One year safety and efficacy of inosine to increase the serum urate level for patients with Parkinson's disease in Japan

Iwaki, Hirotaka; Ando, Rina; Miyaue, Noriyuki; Tada, Satoshi; Tsujii, Tomoaki; Yabe, Hayato; Nishikawa, Noriko; Nagai, Masahiro; Nomoto, Masahiro

doi:10.1016/j.jns.2017.10.030

Cited by 23 publications

(15 citation statements)

References 25 publications

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“…Intracellular urate accumulation was required for its anti-inflammatory effects and protected DA neurons from neurotoxicity induced by microglia activation. The approach that elevating serum urate level by oral inosine, a urate precursor, was indicated generally safe, tolerable, and effective in early PD, which was proposed to become a potential therapy for PD [ 41 , 42 ]. Therefore, our findings contribute to the role of urate in anti-inflammation apart from its function on inhibiting oxidative stress [ 15 , 18 ], which potentially provide a better understanding of controlling these two risk factors for therapeutic treatment in PD.…”

Section: Discussionmentioning

confidence: 99%

Urate inhibits microglia activation to protect neurons in an LPS-induced model of Parkinson’s disease

Bao

Zhang

et al. 2018

J Neuroinflammation

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BackgroundMultiple risk factors contribute to the progression of Parkinson’s disease, including oxidative stress and neuroinflammation. Epidemiological studies have revealed a link between higher urate level and a lower risk of developing PD. However, the mechanistic basis for this association remains unclear. Urate protects dopaminergic neurons from cell death induced by oxidative stress. Here, we investigated a novel role of urate in microglia activation in a lipopolysaccharide (LPS)-induced PD model.MethodsWe utilized Griess, ELISA, real-time PCR, Western blot, immunohistochemistry, and immunofluorescence to detect the neuroinflammation. For Griess, ELISA, Western blot, and immunofluorescence assay, cells were seeded in 6-well plates pre-coated with poly-l-lysine (PLL) and incubated for 24 h with the indicated drugs. For real-time PCR assay, cells were seeded in 6-well plates pre-coated with PLL and incubated for 6 h with the indicated drugs. For animal experiments, rats were injected with urate or its vehicle twice daily for five consecutive days before and after stereotaxic surgery. Rats were killed and brain tissues were harvested after 4 weeks of LPS injection.ResultsIn cultured BV2 cells and rat primary microglia, urate suppressed proinflammatory cytokine production and inducible cyclooxygenase 2 and nitric oxide synthase expression to protect dopaminergic neurons from the toxic effects of activated microglia. The neuroprotective effects of urate may also be associated with the stimulation of anti-inflammatory factors interleukin 10 and transforming growth factor β1. Intracellular urate level was increased in a dose-dependent manner upon co-treatment with urate and LPS as compared with LPS alone, an effect that was abrogated by pretreatment with probenecid (PBN), an inhibitor of both glucose transporter 9 and urate transporter 1 (URAT1). PBN also abolished the anti-inflammatory effect of urate. Consistent with these in vitro observations, the number of tyrosine hydroxylase-positive neurons was decreased and the loss of motor coordination was reversed by urate administration in an LPS-induced rat model of PD. Additionally, increased plasma urate level abolished the reduction of URAT1 expression, the increase in the expression of interleukin-1β, and the number of ionized calcium-binding adaptor molecule 1-positive microglia along with changes in their morphology.ConclusionsUrate protects neurons against cytotoxicity induced by microglia activation via modulating urate transporter-mediated intracellular urate level.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1175-8) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Urate inhibits microglia activation to protect neurons in an LPS-induced model of Parkinson’s disease

Bao

Zhang

et al. 2018

J Neuroinflammation

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“…In humans, serum urate levels can be increased with reasonable safety by supplementation with its biosynthetic precursor inosine [212][213][214]. In pilot studies in PD patients, individually tailored dosing schedules (500-3000 mg daily) have been shown to maintain serum urate in the range of 6-8 mg/dl [215,216]. Episodes of urolithiasis were seen in a significant minority of patients, but could be managed with dosage reduction.…”

Section: Scavenging Peroxynitrite-derived Radicals-benefits Of Supplementioning

confidence: 99%

Nutraceuticals Targeting Generation and Oxidant Activity of Peroxynitrite May Aid Prevention and Control of Parkinson’s Disease

McCarty

Lerner

2020

IJMS

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Parkinson’s disease (PD) is a chronic low-grade inflammatory process in which activated microglia generate cytotoxic factors—most prominently peroxynitrite—which induce the death and dysfunction of neighboring dopaminergic neurons. Dying neurons then release damage-associated molecular pattern proteins such as high mobility group box 1 which act on microglia via a range of receptors to amplify microglial activation. Since peroxynitrite is a key mediator in this process, it is proposed that nutraceutical measures which either suppress microglial production of peroxynitrite, or which promote the scavenging of peroxynitrite-derived oxidants, should have value for the prevention and control of PD. Peroxynitrite production can be quelled by suppressing activation of microglial NADPH oxidase—the source of its precursor superoxide—or by down-regulating the signaling pathways that promote microglial expression of inducible nitric oxide synthase (iNOS). Phycocyanobilin of spirulina, ferulic acid, long-chain omega-3 fatty acids, good vitamin D status, promotion of hydrogen sulfide production with taurine and N-acetylcysteine, caffeine, epigallocatechin-gallate, butyrogenic dietary fiber, and probiotics may have potential for blunting microglial iNOS induction. Scavenging of peroxynitrite-derived radicals may be amplified with supplemental zinc or inosine. Astaxanthin has potential for protecting the mitochondrial respiratory chain from peroxynitrite and environmental mitochondrial toxins. Healthful programs of nutraceutical supplementation may prove to be useful and feasible in the primary prevention or slow progression of pre-existing PD. Since damage to the mitochondria in dopaminergic neurons by environmental toxins is suspected to play a role in triggering the self-sustaining inflammation that drives PD pathogenesis, there is also reason to suspect that plant-based diets of modest protein content, and possibly a corn-rich diet high in spermidine, might provide protection from PD by boosting protective mitophagy and thereby aiding efficient mitochondrial function. Low-protein diets can also promote a more even response to levodopa therapy.

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“…Furthermore, elevated serum urate has also been shown to increase the risk of hypertension, coronary heart disease, gout and stroke over the longer term. Although the number of PD patients so far treated with inosine is small, these side effects are potentially problematic for older patients with PD, potentially limiting its utility [66], though a recently reported trial of 10 PD patients of Asian origin treated with inosine to elevate urate levels to 6.0-8.0mg/dL reported no adverse effects after 1 year of treatment [67]. A multi-centre, randomized, double-blind, placebo-controlled trial, SURE-PD3 (NCT02642393) is currently underway to evaluate the effects of elevating serum urate to 7.1-8.0 mg/dL using inosine in early PD patients.…”

Section: Inosinementioning

confidence: 99%

Drug Repurposing in Parkinson’s Disease

Foltynie

2018

CNS Drugs

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The development of an intervention to slow or halt disease progression remains the greatest unmet therapeutic need in Parkinson's disease. Given the number of failures of various novel interventions in disease-modifying clinical trials in combination with ever increasing and lengthy drug development costs, attention is being turned to utilising existing compounds approved for other indications as novel treatments in Parkinson's disease. Advances in rational and systemic drug repurposing has identified a number of drugs with potential benefits for Parkinson's disease pathology and offers a potentially quicker route to drug discovery. Here, we review the safety and potential efficacy of the most promising candidates repurposed as potential disease-modifying treatments for Parkinson's disease in the advanced stages of clinical testing. Running head: Drug repurposing in Parkinson's disease Key points:  Disease modifying treatments are a great unmet need in Parkinson's disease  Drug repurposing represents a potentially more efficient, less costly route to drug discovery.

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One year safety and efficacy of inosine to increase the serum urate level for patients with Parkinson's disease in Japan

Cited by 23 publications

References 25 publications

Urate inhibits microglia activation to protect neurons in an LPS-induced model of Parkinson’s disease

Urate inhibits microglia activation to protect neurons in an LPS-induced model of Parkinson’s disease

Nutraceuticals Targeting Generation and Oxidant Activity of Peroxynitrite May Aid Prevention and Control of Parkinson’s Disease

Drug Repurposing in Parkinson’s Disease

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