cognitive function were examined through multivariate linear regression analysis. Additionally, mediation analysis was performed to investigate whether white matter integrity mediated the relationship between uric acid levels and cognitive function. Results The findings revealed a positive correlation between plasma uric acid levels and extensive preservation of white matter microstructure in various regions, including the fornix, cerebellar, internal capsule, frontotemporal and frontooccipital lobe bundles among ALS patients. Mediation analysis indicated that fractional anisotropy in the hippocampal portion of the cingulum fully mediated the effects of plasma uric acid levels on executive function in ALS patients. Interpretation Our results suggested that elevated plasma uric acid may preserve the integrity of white matter microstructure in ALS patients. Furthermore, we have identified evidence supporting the mediating influence of the hippocampal portion of the cingulum in linking plasma uric acid levels to cognitive function among ALS patients.

Targeting uric acid: a promising intervention against oxidative stress and neuroinflammation in neurodegenerative diseases

Article

Full-text available

Jan 2025

Oxidative stress and neuroinflammation are recognized as key factors in the development of neurodegenerative diseases, yet effective interventions and biomarkers to address oxidative stress and neuroinflammation in these conditions are limited. Uric acid (UA), traditionally associated with gout, is now gaining prominence as a potential target in neurodegenerative diseases. Soluble UA stands out as one of the most vital antioxidant compounds produced by the human body, accounting for up to 55% of the extracellular capacity to neutralize free radicals. While there is increasing evidence supporting the neuroprotective properties of UA in Parkinson’s disease and Alzheimer’s disease, gaps in knowledge still exist regarding the underlying mechanisms and how to effectively translate these benefits into clinical practice. Moreover, the current UA elevation therapy exhibits unstable antioxidant properties, individual variability, and even adverse effects, limiting its potential clinical applications. This review consolidates recent advancements in understanding how UA exerts neuroprotective effects on neurodegenerative diseases and emphasizes the dual roles of UA in managing oxidative stress and neuroinflammation. Additionally, the review elucidates the mechanisms through which UA confers neuroprotection. Based on this, the review underscores the significance of UA as a potential biomarker and aims to provide a comprehensive understanding of its potential as a therapeutic target, while also addressing possible challenges to clinical implementation.

Association between the serum uric acid/serum creatinine ratio and cognitive function in older adults: NHANES in the United States

Article

Full-text available

Jul 2024

Cognitive impairment can potentially become a significant health concern in older adults. However, early effective diagnostic methods are still lacking. Therefore, we utilized the NHANES database in the US to investigate the relationship between serum uric acid to serum creatinine (SUA/SCR) ratio and cognitive impairment. In our study, a total of 3874 participants were included (2001–2002, 2011–2014). Weighted t tests or chi-square tests were utilized to analyze the basic characteristics of the population. Weighted logistic regression analysis, smooth-fit curves, threshold effects, and subgroup analysis were conducted to investigate the correlation between the SUA/SCR and cognitive impairment. In this study, the SUA/SCR was significantly lower in individuals with cognitive impairment. The logistic regression model, after adjusting for all covariates, revealed that the Q2–Q4 were 0.65 (95% CI 0.49, 0.86), 0.60 (95% CI 0.40, 0.90), 0.55 (95% CI 0.39, 0.77) respectively. This indicates that participants in the Q4 had a 45% reduced risk of cognitive impairment. Smooth-fit curves and threshold effect analysis revealed a nonlinear relationship between SUA/SCR and cognitive impairment, with a turning point at 4.13. Subgroup analysis showed no statistically significant differences in the relationship between SUA/SCR and cognitive impairment among different subgroups (P > 0.05). Our findings indicate a negative correlation between the SUA/SCR and the risk of cognitive impairment in the population of adults aged 60 and above in the US. This suggests that the SUA/SCR holds promise as a potential indicator for cognitive impairment.

Causality between serum uric acid and diabetic microvascular complications - a mendelian randomization study

Article

Full-text available

Jun 2024

Background The aim of this study was to investigate whether a causal relationship exists between serum uric acid (SUA) and diabetic microvascular complications using a two-sample Mendelian randomization (MR) method. Methods We used the MR approach, utilizing genome-wide association study (GWAS) summary statistics, to estimate the causal effect of SUA on diabetic microvascular complications in European individuals. The summary statistical data of SUA were obtained from the open database (IEU OPEN GWAS PROJECT) (p < 5 × 10− 8), and data on diabetic microvascular complications (diabetic nephropathy, diabetic neuropathy, diabetic retinopathy) were obtained from the FinnGen consortium. F-statistics were calculated to assess the correlation between instrumental variables (IVs) and SUA, and single nucleotide polymorphisms (SNPs) associated with confounders or outcomes were excluded by consulting the PhenoScanner database. Inverse variance weighting (IVW) was used for primary estimation, and MR‒Egger, weighted median (WM), and Mendelian randomization pleiotropy residuals sum and outliers (MR-PRESSO) were used for additional assessment. Heterogeneity was assessed using the Cochran’s Q test, and polytropy was assessed using the MR‒Egger intercept. Results MR analysis revealed a causal relationship between a genetically predicted increase in SUA and diabetic nephropathy [OR = 1.32, 95%(CI) = 1.07–1.63, p = 0.008]. The results were consistent with those after MR-PRESSO [OR = 1.30, 95%(CI) = 1.07–1.58, p = 0.008]. There was a causal relationship between type 2 diabetes mellitus (T2DM) and renal complication IVW [OR = 1.27, 95%(CI) = 1.00–1.62, p = 0.049]. These results were consistent with those after MR-PRESSO [OR = 1.27, 95%(CI) = 1.00–1.62, p = 0.050]. There was no significant causal relationship between the genetically predicted increase in SUA and diabetic retinopathy [OR 1.09, 95%(CI) = 0.94–1.26, p = 0.249] or diabetic neuropathy [OR = 1.08, 95%(CI) = 0.84–1.40, p = 0.549]. Conclusions This MR analysis suggests a causal relationship between genetically predicted uric acid increases and diabetic microvascular complications. A significant causal relationship exists between SUA and diabetic nephropathy but not between SUA and diabetic retinopathy or diabetic neuropathy.

Targets to Search for New Pharmacological Treatment in Idiopathic Parkinson’s Disease According to the Single-Neuron Degeneration Model

Article

Full-text available

Jun 2024

One of the biggest problems in the treatment of idiopathic Parkinson’s disease is the lack of new drugs that slow its progression. L-Dopa remains the star drug in the treatment of this disease, although it induces severe side effects. The failure of clinical studies with new drugs depends on the use of preclinical models based on neurotoxins that do not represent what happens in the disease since they induce rapid and expansive neurodegeneration. We have recently proposed a single-neuron degeneration model for idiopathic Parkinson’s disease that requires years to accumulate enough lost neurons for the onset of motor symptoms. This single-neuron degeneration model is based on the excessive formation of aminochrome during neuromelanin synthesis that surpass the neuroprotective action of the enzymes DT-diaphorase and glutathione transferase M2-2, which prevent the neurotoxic effects of aminochrome. Although the neurotoxic effects of aminochrome do not have an expansive effect, a stereotaxic injection of this endogenous neurotoxin cannot be used to generate a preclinical model in an animal. Therefore, the aim of this review is to evaluate the strategies for pharmacologically increasing the expression of DT diaphorase and GSTM2-2 and molecules that induce the expression of vesicular monoamine transporter 2, such as pramipexole.

Investigating the Therapeutic Potential of Uric Acid in Alzheimer's Disease: Insights from the cGMP-PKG Signaling Pathway

Preprint

Full-text available

Feb 2024

Background: Alzheimer's disease (AD) is characterized by neuroinflammation and oxidative stress, both contributing to disease progression. Uric acid (UA) has emerged as a potential therapeutic agent due to its anti-inflammatory and antioxidative properties. However, the precise mechanisms underlying UA's role in AD pathogenesis remain unclear. Methods: BV2 microglial cells were subjected to treatments with UA, lipopolysaccharide (LPS), or a combination of both. Analyses of gene expression profiling, protein assessment, ELISA, ROS assays, and proteomic analysis were performed. Statistical analyses involved one-way ANOVA followed by Dunnett's multiple comparison tests and Student’s unpaired t-test for group comparisons. Results: UA treatment markedly suppressed LPS-induced upregulation of NF-𝜅B and NLRP3 mRNA expression (p < 0.001). Inflammatory cytokine release (IL-1β and TNF𝜶) was reduced by up to 50% (p < 0.05) with UA treatment, while oxidative stress was mitigated, evidenced by an 84% reduction in ROS levels (p < 0.001) and a 32% increase in antioxidant enzyme activity (p < 0.01). Proteomic analysis unveiled significant alterations in key signaling pathways pertinent to AD pathology, including downregulation of cholesterol metabolism (p < 0.05) and upregulation of cGMP-PKG (p < 0.001) and Wnt signaling pathways (p < 0.001). Notably, UA treatment induced increased expression of Atp2b4, a pivotal regulator of calcium homeostasis, suggesting its potential role in mediating the observed antioxidative effects. Conclusions: UA exhibits promising anti-inflammatory and antioxidative effects in BV2 microglial cells, underscoring its potential as a therapeutic avenue for AD. These findings offer valuable insights into UA's molecular mechanisms and advocate for further investigation to validate its clinical efficacy in managing AD. Understanding UA's role in modulating neuroinflammatory pathways and oxidative stress could pave the way for novel therapeutic interventions in AD management.

Microbiota-gut-liver-brain axis and hepatic encephalopathy

Article

Full-text available

Jan 2024

Hepatic encephalopathy (HE) is a clinical manifestation of neurological and psychiatric abnormalities that are caused by complications of liver dysfunction including hyperammonemia, hyperuricemia, and portal hypertension. Accumulating evidence suggests that HE could be reversed through therapeutic modifications of gut microbiota. Multiple preclinical and clinical studies have indicated that gut microbiome affects the physiological function of the liver, such as the regulation of metabolism, secretion, and immunity, through the gut-liver crosstalk. In addition, gut microbiota also influences the brain through the gut-brain crosstalk, altering its physiological functions including the regulation of the immune, neuroendocrine, and vagal pathways. Thus, key molecules that are involved in the microbiota-gut-liver-brain axis might be able to serve as clinical biomarkers for early diagnosis of HE, and could be effective therapeutic targets for clinical interventions. In this review, we summarize the pathophysiology of HE and further propose approaches modulating the microbiota-gut-liver-brain axis in order to provide a comprehensive understanding of the prevention and potential clinical treatment for HE with a microbiota-targeted therapy.

Association Study Between Kynurenine 3-Monooxygenase (KMO) Gene and Parkinson’s Disease Patients

Article

Full-text available

Dec 2023
MOL NEUROBIOL

The influence of various risk factors such as aging, intricate cellular molecular processes, and lifestyle factors like smoking, alcohol consumption, caffeine intake, and occupational factors has received increased focus in relation to the risk and development of Parkinson’s disease (PD). Limited research has been conducted on the assessment of lifestyle impact on kynurenine 3-monooxygenase (KMO) gene in PD. A total of 164 subjects, including 82 PD cases and 82 healthy individuals, were recruited based on specific inclusion and exclusion criteria. The severity of PD and clinical assessment were evaluated using the Unified Parkinson’s Disease Rating Scale (UPDRS) and Hoehn and Yahr (HY) scaling. Sanger sequencing was performed to analyse the KMO gene in the recruited subjects, and case–control studies were conducted. The UPDRS assessment revealed significant impairments in smell, tremors, walking, and posture instability in the late-onset PD cohorts. The HY scaling indicated a higher proportion of late-onset cohorts in stage 2. Moreover, both alcoholic and non-alcoholic groups showed significantly increased levels of 3-HK in late-onset PD. Gene analysis identified missense variants at position g.241593373 T > A (rs752312199) and intronic variants at positions g.241592623A > G (rs640718), g.241592800C > A (rs990388262), g.241592802A > C (rs1350160268), g.241592808 T > C (rs1478255936), and g.241592812G > T (rs948928931). The alterations in the KMO gene were found to influence the levels of kynurenic acid (KYNA) and 3-hydroxykynurenine (3-HK). Genomic analysis revealed a high prevalence of missense mutations in the late-onset PD groups, leading to a decline in 3-HK levels in patients. This leads to the reduction of the progression of disease in late-onset groups which shows that this mutation may lead to the protective effect on the PD subjects. This study suggests the use of KYNA and 3-HK as potential biomarkers in analysing the progression of disease. This study is limited by its small sample size. To overcome this limitation, a larger study involving in greater number of participants is needed to thoroughly investigate the KMO gene and KP metabolites, to enhance our understanding of Parkinson’s disease progression, and to enhance diagnostic capabilities.

Association between elevated serum uric acid levels and high estimated glomerular filtration rate with reduced risk of low muscle strength in older people: a retrospective cohort study

Article

Full-text available

Oct 2023
BMC Geriatr

Background We aimed to investigate the interaction between serum uric acid (SUA) levels with estimated glomerular filtration rate (eGFR) to low muscle strength (LMS) among older people in China. Methods Cohort data were obtained from China Health and Retirement Longitudinal Study (CHARLS) in 2011 and 2015. A total of 2,822 community-dwelling adults aged 60 and above were enrolled for the follow-up. Serum uric acid was collected after 8 h of fasting, and handgrip strength was measured with a dynamometer. eGFR was calculated with an equation based on the Chinese population. A generalized additive model was employed for interaction analysis and progressively adjusted confounders. Results During the follow-up, a total of 659 individuals were excluded due to the lack of grip strength data, leaving 2,163 participants for analysis. Despite the protective effect of high uric acid against low muscle strength, especially in older females, it is not statistically significant (OR = 0.69, 95%CI = 0.45–1.04, P = 0.075). Following the progressive adjustment of covariates, the association between higher eGFR and elevated SUA levels remained statistically significant in females, showing a reduced odds ratio with low muscle strength (OR = 0.82, 95%CI = 0.70–0.97, P = 0.021). However, this trend was not observed in male participants. Conclusions This Chinese population-based cohort study suggests that among older females, a higher serum uric acid level combined with a higher estimated glomerular filtration rate is linked to a reduced risk of low muscle strength. This implies that the relationship between high serum uric acid levels and the risk of low grip strength might differ by gender.

Uric acid regulates α-synuclein transmission in Parkinsonian models

Article

Full-text available

Aug 2023

Ample evidence demonstrates that α-synuclein (α-syn) has a critical role in the pathogenesis of Parkinson’s disease (PD) with evidence indicating that its propagation from one area of the brain to others may be the primary mechanism for disease progression. Uric acid (UA), a natural antioxidant, has been proposed as a potential disease modifying candidate in PD. In the present study, we investigated whether UA treatment modulates cell-to-cell transmission of extracellular α-syn and protects dopaminergic neurons in the α-syn-enriched model. In a cellular model, UA treatment decreased internalized cytosolic α-syn levels and neuron-to-neuron transmission of α-syn in donor-acceptor cell models by modulating dynamin-mediated and clathrin-mediated endocytosis. Moreover, UA elevation in α-syn-inoculated mice inhibited propagation of extracellular α-syn which decreased expression of phosphorylated α-syn in the dopaminergic neurons of the substantia nigra leading to their increased survival. UA treatment did not lead to change in markers related with autophagolysosomal and microglial activity under the same experimental conditions. These findings suggest UA may control the pathological conditions of PD via additive mechanisms which modulate the propagation of α-syn.

Serum Uric Acid as a Putative Biomarker in Prodromal Parkinson’s Disease: Longitudinal Data from the PPMI Study

Article

Full-text available

Jul 2023

Background The role of blood uric acid as a biomarker in symptomatic motor PD has been increasingly established in the literature. Objective Our present study assessed the role of serum uric acid as a putative biomarker in a prodromal PD cohort [REM Sleep Behavior disorder (RBD) and Hyposmia] followed longitudinally. Methods Longitudinal 5-year serum uric acid measurement data of 39 RBD patients and 26 Hyposmia patients with an abnormal DATSCAN imaging were downloaded from the Parkinson’s Progression Markers Initiative database. These cohorts were compared with 423 de novo PD patients and 196 healthy controls enrolled in the same study. Results After adjusting for age, sex, body mass index, and concomitant disorders (hypertension/gout), baseline and longitudinal serum uric acid levels were higher in the RBD subgroup as compared to the established PD cohort (p = 0.004 and p = 0.001). (Baseline RBD 6.07±1.6 vs. Baseline PD 5.35±1.3 mg/dL and Year-5 RBD 5.7±1.3 vs. Year-5 PD 5.26±1.33). This was also true for longitudinal measurements in the Hyposmic subgroup (p = 0.008) (Baseline Hyposmic 5.7±1.6 vs. PD 5.35±1.3 mg/dL and Year-5 Hyposmic 5.58±1.6 vs. PD 5.26±1.33). Conclusion Our results indicate that serum uric acid levels are higher in prodromal PD subjects with ongoing dopaminergic degeneration compared to those with manifest PD. These data indicate that the well-established decrease in the levels of serum uric acid occurs with the transition from prodromal to clinical PD. Whether the higher levels of serum uric acid observed in prodromal PD may provide protection against conversion to full-blown clinical PD will require further study.

Role of uric acid as a biomarker of cognitive function in schizophrenia during maintenance period

Article

Full-text available

Mar 2023

Background Previous studies involving uric acid (UA) in some specialized disease populations have found that high UA is associated with enhanced patient function. The mechanism to explain this association may be that UA, an important antioxidant, exerts neuroprotective effects. Patients with schizophrenia (SCZ) have severe oxidative stress abnormalities, and cognitive impairment is a major obstacle to their rehabilitation. Only few studies have been conducted on UA and cognitive impairment in SCZ. This study aims to clarify the relationship between UA and cognitive impairment and explore whether UA could be used as a potential biological marker of cognition in SCZ during maintenance period. Methods A total of 752 cases of SCZ during maintenance period from Baiyun Jingkang Hospital were included. Cognition was measured using the Mini-Mental State Examination scale. UA was measured using the Plus method. The participants were grouped on the basis of UA to evaluate the association of cognition with low-normal (3.50–5.07 mg/dL for men, 2.50–4.19 mg/dL for women), middle-normal (5.07–6.39 mg/dL for men, 4.19–5.18 mg/dL for women), high-normal (6.39–7.00 mg/dL for men, 5.18–6.00 mg/dL for women), and high (>7.00 mg/dL for men, >6.00 mg/dL for women) levels of UA. Multiple logistic regression and linear regression models and restricted cubic spline (RCS) were utilized to evaluate the relationship. Results Uric acid was positively associated with cognitive function. Subgroup analyses showed that high UA was associated with enhanced cognition in participants with low anticholinergic cognitive burden (ACB). Conclusion Uric acid may be used as a simple objective biological indicator to assess cognition in SCZ during maintenance period.

A Preclinical Model for Parkinson’s Disease Based on Transcriptional Gene Activation via KEAP1/NRF2 to Develop New Antioxidant Therapies

Article

Full-text available

Mar 2023

Investigations of the effect of antioxidants on idiopathic Parkinson’s disease have been unsuccessful because the preclinical models used to propose these clinical studies do not accurately represent the neurodegenerative process of the disease. Treatment with certain exogenous neurotoxins induces massive and extremely rapid degeneration; for example, MPTP causes severe Parkinsonism in just three days, while the degenerative process of idiopathic Parkinson´s disease proceeds over many years. The endogenous neurotoxin aminochrome seems to be a good alternative target since it is formed in the nigrostriatal system neurons where the degenerative process occurs. Aminochrome induces all the mechanisms reported to be involved in the degenerative processes of idiopathic Parkinson’s disease. The presence of neuromelanin-containing dopaminergic neurons in the postmortem brain of healthy elderly people suggests that neuromelanin synthesis is a normal and harmless process despite the fact that it requires oxidation of dopamine to three ortho-quinones that are potentially toxic, especially aminochrome. The apparent contradiction that neuromelanin synthesis is harmless, despite its formation via neurotoxic ortho-quinones, can be explained by the protective roles of DT-diaphorase and glutathione transferase GSTM2-2 as well as the neuroprotective role of astrocytes secreting exosomes loaded with GSTM2-2. Increasing the expression of DT-diaphorase and GSTM2-2 may be a therapeutic goal to prevent the degeneration of new neuromelanin-containing dopaminergic neurons. Several phytochemicals that induce DT-diaphorase have been discovered and, therefore, an interesting question is whether these phytochemical KEAP1/NRF2 activators can inhibit or decrease aminochrome-induced neurotoxicity.

The glucocerebrosidase mutations and uric acid levels in Parkinson’s disease: A 3-years investigation of a potential biomarker”

Article

Full-text available

Dec 2022

Background Blood uric acid level indicates an emerging biomarker in Parkinson's disease (PD). This study aimed to evaluate longitudinal uric acid levels among different kinds of glucocerebrosidase (GBA) mutations and to compare it among sporadic PD, genetic cohort Parkinson's disease (GENPD), genetic cohort unaffected (GENUN), and healthy control (HC) patients. Methods We conducted a study on 654 individuals from the Parkinson's progression markers initiative (PPMI) database. Baseline characteristics, uric acid levels, movement disorder society unified Parkinson's disease rating scale III (MDS-UPDRS III), Hoehn and Yahr Parkinson stage (H&Y stage), and DaT scan specific binding ratio (SBR) data were obtained. Different GBA mutations were collected and categorized into three groups. Longitudinal measurements of uric acid and MDS-UPDRS III score were evaluated during 3-years of follow-up. Result GENPD cohort exhibited a greater MDS-UPDRS III score, H&Y stage, and lower SBR in the right caudate, left caudate, and right putamen compared to sporadic PD. Baseline uric acid level was similar among all groups and different GBA variants. After adjustment for age, sex, and body mass index, the uric acid level was significantly lower in the GENPD group than in HC during year 2 (P-value: 0.009). No significant longitudinal differences were detected for the MDS-UPDRS III score and three groups of GBA mutations. Conclusion This is the first study to assess uric acid levels and MDS-UPDRS III scores among different GBA mutation variants within 3-years of follow-up. We found similar clinical characteristics among different subtypes of GBA mutations.

Association between gout and the development of Parkinson’s disease: a systematic review and meta-analysis

Article

Full-text available

Oct 2022
BMC NEUROL

Background As a natural antioxidant, uric acid plays a protective role against neurodegenerative disorders, including Parkinson’s disease (PD). Therefore, the risk of PD has been found to be lower in people with hyperuricemia. In this article, we conducted a systematic review and meta-analysis to investigate whether gout affects the future risk of developing PD. Methods We searched PubMed, Scopus, the Web of Science, and Google Scholar to find relevant studies, up to March 16, 2022. Studies investigating the risk of PD, following a gout diagnosis, were included if they were cross-sectional, case–control or cohort studies. The Newcastle Ottawa Scale (NOS) checklist was used to assess the quality of all included studies. The meta-analysis was performed using STATA 17.0. Results Ten studies were included, which were comprised of three case-controls, six cohort studies and one nested case–control study. We found no significant association between gout and the risk of PD among both sexes (RR = 0.94, 95% CI: 0.86–1.04), although the association was significant for females (RR = 1.09; 95% CI: 1.02–1.17). Subgroup analysis also showed no significant findings by age group, whether they were receiving treatment for gout, study design, quality assessment score, and method of gout ascertainment. In contrast, the studies that defined PD according to the use of drugs showed significant results (RR = 0.82; 95% CI: 0.76–0.89). There was a significant publication bias on the association between gout and PD. Conclusions The presence of gout had no significant effect on the risk of subsequently developing PD. Further analyses are recommended to investigate the effects of demographic and behavioral risk factors.

Uric Acid Enhances Neurogenesis in a Parkinsonian Model by Remodeling Mitochondria

Article

Full-text available

Jun 2022

Background Adult neurogenesis is the process of generating new neurons to enter neural circuits and differentiate into functional neurons. However, it is significantly reduced in Parkinson’s disease (PD). Uric acid (UA), a natural antioxidant, has neuroprotective properties in patients with PD. This study aimed to investigate whether UA would enhance neurogenesis in PD. Methods We evaluated whether elevating serum UA levels in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonian mouse model would restore neurogenesis in the subventricular zone (SVZ). For a cellular model, we primary cultured neural precursor cells (NPCs) from post-natal day 1 rat and evaluated whether UA treatment promoted cell proliferation against 1-methyl-4-phenylpyridinium (MPP ⁺ ). Results Uric acid enhanced neurogenesis in both in vivo and in vitro parkinsonian model. UA-elevating therapy significantly increased the number of bromodeoxyuridine (BrdU)-positive cells in the SVZ of PD animals as compared to PD mice with normal UA levels. In a cellular model, UA treatment increased the expression of Ki-67. In the process of modulating neurogenesis, UA elevation up-regulated the expression of mitochondrial fusion markers. Conclusion In MPTP-induced parkinsonian model, UA probably enhanced neurogenesis via regulating mitochondrial dynamics, promoting fusion machinery, and inhibiting fission process.

The Influence of Serum Uric Acid on the Brain and Cognitive Dysfunction

Article

Full-text available

Apr 2022

Uric acid is commonly known for its bad reputation. However, it has been shown that uric acid may be actively involved in neurotoxicity and/or neuroprotection. These effects could be caused by oxidative stress or inflammatory processes localized in the central nervous system, but also by other somatic diseases or systemic conditions. Our interest was to summarize and link the current data on the possible role of uric acid in cognitive functioning. We also focused on the two putative molecular mechanisms related to the pathological effects of uric acid—oxidative stress and inflammatory processes. The hippocampus is a prominent anatomic localization included in expressing uric acid's potential impact on cognitive functioning. In neurodegenerative and mental disorders, uric acid could be involved in a variety of ways in etiopathogenesis and clinical presentation. Hyperuricemia is non-specifically observed more frequently in the general population and after various somatic illnesses. There is increasing evidence to support the hypothesis that hyperuricemia may be beneficial for cognitive functioning because of its antioxidant effects but may also be a potential risk factor for cognitive dysfunction, in part because of increased inflammatory activity. In this context, gender specificities must also be considered.

Elevated Serum Uric Acid Increases the Risk of Ischemic Stroke Recurrence and Its Inflammatory Mechanism in Older Adults

Article

Full-text available

Mar 2022

Background Serum uric acid (UA) has been reported to be associated with ischemic stroke and inflammation. However, whether or not UA is related to the recurrence of ischemic stroke, and whether inflammation plays a role in the relationship between them remain inconclusive. Objective We sought to explore the relationship between UA and the recurrence of ischemic stroke and to define the role of neutrophil-to-lymphocyte ratio (NLR) in the aforementioned relationship. Methods A total of 8,995 patients were included in this study. Basic information and blood samples were collected, and whether or not each participant experienced ischemic stroke recurrence within 3 years was documented. Patients were stratified into three groups according to their UA level, as follows: ≤ 266, 267–339, and ≥ 340 μmol/L. COX regression and restricted cubic spline regression models were used to evaluate the clinical correlation between UA and ischemic stroke recurrence, mediation analysis and interaction and joint analysis were used to evaluate the role of NLR in the association of UA and ischemic stroke recurrence, and sensitivity and subgroup analyses were performed to test the robustness of the data. Results Ischemic stroke recurrence was related to male sex, older age, higher UA level, higher NLR, hypertension, diabetes, and cardiovascular disease. Following adjustment for potential confounders, a high level of UA (≥ 340 μmol/L) increased the risk of recurrence by 92.6% in patients with previous ischemic stroke. We also found that NLR affects the association between UA and the recurrence of ischemic stroke in older adults, suggesting that patients with high NLR and high UA levels are at greater risk for ischemic stroke recurrence. Conclusion UA level is non-linearly associated with recurrence, and NLR has an additive interaction between UA and ischemic stroke recurrence.

Asymptomatic Hyperuricemia Promotes Recovery from Ischemic Organ Injury by Modulating the Phenotype of Macrophages

Article

Full-text available

Feb 2022

Acute organ injury, such as acute kidney injury (AKI) and disease (AKD), are major causes of morbidity and mortality worldwide. Hyperuricemia (HU) is common in patients with impaired kidney function but the impact of asymptomatic HU on the different phases of AKI/AKD is incompletely understood. We hypothesized that asymptomatic HU would attenuate AKD because soluble, in contrast to crystalline, uric acid (sUA) can attenuate sterile inflammation. In vitro, 10 mg/dL sUA decreased reactive oxygen species and interleukin-6 production in macrophages, while enhancing fatty acid oxidation as compared with a physiological concentration of 5 mg/dL sUA or medium. In transgenic mice, asymptomatic HU of 7–10 mg/dL did not affect post-ischemic AKI/AKD but accelerated the recovery of kidney excretory function on day 14. Improved functional outcome was associated with better tubular integrity, less peritubular inflammation, and interstitial fibrosis. Mechanistic studies suggested that HU shifted macrophage polarization towards an anti-inflammatory M2-like phenotype characterized by expression of anti-oxidative and metabolic genes as compared with post-ischemic AKI-chronic kidney disease transition in mice without HU. Our data imply that asymptomatic HU acts as anti-oxidant on macrophages and tubular epithelial cells, which endorses the recovery of kidney function and structure upon AKI.

Serum Uric Acid Levels in Parkinson’s Disease: A Cross-Sectional Electronic Medical Record Database Study from a Tertiary Referral Centre in Romania

Article

Full-text available

Feb 2022
MED LITH

Background and Objectives: Parkinson’s disease (PD) is a prevalent neurodegenerative condition responsible for progressive motor and non-motor symptoms. Currently, no prophylactic or disease-modifying interventions are available. Uric acid (UA) is a potent endogenous antioxidant, resulting from purine metabolism. It is responsible for about half of the antioxidant capacity of the plasma. Increasing evidence suggests that lower serum UA levels are associated with an increased risk of developing PD and with faster disease progression. Materials and Methods: We conducted an electronic medical record database study to investigate the associations between UA levels and different characteristics of PD. Results: Out of 274 datasets from distinct patients with PD, 49 complied with the predefined inclusion and exclusion criteria. Lower UA levels were significantly associated with the severity of parkinsonism according to the Hoehn and Yahr stage (rs = 0.488, p = 0.002), with the motor complications of long-term dopaminergic treatment (r = 0.333, p = 0.027), and with the presence of neurocognitive impairment (r = 0.346, p = 0.021). Conclusions: Oxidative stress is considered a key player in the etiopathogenesis of PD, therefore the involvement of lower UA levels in the development and progression of PD is plausible. Data on the potential therapeutic roles of elevating serum UA (e.g., by precursor administration or diet manipulation) are scarce, but considering the accumulating epidemiological evidence, the topic warrants further research.

Potential roles of uric acid in perioperative neurocognitive disorders

Article

Apr 2025

Neuroprotective effect of Cistanche deserticola glycosides in MPTP-Induced Parkinson’s disease mouse model involves Nrf2 activation

Article

Mar 2025
J TOXICOL ENV HEAL A

Neuropharmacology of endophytic fungal bioactives: Promising leads for brain disorders

Chapter

Jan 2025

Sheetal Vats

Impact of Nutrition on the Gut Microbiota: Implications for Parkinson's Disease

Article

Jan 2025
NUTR REV

Parkinson’s disease (PD) is a multifactorial neurodegenerative disease that is characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta and by the anomalous accumulation of α-synuclein aggregates into Lewy bodies and Lewy neurites. Research suggests 2 distinct subtypes of PD: the brain-first subtype if the pathology arises from the brain and then spreads to the peripheral nervous system (PNS) and the body-first subtype, where the pathological process begins in the PNS and then spreads to the central nervous system. This review primarily focuses on the body-first subtype. The influence of the gut microbiota on the development of PD has been the subject of growing interest among researchers. It has been suggested that gut inflammation may be closely associated with pathogenesis in PD, therefore leading to the hypothesis that gut microbiota modulation could play a significant role in this process. Nutrition can influence gut health and alter the risk and progression of PD by altering inflammatory markers. This review provides an overview of recent research that correlates variations in gut microbiota composition between patients with PD and healthy individuals with the impact of certain nutrients and dietary patterns, including the Mediterranean diet, the Western diet, and the ketogenic diet. It explores how these diets influence gut microbiota composition and, consequently, the risk of PD. Last, it examines fecal transplantation and the use of prebiotics, probiotics, or synbiotics as potential therapeutic strategies to balance the gut microbiome, aiming to reduce the risk or delay the progression of PD.

The uric acid lowering potential of bioactive natural products and extracts derived from traditional Chinese medicines: A review and perspective

Article

Jan 2025

Inosine exerts dopaminergic neuroprotective effects via mitigation of NLRP3 inflammasome activation

Article

Dec 2024
NEUROPHARMACOLOGY

Changes in serum uric acid, glutathione, and amyloid-β1-42 levels in Parkinson's disease patients and their association with disease progression and cognitive decline

Article

Oct 2024
CURR MED RES OPIN

Objective: This study aims to evaluate the diagnostic significance of serum uric acid (UA), glutathione (GSH), and amyloid-β1-42 (Aβ1-42) levels in relation to disease progression and cognitive impairment in patients with Parkinson's disease (PD). Methods: A total of 209 PD patients with disease duration ranging from 4.0 to 6.8 years were enrolled. Based on the Hoehn-Yahr staging system, patients were classified into Early (n = 67), Medium-term (n = 70), and Advanced (n = 72) stages. Cognitive function was assessed using the Mini-Mental State Examination (MMSE), dividing the cohort into CD (cognitive dysfunction, n = 94) and NO-CD (no cognitive dysfunction, n = 115) groups. Serum UA, GSH, and Aβ1-42 levels were analyzed for correlations with clinical data. Independent risk factors and diagnostic value were determined through multivariable logistic regression models and receiver operating characteristic curve analysis. Results: Serum UA and GSH levels progressively declined with advancing disease stage, while Aβ1-42 increased. Compared to the NO-CD group, the CD group showed lower serum UA and GSH levels, and higher Aβ1-42 levels. Serum UA and GSH were inversely correlated with disease duration, levodopa equivalent daily dose, and Unified Parkinson's Disease Rating Scale scores, while Aβ1-42 showed positive correlations. UA (p = 0.006), GSH (p < 0.001), and Aβ1-42 (p = 0.040) were independent predictors of disease stage. Similarly, UA (p = 0.003), GSH (p < 0.001), and Aβ1-42 (p < 0.001) were independent predictors of cognitive dysfunction. The combined assessment of these markers demonstrated a higher area under the curve (AUC) than individual markers for disease and cognitive decline identification. Conclusions: Serum UA, GSH, and Aβ1-42 are independent predictors of disease progression and cognitive decline in PD patients. Their combined use offers enhanced diagnostic accuracy for disease staging and cognitive impairment in PD.

Uric Acid: A Biomarker and Pathogenic Factor of Affective Disorders and Neurodegenerative Diseases

Article

Oct 2024
CURR PHARM DESIGN

Uric acid (UA), the end-product of purine metabolism, has a complicated physiological role in the body, showing the combination of regulating inflammatory response, promoting oxidation/anti-oxidation, and modifying autophagy activity in vivo. Meanwhile, various research and theories support that inflammation, oxidative stress, and other risk factors promote the onset and progression of affective disorders and neurodegenerative diseases. Existing studies suggest that UA may be involved in the pathophysiological processes of affective disorders in various ways, and there has been a gradual advance in the understanding of the interplay between UA levels and affective disorders and neurodegenerative diseases. This review summarized the role of UA in the process of inflammation, oxidative stress, and autophagy. On this basis, we discussed the correlation between UA and affective disorders and several neurodegenerative diseases, and simultaneously analyzed the possible mechanism of its influence on affective disorders and neurodegenerative diseases, to provide a theoretical basis for UA as a biomarker or therapeutic target for the diagnosis of these diseases.

The SIRT-1/Nrf2/HO-1 Axis: Guardians of Neuronal Health in Neurological Disorders

Article

Oct 2024

Integrated Microbiome and Metabolome Analysis Reveals Hypothalamic‐Comorbidities Related Signatures in Craniopharyngioma

Article

Full-text available

Sep 2024

Craniopharyngioma (CP) is an intracranial tumor with high mortality and morbidity. Though biologically benign, CP will damage the hypothalamus, inducing comorbidities such as obesity, metabolic syndrome, and cognitive impairments. The roles of gut microbiome and serum metabolome in CP‐associated hypothalamic comorbidities are aimed to be explored. Patients with CP are characterized by increased Shannon diversity, Eubacterium, Clostridium, and Roseburia, alongside decreased Alistipes and Bacteroides. CP‐enriched taxa are positively correlated with dyslipidemia and cognitive decline, while CP‐depleted taxa are negatively associated with fatty liver. Subsequent serum metabolomics identified notably up‐regulated purine metabolism, and integrative analysis indicated an association between altered microbiota and elevated hypoxanthine. Phenotypic study and multi‐omics analysis in the Rax‐CreERT2::BrafV600E/+::PtenFlox/+ mouse model validated potential involvement of increased Clostridium and dysregulated purine metabolism in hypothalamic comorbidities. To further consolidate this, intervention experiments are performed and it is found that hypoxanthine co‐variated with the severity of hypothalamic comorbidities and abundance of Clostridium, and induced dysregulated purine metabolism along with redox imbalance in target organs (liver and brain cortex). Overall, the study demonstrated the potential of increased Clostridium and up‐regulated purine metabolism as signatures of CP‐associated hypothalamic‐comorbidities, and unveiled that elevated Clostridium, dysregulated purine metabolism, and redox imbalance may mediate the development and progression of CP‐associated hypothalamic‐comorbidities.

Uric acid in health and disease: From physiological function to pathogenic mechanism

Article

Feb 2024
PHARMACOL THERAPEUT

Positive Effects of Uric Acid on White Matter Microstructures and Treatment Response in Patients With Schizophrenia

Article

Feb 2024

Background and Hypothesis Schizophrenia involves microstructural changes in white matter (WM) tracts. Oxidative stress is a key factor causing WM damage by hindering oligodendrocyte development and myelin maturation. Uric acid (UA), an endogenous antioxidant, may protect against oxidative stress. We investigated the effect of UA on WM connectivity in antipsychotic-naive or -free patients with early- or chronic-stage schizophrenia. Study Design A total of 192 patients with schizophrenia (122 recent-onset [ROS] and 70 chronic [CS]) and 107 healthy controls (HCs) participated in this study. Diffusion tensor imaging data and serum UA levels at baseline were obtained. Study Results Fractional anisotropy was lower in the widespread WM regions across the whole brain, and diffusivity measures were higher in both schizophrenia groups than in HCs. The CS group showed lower diffusivity in some WM tracts than the ROS or HC groups. The linear relationship of serum UA levels with axial and mean diffusivity in the right frontal region was significantly different between schizophrenia stages, which was driven by a negative association in the CS group. WM diffusivity associated with serum UA levels correlated with 8-week treatment responses only in patients with CS, suggesting UA to be protective against long-term schizophrenia. Conclusions UA may protect against the WM damage associated with the progression of schizophrenia by reducing oxidative stress and supporting WM repair against oxidative damage. These results provide insights into the positive role of UA and may facilitate the development of novel disease-modifying therapies.

Mitochondrial homeostasis regulation: A promising therapeutic target for Parkinson's disease

Article

Dec 2023

Xanthine or hypoxanthine or both may play therapeutical effect in Parkinson's disease through the endocannabinoid system

Article

Dec 2023
MED HYPOTHESES

Aureusidin ameliorates 6-OHDA-induced neurotoxicity via activating Nrf2/HO-1 signaling pathway and preventing mitochondria-dependent apoptosis pathway in SH-SY5Y cells and Caenorhabditis elegans

Article

Dec 2023
CHEM-BIOL INTERACT

Role of Astrogliosis in the Pathogenesis of Parkinson’s Disease: Insights into Astrocytic Nrf2 Pathway as a Potential Therapeutic Target

Article

Oct 2023
CNS NEUROL DISORD-DR

Recently, Parkinson’s disease (PD) has become a remarkable burden on families and society with an acceleration of population aging having several pathological hallmarks such as dopaminergic neuronal loss of the substantia nigra pars compacta, α-synucleinopathy, neuroinflammation, autophagy, last but not the least astrogliosis. Astrocyte, star-shaped glial cells perform notable physiological functions in the brain through several molecular and cellular mechanisms including nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. It has been well established that the downregulation of the astrocytic Nrf2 signaling pathway plays a crucial role in the pathogenesis of PD because it is a master regulator of cellular defense mechanism along with a regulator of numerous detoxifying and antioxidant enzymes gene expression. Fascinatingly, upregulation of the astrocytic Nrf2 signaling pathway attenuates the degeneration of nigrostriatal neurons, restores neuronal proliferation, rejuvenates astrocytic functions, and exhibits neuroprotective effects via numerous cellular and molecular mechanisms in the PD-like brain of the experimental animal. Here, we discuss the numerous in-vitro and in-vivo studies that evaluate the neuroprotective potential of the astrocytic Nrf2 signaling pathway against experimentally-induced PD-like manifestation. In conclusion, based on available preclinical reports, it can be assumed that the astrocytic Nrf2 signaling pathway could be an alternative target in the drug discovery process for the prevention, management, and treatment of PD.

Protective Effects of Safflor Yellow A Against H 2 O 2 -induced Oxidative Stress Injury in PC12 Cells via Nrf2/HO-1 Pathway

Article

May 2023

Background Safflor yellow (SY) is a water-capacitive component of dried flowers, mainly from safflor in the safflower family, which contains a large amount of bruthin A, or Safflor yellow A (SYA) for short. Studies have reported the protective effects of SYA against oxidative stress injury in nerve cells. Materials and Methods In this study, H 2 O 2 -treated PC12 cells were used as experimental materials to explore how SYA plays a protective role against nerve cells after oxidative stress and to analyze the molecular mechanism of SYA. PC12 cells were treated with H 2 O 2 and SYA solution. Cell proliferation is then detected with Cell Counting Kit-8 (CCK-8). The detection method is 5-(and 6)-chloromethyl-2′,7′-dichloro-dihydrofluorescein diacetate (CM-H2DCF-DA) staining reactive oxygen species (ROS). Levels of apoptosis-related proteins, including Bcl2-associated X protein (Bax), B-cell lymphoma (Bcl-2), caspase-3, and cleaved caspase-3, and oxidative stress regulators, namely, nuclear factor erythroid-2-related actor 2 (Nrf2) and heme oxygenase 1 (HO-1), were detected by western blotting. Results The CCK-8 assay results showed that the survival rate of H 2 O 2 -induced PC12 cells was significantly increased after SYA treatment. Fluorescence microscopy (CM-H2DCF-DA staining) indicated that SYA decreased H 2 O 2 -induced apoptosis in PC12 cells by reducing intracellular ROS. Western blotting analysis showed that SYA upregulated the expression of Nrf2, HO-1, and Bcl-2 and downregulated the expression of Bax, caspase 3, and cleaved caspase-3 in H 2 O 2 -induced PC12 cells. Conclusion SYA does protect the nerve cells from oxidative stress damage. Its mechanism of action is mainly related to whether the Nrf2/HO-1 pathway is activated.

Glutathione-Mediated Neuroprotective Effect of Purine Derivatives

Article

Full-text available

Aug 2023
INT J MOL SCI

Numerous basic studies have reported on the neuroprotective properties of several purine derivatives such as caffeine and uric acid (UA). Epidemiological studies have also shown the inverse association of appropriate caffeine intake or serum urate levels with neurodegenerative diseases such as Alzheimer disease (AD) and Parkinson’s disease (PD). The well-established neuroprotective mechanisms of caffeine and UA involve adenosine A2A receptor antagonism and antioxidant activity, respectively. Our recent study found that another purine derivative, paraxanthine, has neuroprotective effects similar to those of caffeine and UA. These purine derivatives can promote neuronal cysteine uptake through excitatory amino acid carrier protein 1 (EAAC1) to increase neuronal glutathione (GSH) levels in the brain. This review summarizes the GSH-mediated neuroprotective effects of purine derivatives. Considering the fact that GSH depletion is a manifestation in the brains of AD and PD patients, administration of purine derivatives may be a new therapeutic approach to prevent or delay the onset of these neurodegenerative diseases.

Oxidative Metabolism Genes in Ovarian Neoplasms

Article

Jun 2023

BACKGROUND: Reactive oxygen species play important and ambiguous role in carcinogenesis, and local oxidative metabolism may differ significantly from systemic metabolism and determine the processes occurring in tumor tissues. AIM: This study aimed to examine the expressions of key oxidative metabolism genes, particularly CYB5R, POR, NOX4, SOD1, NF-B, and NRF2, in ovarian neoplasm tissues, and determine cytochrome b5 reductase and cytochrome P450 reductase activity, blood neutrophil activity, and antioxidant indices in the blood plasma and peritoneal fluid. MATERIALS AND METHODS: The study included two groups of patients: a study group (n = 10) with ovarian adenocarcinoma and a comparison group (n = 6) with benign ovarian neoplasms. The expressions of CYB5R1, CYB5R2/R4, CYB5R3, POR, BIRC3, NOX4, NRF2, NF-B, SOD1, HMOX1, and BCL2 genes, cytochrome b5 reductase, and cytochrome P450 reductase activity, oxidative activity of blood neutrophils, and antioxidant potential of plasma and peritoneal fluid were evaluated in these two groups of women. RESULTS: The expression levels of CYB5R3 and BCL2 were significantly lower in adenocarcinoma tissues. The activities of cytochrome b5 reductase and cytochrome P450 reductase increased in the group with adenocarcinoma. On average, the activity of blood neutrophils corresponded to the reference values. For blood plasma, the antioxidant capacity were not different, whereas the antioxidant capacity in the peritoneal fluid increased approximately twofold in ovarian cancer. CONCLUSIONS: Significantly increased cytochrome b5 reductase activity in adenocarcinoma tissues may be a response to intracellular oxidative stress, whereas CYB5R3 gene expression may be reduced by a negative feedback mechanism. The activities of cytochrome P450 reductase and its gene change to a lesser extent in the presence of ovarian adenocarcinoma. The oxidative balance in the blood and peritoneal fluid correlated with the tissue expressions of NF-B and NRF2.

Uric acid en route to gout

Chapter

Full-text available

Jun 2023

Wei-Zheng Zhang

Gout and hyperuricemia (HU) have generated immense attention due to increased prevalence. Gout is a multifactorial metabolic and inflammatory disease that occurs when increased uric acid (UA) induce HU resulting in monosodium urate (MSU) crystal deposition in joints. However, gout pathogenesis does not always involve these events and HU does not always cause a gout flare. Treatment with UA-lowering therapeutics may not prevent or reduce the incidence of gout flare or gout-associated comorbidities. UA exhibits both pro- and anti-inflammation functions in gout pathogenesis. HU and gout share mechanistic and metabolic connections at a systematic level, as shown by studies on associated comorbidities. Recent studies on the interplay between UA, HU, MSU and gout as well as the development of HU and gout in association with metabolic syndromes, non-alcoholic fatty liver disease (NAFLD), and cardiovascular, renal and cerebrovascular diseases are discussed. This review examines current and potential therapeutic regimens and illuminates the journey from disrupted UA to gout.

Association between uric acid and cognitive dysfunction: A cross-sectional study with newly diagnosed, drug-naïve with bipolar disorder

Article

Feb 2023
J AFFECT DISORDERS

Background: Cognitive impairment is one of the major symptoms of individuals with bipolar disorder (BD). Purine system disorders may play an important role in cognitive dysfunction. So far, the relationship between cognitive deficits and purinergic metabolism in BD has been seldom discussed in previous studies. This study aims to explore its relevance and potential biological mechanisms. Methods: In this cross-sectional study, 205 first time diagnosed drug-naive individuals with BD and 97 healthy volunteers were recruited. The uric acid(UA) level was measured using automatic biochemical analyzer, and cognitive function was assessed by Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and Stroop color-word test. In addition, general information and clinical symptoms were collected and evaluated. Results: In this study, the UA level of BD group (U = 8475.000, p = 0.038) was found to be significantly higher than that of the healthy controls, but the scores of RBANS (t = -11.302, p < 0.001) and Stroop color-word test (t = -6.962, p < 0.001) were significantly lower than that of the healthy controls. In gender subgroup analysis, females had lower UA level and higher RBANS scores. In correlation analysis, the cognitive function of individuals with BD was found to present a significant negative correlation with UA level in attention (r = -0.23, p = 0.001) and delayed memory(r = -0.16, p = 0.022). Limitations: This is a cross-sectional design. Conclusion: Elevated UA levels may be a potential mechanism of cognitive impairment in BD. This provides a new possible strategy for the prevention and treatment of cognitive impairment in BD.

Conductive Metal–Organic Framework Microelectrodes Regulated by Conjugated Molecular Wires for Monitoring of Dopamine in the Mouse Brain

Article

Jan 2023

Herein, we demonstrated a strategy to regulate the conductive metal-organic framework (MOF) surface, by the conjugated molecule wires for selective and sensitive determination of dopamine (DA) in the live brain. The MOFs were decorated at the carbon fiber electrode deposited by Au nanoleaves as the upper electric transducer to provide rich electrocatalytic sites for electron transfer of neurochemicals at the electrode surface, leading to greatly enhanced sensitivity for detection of neurochemicals. On the other hand, the conjugated molecular wire, 4-(thiophen-3-ylethynyl)-benzaldehyde (RP1), was synthesized and assembled as an underlying bridge to regulate the electrochemical processes at the MOF-based electrode, specifically decreasing the reaction Gibbs free energy of DA oxidation, thus selectively promoting the heterogeneous electron transfer of DA from the MOF layer to the electrode surface. Owing to the electrocatalytic activity for DA oxidation, the present microsensor exhibited high selectivity for real-time tracking of DA in a good linear relationship in the range of 0.004-0.4 μM with a detection limit of 1 nM. Eventually, this functionalized electrode was successfully applied for in vivo monitoring of DA in mouse brains with Parkinson's disease (PD) model. The results indicated that the levels of DA were obviously decreased in both acute and subacute PD models. Moreover, the level of DA strongly depended on the amount of uric acid (UA), a physiological antioxidant, which rose as the UA amount was lower than 200 mg kg-1 but was downregulated again after treatment by a higher amount of UA.

Le risque de maladie de Parkinson dans une population méditerranéenne de patients goutteux : étude cas-témoins

Article

Oct 2022
Rev Rhum

Objectif : des taux sanguins élevés d’acide urique, considéré comme un puissant antioxydant, ont été associés à un effet neuroprotecteur dans la maladie de Parkinson (MP). Cependant, la relation entre la goutte et la MP reste contradictoire. L’objectif est d’étudier si l’effet neuroprotecteur de l’acide urique est maintenu chez les patients goutteux au sein d’une large population urbaine méditerranéenne. Méthodes : étude cas-témoins s’appuyant sur la base de données des dossiers médicaux électroniques des soins primaires du système de santé publique de Barcelone. Cette base de données contient les données anonymes de 1 520 934 patients. Tous les sujets âgés de plus de 40 ans, avec un nouveau diagnostic de MP ou une nouvelle prescription de médicaments dopaminergiques, ont été inclus (cas incidents). Chaque cas a été apparié sur l’âge et le sexe à quatre témoins sélectionnés de manière aléatoire, selon la méthode d’appariement en pourcentages. Les données rétrospectives des facteurs de risque de MP ont également été collectées pour chaque individu. Un modèle de régression logistique multivariée a été utilisé pour évaluer l’association entre la goutte et la MP, ajustée pour la présence d’autres facteurs de risques. Résultats : un nouveau diagnostic de MP a été posé chez 17 629 individus (taux de diagnostic incidents de 2,2 pour 1000 individus). Le modèle de régression logistique multivariée a montré pour la goutte : un ORa=0,83 (0,76-0,91). Après stratification des individus par âge, l’ORa était de 0,99 (0,85-1,16) pour les sujets de moins de 75 ans et de 0,77 (0.70-0.86) pour ceux de 75 ans ou plus. La dyslipidémie, l’hypertension et le diabète ont été associés à un risque accru de MP. Le tabagisme a montré un rôle préventif dans l’apparition de la maladie. Conclusion : notre étude, la première réalisée au sein d’une population méditerranéenne, a révélé un effet protecteur de la goutte contre le risque de MP chez les hommes et les femmes de plus de 75 ans.

Higher serum uric acid with a high eGFR is associated with decreased risk of low muscle strength in aged population: a retrospective cohort study

Preprint

Full-text available

Aug 2022

Background We aimed to investigate the interaction between serum uric acid levels with estimated glomerular filtration rate (eGFR) to low muscle strength (LMS) in a large Chinese elderly population. Methods Cohort data were obtained from China Health and Retirement Longitudinal Study (CHARLS) in 2011 and 2015. Two thousand seven hundred forty-five community-dwelling older participants were enrolled for the follow-up. Serum uric acid was collected after 8 hours of fasting, and handgrip strength was measured with a dynamometer. eGFR was calculated with an equation based on the Chinese population. A generalized additive model was employed for interaction analysis and progressively adjusted confounders. Results In this study, we found that men with a low eGFR (<60 mL/min/1.73 m²) reported higher SUA levels (5.91 ± 1.27) and older (72.53 ± 6.38) than those who had a high eGFR while women share the same difference with a lower eGFR in higher SUA levels (5.00 ± 1.34) and older (72.81 ± 6.83). After progressively adjusting covariates, in females, the OR for higher eGFR with higher SUA level remained significantly with low muscle strength (OR=0.80 95%CI=0.68-0.95 P=0.0102). This correlation, however, was not observed in men. Conclusions This population-based cohort study in Chinese revealed that high serum uric acid level with higher eGFR seems to be significantly associated with a lower risk of low muscle strength in the elderly, especially in females.

Risk of Parkinson's disease in a gout Mediterranean population: A case-control study

Article

Apr 2022
JOINT BONE SPINE

Introduction High levels of serum urate has been associated to a neuroprotective effect in Parkinson's disease (PD) as an antioxidant agent. However, the relation between gout and PD remains contradictory. Objective to study if the neuroprotective effect of serum urate is maintained in patients with gout in a large urban Mediterranean population. Methods primary care based matched case-control study, carried out using an electronic health record database from the public primary care health system of Barcelona. The database contains anonymous data from 1,520,934 patients. All patients, over 40 years old, with a new diagnostic record of PD, or a new prescription of dopaminergic drugs were included (incident cases). We randomly selected four controls for each case, matched by gender and age, with the frequency matching approach. Retrospective data of PD risk factors were also collected for each individual. A multivariate logistic regression model was used to evaluate the association of gout and PD, adjusted by the presence of other risk factors. Results A new PD diagnosis was found in 17,629 individuals (incident diagnosis rate of 2.2 per 1000 individuals). Multivariate Logistic regression model showed for gout: aOR = 0.83 (0.76-0.91). When stratified by age, aOR for those under 75 years was 0.99 (0.85-1.16) and 75 or over OR = 0.77 (0.70-0.86). Dyslipidemia, hypertension and diabetes mellitus were associated with an increased risk of PD. Tobacco consumption was protective. Conclusion Our study, the first one made in a Mediterranean population, shows a PD protective effect of gout in both men and women over 75 years old.

Folic acid-modified lysozyme protected gold nanoclusters as an effective anti-inflammatory drug for rapid relief of gout flares in hyperuricemic rats

Article

Apr 2022
Mater Des

Background Gout normally occurs when excess urate crystals accumulate in the joints that induce inflammation. The inflammations further result in gout flares, causing serious pain. Some anti-inflammatory drugs can relieve pain, but they have various side effects. Nanomedicines can reduce side effects but are mostly based on the delivery of additional organic drugs, which adds complexity and may cause other health problems. We developed folic acid (FA)-modified lysozyme (Lys)-protected gold nanoclusters (AuNCs) (i.e., FLA) by a one-pot method, and successfully used FLA as an effective anti-inflammatory drug for relief of gout flares in hyperuricemic rats. Methods The morphological changes of the cells were studied by Transmission electron microscopy (TEM) and fluorescence microscopy. Western blot was conducted to understand the inflammation factors. AutoDock Vina was used for molecular docking of FLA. Results FLA reduced the inflammation, oxidative stress level in vitro. By injecting FLA into gout rat models, inflammations, cartilage destructions and pain during gout flares were also significantly relieved. Conclusion Compared with complicated nano-delivery systems, FLA directly exhibits exciting therapeutic efficiency against gout flares, which will have considerable prospects in the clinic.

Natural compounds lower uric acid levels and hyperuricemia: Molecular mechanisms and prospective

Article

Mar 2022
TRENDS FOOD SCI TECH

Background With the change of dietary habits and lifestyles, people tend to have elevated blood uric acid levels at a younger age, and this can cause serious health problems, such as hyperuricemia, gout, cardiovascular diseases and nephropathy. However, current clinical uric acid-lowering drugs mostly have side effects. Natural compounds from food and other plants have the properties of lowering uric acid. Scope and approach The objective of this review is to discuss the potential activities of natural compounds from food and other plants in lowering blood uric acid and the molecular mechanisms involved. Also discussed are the dietary sources of purines and key events in purine and uric acid metabolism, as well as hyperuricemia due to overproduction and underexcretion of uric acid. Key findings and conclusions Flavonoids, especially flavones and flavonols as well as saponins, terpenoids and alkaloids, have shown uric acid-lowering effects. These compounds could reduce blood uric acid by inhibiting xanthine oxidoreductase and regulating uric acid transporters. Based on this information and the purine contents of different food items, a dietary approach is discussed for the lowering of uric acid as an adjuvant or replacement of therapeutic drugs for hyperuricemia.

The potential role of neuroinflammation and transcription factors in Parkinson disease

Article

Full-text available

Mar 2017

Parkinson disease (PD) is a neurodegenerative disorder characterized by dopaminergic neurons affected by inflammatory processes. Post-mortem analyses of brain and cerebrospinal fluid from PD patients show the accumulation of proinflammatory cytokines, confirming an ongoing neuroinflammation in the affected brain regions. These inflammatory mediators may activate transcription factors—notably nuclear factor κB, Ying-Yang 1 (YY1), fibroblast growth factor 20 (FGF20), and mammalian target of rapamycin (mTOR)—which then regulate downstream signaling pathways that in turn promote death of dopaminergic neurons through death domain-containing receptors. Dopaminergic neurons are vulnerable to oxidative stress and inflammatory attack. An increased level of inducible nitric oxide synthase observed in the substantia nigra and striatum of PD patients suggests that both cytokine—and chemokine-induced toxicity and inflammation lead to oxidative stress that contributes to degeneration of dopaminergic neurons and to disease progression. Lipopolysaccharide activation of microglia in the proximity of dopaminergic neurons in the substantia nigra causes their degeneration, and this appears to be a selective vulnerability of dopaminergic neurons to inflammation. In this review, we will look at the role of various transcription factors and signaling pathways in the development of PD.

Serum uric acid levels in patients with Parkinson’s disease: A meta-analysis

Article

Full-text available

Mar 2017
PLOS ONE

Background Lower serum uric acid (UA) levels have been reported as a risk factor in Parkinson’s disease (PD). However, the results have been inconsistent so far. Objectives The aim of the present study was to clarify the potential relationship of uric acid with PD. Methods Comprehensive electronic search in pubmed, web of science, and the Cochrane Library database to find original articles about the association between PD and serum uric acid levels published before Dec 2015. Literature quality assessment was performed with the Newcastle-Ottawa Scale. Random-effects model was used to estimate the standardized mean differences (SMDs) with 95% confidence intervals (CIs). Heterogeneity across studies was assessed using I² and H² statistics. Sensitivity analyses to assess the influence of individual studies on the pooled estimate. Publication bias was investigated using funnel plots and Egger’s regression test. Analyses were performed by using Review Manager 5.3 and Stata 11.0. Results Thirteen studies with a total of 4646 participants (2379 PD patients and 2267 controls) were included in this meta-analysis. The current results showed that the serum UA levels in PD patients were significantly lower compared to sex and age-matched healthy controls (SMD: -0.49, 95% CI: [-0.67, -0.30], Z = 5.20, P < 0.001) and these results showed no geographic regional (Asia: SMD = −0.65, 95% CI [−0.84, −0.46], Z = 6.75, p <0.001; Non-Asia: SMD = −0.25, 95% CI [−0.43, −0.07], Z = 2.70, p = 0.007) and sex differences (women: SMD = −0.53, 95% CI [−0.70, −0.35], z = 5.98, p <0.001; men: SMD = −0.66, 95% CI [−0.87, −0.44], z = 6.03, p <0.001). Serum UA levels in middle-late stage PD patients with higher H&Y scales were significantly lower than early stage PD patients with lower H&Y scales (SMD = 0.63, 95% CI [0.36,0.89], z = 4.64, p <0.001). Conclusions Our study showed that the serum UA levels are significantly lower in PD and the level is further decreased as the disease progresses. Thus it might be a potential biomarker to indicate the risk and progression of PD.

Lower serum uric acid is associated with mild cognitive impairment in early Parkinson’s disease: a 4-year follow-up study

Article

Full-text available

Dec 2016
J NEURAL TRANSM

Cognitive deficits are common in Parkinson’s disease (PD) and many patients eventually develop dementia; however, its occurrence is unpredictable. Serum uric acid (UA) has been proposed as a biomarker of PD, both in the preclinical and clinical phase of the disease. The aim of this pilot study was to evaluate relationships between baseline serum UA levels and occurrence of mild cognitive impairment (MCI) at 4-year follow-up in a cohort of early PD patients. Early PD patients, not presenting concomitant diseases, cognitive impairment or treatment possibly interfering with UA levels, underwent neuropsychological testing at baseline and 4-year follow-up. UA levels were determined in serum at baseline. MCI was found in 23 out of 42 PD patients completing 4-year follow-up. Patients presenting MCI had significantly higher age at onset and lower Frontal Assessment Battery scores at baseline as compared with patients cognitively intact. Logistic regression analysis showed that both serum UA levels (OR = 0.54, p = 0.044) and age (OR = 1.16, p = 0.009) contribute to the occurrence of MCI at 4-year follow-up. Our pilot study suggests that lower levels of serum UA in the early disease stages are associated to the later occurrence of MCI. These results need to be confirmed by further studies on larger samples.

Therapeutic effects of paeonol on methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid-induced Parkinson's disease in mice

Article

Full-text available

Jul 2016

Paeonol is a major phenolic compound of the Chinese herb, Cortex Moutan, and is known for its antioxidant, anti-inflammatory and antitumor properties. The present study was designed to investigate the therapeutic potential and underlying mechanisms of paeonol on a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid (MPTP/p)-induced mouse model of Parkinson's disease (PD). MPTP (25 mg/kg), followed by probenecid (250 mg/kg), was administered via i.p. injection for five consecutive days to induce the mouse model of PD. Paeonol (20 mg/kg) was administrated orally for 21 days. Behavior was assessed using the rotarod performance and open‑field tests. Additionally, the levels of tyrosine hydroxylase (TH), microglia, interleukin‑1β (IL‑1β), and brain‑derived neurotrophic factor (BDNF) in the substantia nigra pars compacta (SNpc) were evaluated by immunohistochemical staining. MPTP/p‑induced motor deficits were observed to be significantly improved following long‑term treatment with paeonol. Paeonol treatment decreased MPTP/p‑induced oxidative stress, as determined by evaluating the activity levels of superoxide dismutase, catalase and glutathione. Additionally, MPTP/p‑induced neuroinflammation was assessed by examining the levels of microglia and IL‑1β, which were significantly decreased following paeonol treatment. Paeonol treatment improved the MPTP/p‑induced dopaminergic neurodegeneration, as measured by observing the increased TH level in the SNpc. Furthermore, the BDNF level was significantly elevated in the paeonol treatment group compared with mice treated with MPTP/p only. In conclusion, paeonol exerted therapeutic effects in the MPTP/p‑induced mouse model of PD, possibly by decreasing the damage from oxidative stress and neuroinflammation, and by enhancing the neurotrophic effect on dopaminergic neurons. The results demonstrate paeonol as a potential novel treatment for PD.

Comparison of Airway and Systemic Malondialdehyde Levels for Assessment of Oxidative Stress in Cystic Fibrosis

Article

Full-text available

May 2015
LUNG

Oxidative stress plays a pivotal role in the pathogenesis of cystic fibrosis (CF). In this study, airway and systemic oxidative stress was investigated in CF using malondialdehyde (MDA), an established by-product of polyunsaturated fatty acid peroxidation. Exhaled breath condensate (EBC), sputum, and plasma were collected from 40 stable CF patients during routine clinical visits and from 25 healthy controls. MDA was measured by high-performance liquid chromatography. MDA levels in sputum (279.8 ± 14.7 vs. 92.7 ± 9.2 nmol/L, p < 0.0001), EBC (139.9 ± 6.7 vs. 71.5 ± 4.3 nmol/L, p < 0.0001), and plasma (176.1 ± 15.9 vs. 129.6 ± 12.9 nmol/L, p < 0.05) were increased in patients with CF compared to healthy controls. MDA measurement in sputum [area under receiver operating characteristic curve (AUC): 0.977, p < 0.0001] or EBC (AUC: 0.94, p < 0.0001) discriminated between patients and controls with greater accuracy than in plasma (AUC: 0.677, p < 0.05). Sputum and EBC MDA levels were elevated in patients with severe pulmonary dysfunction [forced expiratory volume in 1 s (FEV1) <50 % predicted] compared to those with mild-to-moderate functional impairment (FEV1 ≥50 % predicted) (p < 0.05). MDA concentrations in CF patients colonized either with Pseudomonas aeruginosa or with other bacteria were similar (p = NS). The intra- and inter-assay repeatabilities of MDA measurements was similar in all the three types of samples, while the between-visit variability was higher in plasma. MDA is a potential new airway marker of oxidative stress in patients with CF. Sputum MDA differentiates best between patients and healthy subjects.

Cognitive impairment in Parkinson's disease

Article

Full-text available

Mar 2015
POSTGRAD MED J

Cognitive impairment is a significant non-motor symptom of Parkinson's disease (PD). Longitudinal cohort studies have demonstrated that approximately 50% of those with PD develop dementia after 10 years, increasing to over 80% after 20 years. Deficits in cognition can be identified at the time of PD diagnosis in some patients and this mild cognitive impairment (PD-MCI) has been studied extensively over the last decade. Although PD-MCI is a risk factor for developing Parkinson's disease dementia there is evidence to suggest that PD-MCI might consist of distinct subtypes with different pathophysiologies and prognoses. The major pathological correlate of Parkinson's disease dementia is Lewy body deposition in the limbic system and neocortex although Alzheimer's related pathology is also an important contributor. Pathological damage causes alteration to neurotransmitter systems within the brain, producing behavioural change. Management of cognitive impairment in PD requires a multidisciplinary approach and accurate communication with patients and relatives is essential. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Nrf2 Signaling Contributes to the Neuroprotective Effects of Urate against 6-OHDA Toxicity

Article

Full-text available

Jun 2014
PLOS ONE

Background Mounting evidence shows that urate may become a biomarker of Parkinson's disease (PD) diagnosis and prognosis and a neuroprotectant candidate for PD therapy. However, the cellular and molecular mechanisms underlying its neuroprotective actions remain poorly understood. Results In this study, we showed that urate pretreatment protected dopaminergic cell line (SH-SY5Y and MES23.5) against 6-hydroxydopamine (6-OHDA)- and hydrogen peroxide- induced cell damage. Urate was found to be accumulated into SH-SY5Y cells after 30 min treatment. Moreover, urate induced NF-E2-related factor 2 (Nrf2) accumulation by inhibiting its ubiquitinationa and degradation, and also promoted its nuclear translocation; however, it did not modulate Nrf2 mRNA level or Kelch-like ECH-associated protein 1 (Keap1) expression. In addition, urate markedly up-regulated the transcription and protein expression of γ-glutamate-cysteine ligase catalytic subunit (γ-GCLC) and heme oxygenase-1 (HO-1), both of which are controlled by Nrf2 activity. Furthermore, Nrf2 knockdown by siRNA abolished the intracellular glutathione augmentation and the protection exerted by urate pretreatment. Conclusion Our findings demonstrated that urate treatment may result in Nrf2-targeted anti-oxidant genes transcription and expression by reducing Nrf2 ubiquitination and degradation and promoting its nuclear translocation, and thus offer neuroprotection on dopaminergic cells against oxidative stresses.

Hyperuricemia Causes Pancreatic Î²-Cell Death and Dysfunction through NF-ÎºB Signaling Pathway

Article

Full-text available

Oct 2013
PLOS ONE

Accumulating clinical evidence suggests that hyperuricemia is associated with an increased risk of type 2 diabetes. However, it is still unclear whether elevated levels of uric acid can cause direct injury of pancreatic β-cells. In this study, we examined the effects of uric acid on β-cell viability and function. Uric acid solution or normal saline was administered intraperitoneally to mice daily for 4 weeks. Uric acid-treated mice exhibited significantly impaired glucose tolerance and lower insulin levels in response to glucose challenge than did control mice. However, there were no significant differences in insulin sensitivity between the two groups. In comparison to the islets in control mice, the islets in the uric acid-treated mice were markedly smaller in size and contained less insulin. Treatment of β-cells in vitro with uric acid activated the NF-κB signaling pathway through IκBα phosphorylation, resulting in upregulated inducible nitric oxide synthase (iNOS) expression and excessive nitric oxide (NO) production. Uric acid treatment also increased apoptosis and downregulated Bcl-2 expression in Min6 cells. In addition, a reduction in insulin secretion under glucose challenge was observed in the uric acid-treated mouse islets. These deleterious effects of uric acid on pancreatic β-cells were attenuated by benzbromarone, an inhibitor of uric acid transporters, NOS inhibitor L-NMMA, and Bay 11-7082, an NF-κB inhibitor. Further investigation indicated that uric acid suppressed levels of MafA protein through enhancing its degradation. Collectively, our data suggested that an elevated level of uric acid causes β-cell injury via the NF-κB-iNOS-NO signaling axis.

Levodopa-induced dyskinesias in Parkinson's disease: Emerging treatments

Article

Full-text available

Oct 2013

Parkinson's disease therapy is still focused on the use of L-3,4-dihydroxyphenylalanine (levodopa or L-dopa) for the symptomatic treatment of the main clinical features of the disease, despite intensive pharmacological research in the last few decades. However, regardless of its effectiveness, the long-term use of levodopa causes, in combination with disease progression, the development of motor complications termed levodopa-induced dyskinesias (LIDs). LIDs are the result of profound modifications in the functional organization of the basal ganglia circuitry, possibly related to the chronic and pulsatile stimulation of striatal dopaminergic receptors by levodopa. Hence, for decades the key feature of a potentially effective agent against LIDs has been its ability to ensure more continuous dopaminergic stimulation in the brain. The growing knowledge regarding the pathophysiology of LIDs and the increasing evidence on involvement of nondopaminergic systems raises the possibility of more promising therapeutic approaches in the future. In the current review, we focus on novel therapies for LIDs in Parkinson's disease, based mainly on agents that interfere with glutamatergic, serotonergic, adenosine, adrenergic, and cholinergic neurotransmission that are currently in testing or clinical development.

Cellular and Molecular Mediators of Neuroinflammation in the Pathogenesis of Parkinson's Disease

Article

Full-text available

Jan 2013
MEDIAT INFLAMM

Neuroinflammation is a host-defense mechanism associated with restoration of normal structure and function of the brain and neutralization of an insult. Increasing neuropathological and biochemical evidence from the brains of individuals with Parkinson's disease (PD) provides strong evidence for activation of neuroinflammatory pathways. Microglia, the resident innate immune cells, may play a major role in the inflammatory process of the diseased brain of patients with PD. Although microglia forms the first line of defense for the neural parenchyma, uncontrolled activation of microglia may directly affect neurons by releasing various molecular mediators such as inflammatory cytokines (tumor necrosis factor- α , interleukin [IL]-6, and IL-1 β ), nitric oxide, prostaglandin E2, and reactive oxygen and nitrogen species. Moreover, recent studies have reported that activated microglia phagocytose not only damaged cell debris but also intact neighboring cells. This phenomenon further supports their active participation in self-enduring neuronal damage cycles. As the relationship between PD and neuroinflammation is being studied, there is a realization that both cellular and molecular mediators are most likely assisting pathological processes leading to disease progression. Here, we discuss mediators of neuroinflammation, which are known activators released from damaged parenchyma of the brain and result in neuronal degeneration in patients with PD.

Nuclear Factor Erythroid 2 - Related Factor 2 Signaling in Parkinson Disease: A Promising Multi Therapeutic Target Against Oxidative Stress, Neuroinflammation and Cell Death

Article

Full-text available

Dec 2012
CNS NEUROL DISORD-DR

Parkinson's disease (PD) is the second most common progressive neurodegenerative disorder with increased oxidative stress as central component. Till date, treatments related to PD are based on restoring dopamine either by targeting neurotransmitter and/or at receptor levels. These therapeutic approaches try to repair damage but do not address the underlying processes such as oxidative stress and neuroinflammation that contribute to cell death. The central nervous system maintains a robust antioxidant defense mechanism consisting of several cytoprotective genes and enzymes whose expression is controlled by antioxidant response element (ARE) which further depends on activation of nuclear factor erythroid 2-related factor 2 (Nrf2). In response to oxidative or electrophilic stress transcription factor Nrf2 binds to ARE and rescues the cells from oxidative stress and neuroinflammation. Recently, Nrf2 has been utilized as a drug target and some agents are currently under clinical trial. Owing to the potential role of Nrf2 in counteracting oxidative stress and neuroinflammation seen in PD, here we have focused on the molecular mechanism of the Nrf2/ARE antioxidant defense pathway in PD. Further, we also summarize published reports on the potential inducers of Nrf2 that demonstrate neuroprotective effects in experimental models of PD with possible future strategies to increase the transcriptional level of Nrf2 as a therapeutic strategy to provide neuroprotection of damaged dopaminergic neurons in PD.

Parkinson's disease: Oxidative stress and therapeutic approaches

Article

Full-text available

Oct 2010

Parkinson’s disease (PD) is a neurodegenerative disorder, caused by reduced levels of catecholamines and oxidative stress. Symptoms seen in the disease include tremor, rigidity, bradykinesia and postural disability. Oxidative stress plays a key role in neurodegeneration and motor abnormalities seen in PD. Altered levels of the protein caused by these changes lead to defective ubiquitin–proteasome pathway. Neurodegeneration seen in PD and Canavan disease has a common mechanism. Recent studies suggest that herbal medicines can improve molecular changes and motor functions seen in PD. KeywordsParkinson’s disease-Antioxidant- Withania somnifera -Neurodegeneration-Canavan disease

Protective effects of urate against 6-OHDA-induced cell injury in PC12 cells through antioxidant action

Article

Full-text available

Nov 2011

There is evidence to support that oxidative stress is increased in Parkinson's disease (PD) and contributes to the degeneration of dopaminergic neurons. Recent research has shown that higher blood urate concentrations have now been linked to decreased risks and progression rates of PD. However, the mechanisms about urate to protect dopaminergic neurons are less clear. Our study investigated the effect of urate on oxidative stress induced by 6-hydroxydopamine (6-OHDA) in neuronal differentiated PC12 cells. We found that urate significantly reduced 6-OHDA-induced lactate dehydrogenas (LDH), malondialdehyde (MDA), and 8-hydroxy-deoxyguanosine (8-OHdG) generation but increased the superoxide dismutase (SOD) activity and glutathione (GSH) levels in the PC12 cells. These results suggested that urate can prevent PC12 cells from oxidative injury induced by 6-OHDA, which may play an important role in the mechanisms underlying the association of high plasma levels of urate with reduced risk and slower progression of PD. Urate treatment could be a potential therapeutic strategy for PD.

Measurement of superoxide dismutase, catalase and glutathione peroxidase in cultured cells and tissue

Article

Full-text available

Jan 2010
NAT PROTOC

Cells contain a large number of antioxidants to prevent or repair the damage caused by reactive oxygen species, as well as to regulate redox-sensitive signaling pathways. General protocols are described to measure the antioxidant enzyme activity of superoxide dismutase (SOD), catalase and glutathione peroxidase. The SODs convert superoxide radical into hydrogen peroxide and molecular oxygen, whereas the catalase and peroxidases convert hydrogen peroxide into water. In this way, two toxic species, superoxide radical and hydrogen peroxide, are converted to the harmless product water. Western blots, activity gels and activity assays are various methods used to determine protein and activity in both cells and tissue depending on the amount of protein required for each assay. Other techniques including immunohistochemistry and immunogold can further evaluate the levels of the various antioxidant enzymes in tissues and cells. In general, these assays require 24-48 h to complete.

Long-Term L-DOPA Treatment Causes Indiscriminate Increase in Dopamine Levels at the Cost of Serotonin Synthesis in Discrete Brain Regions of Rats

Article

Full-text available

Jan 2008

(1) The treatment of choice for Parkinson's disease (PD) is 3,4-dihydroxyphenylalanine (L-DOPA) with peripheral decarboxylase inhibitor, but long-term therapy leads to motor and psychiatric complications. In the present study we investigated 5-hydroxytryptamine (5-HT) and dopamine concentrations in serotonergic and dopaminergic nuclei following chronic administration of L-DOPA to find whether the neurotransmitter synthesis in these brain areas are compensated. (2) Rats were administered L-DOPA (250 mg/kg) and carbidopa (25 mg/kg) daily for 59 and 60 days, and killed on the 60th day, respectively at 24 h and 30 min after the last dose. L-DOPA, norepinephrine, 5-HT, 5-hydroxyindoleacetic acid (5-HIAA), dopamine, homovanillic acid (HVA), and 3,4-dihydroxyphenylacetic acid (DOPAC) were measured in striatum, nucleus raphe dorsalis (NRD), nucleus accumbens (NAc), substantia nigra, cerebellum, and cortex employing HPLC-electrochemical procedure. (3) Prolonged treatment of L-DOPA caused depression in the animals as revealed in a forced swim test. Serotonin content was significantly decreased in all brain regions studied 30 min after long-term L-DOPA, except in NAc. The cortex and striatum showed lowered levels of this indoleamine 24 h after 59 doses of L-DOPA. Dopamine, HVA, and DOPAC concentrations were significantly higher in all the regions studied after 30 min, and in the cerebellum after 24 h of L-DOPA. The levels of DOPAC were elevated in all the brain areas studied 24 h after prolonged L-DOPA treatment. (4) The present results suggest that long-term L-DOPA treatment results in significant loss of 5-HT in serotonergic and dopaminergic regions of the brain. Furthermore, while L-DOPA metabolism per se was uninfluenced, dopamine synthesis was severely impaired in all the regions. The imbalance of serotonin and dopamine formation may be the cause of overt cognitive, motor, and psychological functional aberrations seen in parkinsonian patients following prolonged L-DOPA treatment.

Serum uric acid levels and freezing of gait in Parkinson’s disease

Article

Mar 2017

Uric acid (UA) is a natural antioxidant and iron scavenger in the human body, which has been hypothesized to exert an anti-oxidative effect in Parkinson’s disease (PD). This study aimed to investigate the relationship between serum UA levels and freezing of gait (FOG) in PD. A total of 321 Chinese PD patients with fasting serum UA evaluated were included in the cross-sectional study. Demographics, clinical features, and therapeutic regimen were collected. The Unified PD Rating Scale (UPDRS) III and Hoehn and Yahr (H and Y) stage were used to evaluate the severity of disease, and the Frontal Assessment Battery (FAB) and Montreal Cognitive Assessment (MoCA) scales were used to assess the cognitive function. Patients with FOG showed lower proportion of male, longer disease duration, lower body mass index, lower concentrations of serum UA, higher total levodopa equivalent daily dosage, higher UPDRS III score, greater median H and Y stage, lower scores of FAB and MoCA, and higher frequencies of motor fluctuation, dyskinesia, falls, and festination compared to patients without FOG (P < 0.05). The binary logistic regression model indicated that high UPDRS III score (OR = 1.049, P < 0.001), fluctuation (OR = 2.677, P = 0.035), dyskinesia (OR = 6.294, P = 0.003), festination (OR = 3.948, P < 0.001), falls (OR = 7.528, P < 0.001), and low serum UA levels (OR = 0.990, P < 0.001) were associated with FOG. Our study suggests that low serum UA concentration is associated with the occurrence of FOG in PD.

Dihydromyricetin protects neurons in an MPTP-induced model of Parkinson's disease by suppressing glycogen synthase kinase-3 beta activity

Article

Jul 2016

Aim: It is general believed that mitochondrial dysfunction and oxidative stress play critical roles in the pathology of Parkinson's disease (PD). Dihydromyricetin (DHM), a natural flavonoid extracted from Ampelopsis grossedentata, has recently been found to elicit potent anti-oxidative effects. In the present study, we explored the role of DHM in protecting dopaminergic neurons. Methods: Male C57BL/6 mice were intraperitoneally injected with 1-methyl4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for 7 d to induce PD. Additionally, mice were treated with either 5 or 10 mg/kg DHM for a total of 13 d (3 d before the start of MPTP, during MPTP administration (7 d) and 3 d after the end of MPTP). For the saline or DHM alone treatment groups, mice were injected with saline or DHM for 13 d. On d 14, behavioral tests (locomotor activity, the rotarod test and the pole test) were administered. After the behavioral tests, the mice were sacrificed, and brain tissue was collected for immunofluorescence staining and western blotting. In addition, MES23.5 cells were treated with MPP(+) and DHM, and evaluated using cell viability assays, reactive oxygen species (ROS) measurements, apoptosis analysis and Western blotting. Results: DHM significantly attenuated MPTP-induced mouse behavioral impairments and dopaminergic neuron loss. In the MES23.5 cells, DHM attenuated MPP(+)-induced cell injury and ROS production in a dose-dependent manner. In addition, DHM increased glycogen synthase kinase-3 beta phosphorylation in a dose- and time-dependent manner, which may be associated with DHM-induced dopaminergic neuronal protection. Conclusion: The present study demonstrated that DHM is a potent neuroprotective agent for DA neurons by modulating the Akt/GSK-3β pathway, which suggests that DHM may be a promising therapeutic candidate for PD.

Observer-based tracking control for a class of switched fuzzy systems with fast switching controller

Article

Jan 2014

Observer-based robust tracking control for a class of switched fuzzy (SF) systems with time delay is investigated in this paper. An SF system, which differs from the existing systems, is first employed to describe a non-linear system. Next, a fast switching controller consisting of a number of simple sub-controllers is proposed. The designed controller based on measured output instead of the state information integrates the advantages of both the linear and switching state-feedback controllers but eliminates their disadvantages. Tracking hybrid control schemes, which are based upon a combination of the H ∞ tracking theory, fast switching control algorithm and switching law design, are developed such that the observer-based H ∞ model reference tracking performance is guaranteed. Sufficient conditions for the solvability of the tracking control problem are given for the case in which the state of system is not available. Since convex combination techniques are used to derive the delay independent criteria, some subsystems are allowed to be unstable. Finally, various comparisons of the elaborated examples are performed to demonstrate the effectiveness of the proposed control design approach.

Induction of Nrf2-mediated genes by Antrodia salmonea inhibits ROS generation and inflammatory effects in lipopolysaccharide-stimulated RAW264.7 macrophages

Article

Oct 2014

Antrodia salmonea (AS), a well-known medicinal mushroom in Taiwan, and has been reported to exhibit anti-oxidant, anti-angiogenic, anti-atherogenic, and anti-inflammatory effects. In the present study, we investigated the activation of Nrf2-mediated antioxidant genes in RAW264.7 macrophages by the fermented culture broth of AS, studied the resulting protection against lipopolysaccharide (LPS)-stimulated inflammation, and revealed the molecular mechanisms underlying these protective effects. We found that non-cytotoxic concentrations of AS (25-100 µg/mL) protected macrophages from LPS-induced cell death and ROS generation in a dose-dependent manner. The antioxidant potential of AS was directly correlated with the increased expression of the antioxidant genes HO-1, NQO-1, and γ-GCLC, as well as the level of intracellular GSH followed by an increase in the nuclear translocation and transcriptional activation of the Nrf2-ARE pathway. Furthermore, Nrf2 knockdown diminished the protective effects of AS, as evidenced by the increased production of pro-inflammatory cytokines and chemokines, including PGE2, NO, TNF-α, and IL-1β, in LPS-stimulated macrophages. Notably, AS treatment significantly inhibited the LPS-induced ICAM-1 expression in macrophages. Our data suggest that the anti-inflammatory potential of Antrodia salmonea mediated by the activation of Nrf2-dependent antioxidant defense mechanisms. Results support the traditional usage of this beneficial mushroom for the treatment of free radical-related diseases and inflammation.

Increased expression of astrocyte markers in schizophrenia: Association with neuroinflammation

Article

Apr 2014
AUST NZ J PSYCHIAT

Objective: While schizophrenia may have a progressive component, the evidence for neurodegenerative processes as indicated by reactive astrocytes is inconclusive. We recently identified a subgroup of individuals with schizophrenia with increased expression of inflammatory markers in prefrontal cortex, and hypothesized that this subgroup would also have reactive astrocytes. Method: We measured glial fibrillary acidic protein (GFAP) mRNA by quantitative real-time reverse transcriptase polymerase chain reaction (RT-PCR) and protein levels by immunoblotting in grey matter homogenate from 37 individuals with schizophrenia and 37 unaffected controls. We examined the morphology of GFAP-positive astrocytes in immunostained sections of middle frontal gyrus. We tested if GFAP expression or astrocyte morphology were altered in people with schizophrenia with increased expression of inflammatory markers. We used RNA-Seq data on a subset of patients and controls (n=20/group) to ascertain whether mRNA transcripts associated with astrogliosis were elevated in the individuals with active neuroinflammation. Results: GFAP (mRNA and protein) levels and astrocyte morphology were not significantly different between people with schizophrenia and controls overall. However, individuals with schizophrenia with neuroinflammation had increased expression of GFAP mRNA (t(33)=2.978, p=0.005), hypertrophic astrocyte morphology (χ(2)(2)=6.281, p=0.043), and statistically significant elevated expression of three mRNA transcripts previously associated with astrogliosis. Conclusions: We found clear evidence of astrogliosis in a subset of people with schizophrenia. We suggest that the lack of astrogliosis reported in previous studies may be due to cohort differences in aetiopathology, illness stage, treatment exposure, or a failure to examine subsets of people with schizophrenia.

Berberine prevents nigrostriatal dopaminergic neuronal loss and suppresses hippocampal apoptosis in mice with Parkinson's disease

Article

Feb 2014
INT J MOL MED

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the selective loss of nigral dopaminergic neurons and a reduction in striatal dopaminergic fibers, which result in tremors, rigidity, bradykinesia and gait disturbance. In addition to motor dysfunction, dementia is a widely recognized symptom of patients with PD. Berberine, an isoquinoline alkaloid isolated from Berberis vulgaris L., is known to exert anxiolytic, analgesic, anti-inflammatory, antipsychotic, antidepressant and anti-amnesic effects. In the present study, we investigated the effects of berberine on short-term memory in relation to dopamine depletion and hippocampal neurogenesis using a mouse model of PD, induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid (MPTP/P) treatment. Mice in the berberine-treated groups were orally administered berberine once a day for a total of 5 weeks. Our results revealed that the injection of MPTP/P induced dopaminergic neuronal death in the substantia nigra and fiber loss in the striatum. This resulted in impaired motor balance and coordination, as assessed by the beam walking test. We further demonstrated that MPTP/P-induced apoptosis in the hippocampus deteriorated short-term memory, as shown by the step-down avoidance task. By contrast, neurogenesis in the hippocampal dentate gyrus, which is a compensatory adaptive response to excessive apoptosis, was increased upon PD induction. However, treatment with berberine enhanced motor balance and coordination by preventing dopaminergic neuronal damage. Treatment with berberine also improved short-term memory by inhibiting apoptosis in the hippocampus. Berberine demonstrated maximal potency at 50 mg/kg. Based on these data, treatment with berberine may serve as a potential therapeutic strategy for the alleviation of memory impairment and motor dysfunction in patients with PD.

Neuroprotection by urate on 6-OHDA-lesioned rat model of Parkinson's disease: Linking to Akt/GSK3β signaling pathway

Article

Oct 2012
J NEUROCHEM

Higher plasma urate level is reported to be associated with a reduced risk and slower progression of Parkinson's disease (PD). In this study, we explored the effects of urate on dopaminergic neurons in nigrostriatal pathway in the 6-hydroxydopamine (6-OHDA) unilaterally lesioned rats. Uric acid (UA), when given twice daily at 200 mg/kg intraperitoneally for 10 consecutive days, elevated urate (the anionic form of UA) in plasma and striatum by 55% and 36.8%, respectively, as compared with vehicle group. This regimen of UA was found to ameliorate the behavioral deficits, dopaminergic neuron loss as well as dopamine depletion in the nigrostriatal system. Moreover, UA administration was capable of increasing glutathione level and superoxide dismutase activity while decreasing malondialdehyde accumulation in striatum. In addition, the phosphorylation of both protein kinase B (Akt) and glycogen synthase kinase 3 beta (GSK3β) in the lesioned striata of 6-OHDA-lesioned rats was dramatically reduced as compared with sham-operated rats. This reduction was attenuated in the Parkinsonian rats receiving UA treatment. Similarly, in vitro findings showed that UA alleviated the decrease in Akt activation and the increase in GSK3β activity caused by 6-OHDA. Furthermore, neuroprotection by urate and its regulation on GSK3β phosphorylation at Ser9 was found to be abolished in the presence of PI3K inhibitor. Therefore, our findings demonstrated that urate was able to protect dopaminergic neurons in rat nigrostriatal pathway against the neurotoxicity of 6-OHDA, and showed that its beneficial effects may be related to its regulation on Akt/GSK3β signaling.

Uric acid transport and disease

Article

Jun 2010
J CLIN INVEST

Uric acid is the metabolic end product of purine metabolism in humans. It has antioxidant properties that may be protective but can also be pro-oxidant, depending on its chemical microenvironment. Hyperuricemia predisposes to disease through the formation of urate crystals that cause gout, but hyperuricemia, independent of crystal formation, has also been linked with hypertension, atherosclerosis, insulin resistance, and diabetes. We discuss here the biology of urate metabolism and its role in disease. We also cover the genetics of urate transport, including URAT1, and recent studies identifying SLC2A9, which encodes the glucose transporter family isoform Glut9, as a major determinant of plasma uric acid levels and of gout development.

Sustained expression of interleukin-1?? in mouse hippocampus impairs spatial memory

Article

Oct 2009

Glial activation and neuroinflammation occur in neurodegenerative disease and brain injury, however their presence in normal brain aging suggests that chronic neuroinflammation may be a factor in age-related dementia. Few studies have investigated the impact of sustained elevation of hippocampal interleukin-1beta, a pro-inflammatory cytokine upregulated during aging and Alzheimer's disease, on cognition in mice. We utilized the IL-1beta(XAT) transgenic mouse to initiate bilateral hippocampal overexpression of interleukin-1beta to determine the influence of sustained neuroinflammation independent of disease pathology. Fourteen days following transgene induction, adult male and female IL-1beta(XAT) mice were tested on non-spatial and spatial versions of the Morris water maze. For the spatial component, one retention trial was conducted 48 h after completion of a 3 day acquisition protocol (eight trials per day). Induction of IL-1beta did not impact non-spatial learning, but was associated with delayed acquisition and decreased retention of the spatial task. These behavioral impairments were accompanied by robust reactive gliosis and elevated mRNA expression of inflammatory genes in the hippocampus. Our results suggest that prolonged neuroinflammation response per se may impact mnemonic processes and support the future application of IL-1beta(XAT) transgenic mice to investigate chronic neuroinflammation in age- and pathology-related cognitive dysfunction.

Targeting reactive oxygen species, reactive nitrogen species and inflammation in MPTP neurotoxicity and Parkinson's disease

Article

Nov 2008

Parkinson's disease (PD) is the second most frequent neurodegenerative disorder after Alzheimer's disease. The main clinical features of PD include tremor, bradykinesia, rigidity and postural instability. The primary pathology of PD is degeneration of dopaminergic neurons in the substantia nigra pars compacta, resulting in loss of the nigrostriatal pathway and a reduction of dopamine contents in the striatum. The biochemical and cellular changes that occur following the administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) are remarkably similar to that seen in idiopathic PD. Recent evidence shows that oxidative stress contributes to the cascade leading to dopaminergic cell degeneration in PD. However, oxidative stress is intimately linked to other components of neurodegenerative process, such as nitric oxide stress and inflammation. Recently, there is convincing evidence for the involvement of nitric oxide that reacts with superoxide to produce peroxynitrite and ultimately hydroxyl radical production. In view of these new insights, however, the role of reactive nitrogen species, reactive oxygen species and inflammation against MPTP neurotoxicity is not fully understood. In this review, we discuss the possible role of reactive nitrogen species, reactive oxygen species and inflammation in the dopaminergic neurons against MPTP neurotoxicity.

Uric acid is reduced in the substantia nigra in parkinson's disease: Effect on dopamine oxidation

Article

Dec 1994
BRAIN RES BULL

Postmortem caudate and substantia nigra tissue samples from human parkinsonian patients (PD) and age-matched controls (NC) were analyzed for uric acid (UA), dopamine (DA), and ascorbic acid (AA) by HPLC/UV/ED. Uric acid and DA levels were significantly lower in the substantia nigra of PD by 54% and 85%, respectively. In the caudate, DA levels were significantly lower while UA levels were nonsignificantly reduced (0.10 < p < 0.05). Ascorbic acid levels were not significantly different from the controls in either brain region. Conditions favorable for oxidative stress were evaluated by measuring the oxidation of DA in individual brain homogenates. The rate constant for DA oxidation in control caudate was 0.34 x 10(-2) min-1 and in parkinsonian caudate was 4.20 x 10(-2) min-1. In control and parkinsonian substantia nigra DA oxidation rate constants were 2.82 x 10(-2) min-1 and 4.57 x 10(-2) min-1, respectively. Addition of UA or catalase to parkinsonian homogenate decreased the rate of DA oxidation, while addition of uricase to control homogenate increased the rate of DA oxidation. The data support the hypothesis that UA is decreased in nigrostriatal dopamine neurons in parkinsonian patients which contributes to an environment susceptible to oxidative stress, particularly through dopamine oxidation reactions.

Parkinson's Disease: Mechanisms and Models.

Article

Oct 2003
NEURON

Parkinson's disease (PD) results primarily from the death of dopaminergic neurons in the substantia nigra. Current PD medications treat symptoms; none halt or retard dopaminergic neuron degeneration. The main obstacle to developing neuroprotective therapies is a limited understanding of the key molecular events that provoke neurodegeneration. The discovery of PD genes has led to the hypothesis that misfolding of proteins and dysfunction of the ubiquitin-proteasome pathway are pivotal to PD pathogenesis. Previously implicated culprits in PD neurodegeneration, mitochondrial dysfunction and oxidative stress, may also act in part by causing the accumulation of misfolded proteins, in addition to producing other deleterious events in dopaminergic neurons. Neurotoxin-based models (particularly MPTP) have been important in elucidating the molecular cascade of cell death in dopaminergic neurons. PD models based on the manipulation of PD genes should prove valuable in elucidating important aspects of the disease, such as selective vulnerability of substantia nigra dopaminergic neurons to the degenerative process.

Jaiswal AK.. Nrf2 Signaling in coordinated activation of antioxidant gene expression. Free Rad Biol Med 36: 1199-1207

Article

Jun 2004
FREE RADICAL BIO MED

Anil Jaiswal

Antioxidant response element (ARE)-mediated expression and coordinated induction of antioxidant enzymes is a critical mechanism of protection against chemically induced oxidative/electrophilic stress. NF-E2-related nuclear factors (Nrf1 and Nrf2) bind to ARE and regulate ARE-mediated gene expression and induction. Nrf2 is more potent than Nrf1 in activation of ARE-regulated gene expression. Nrf2 is retained in the cytoplasm by an inhibitor INrf2. Nrf2 binding to INrf2 leads to proteasomal degradation of Nrf2. An increase in oxidative/electrophilic stress, due to chemical exposure, leads to the activation of protein kinase C (PKC) and other cytosolic factors. PKC phosphorylation of Nrf2 at serine 40 results in the escape or release of Nrf2 from INrf2. Nrf2 translocates to the nucleus, forms heterodimers with its unknown partner proteins, and binds to the ARE. This leads to the coordinated activation of ARE-regulated genes. Additional nuclear factor including small Mafs (MafG and MafK), large Maf (c-Maf), c-Fos, and Fra1, also bind to ARE and negatively regulate ARE-mediated gene expression. This is presumably to keep the expression of antioxidant enzymes "in check" to maintain the cellular defenses active and/or to rapidly restore induced enzymes to normal levels. Future investigations are expected to reveal that a balance between positive and negative factors regulates ARE-mediated gene expression and induction. The future studies should also reveal a complete mechanism of signal transduction from antioxidants and xenobiotics to the transcription factors, such as Nrf2, that bind to ARE.

Uric Acid: The Oxidant-Antioxidant Paradox

Article

Jul 2008
NUCLEOS NUCLEOT NUCL

Uric acid, despite being a major antioxidant in the human plasma, both correlates and predicts development of obesity, hypertension, and cardiovascular disease, conditions associated with oxidative stress. While one explanation for this paradox could be that a rise in uric acid represents an attempted protective response by the host, we review the evidence that uric acid may function either as an antioxidant (primarily in plasma) or pro-oxidant (primarily within the cell). We suggest that it is the pro-oxidative effects of uric acid that occur in cardiovascular disease and may have a contributory role in the pathogenesis of these conditions.

Uric acid demonstrates neuroprotective effect on Parkinson's disease mice through Nrf2-ARE signaling pathway

Abstract

No full-text available

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