Improved Parkinsons disease motor score in a single-arm open-label trial of febuxostat and inosine

Watanabe, Haruo; Hattori, Tatsuya; Kume, Akito; Misu, Kazuhiko; Ito, Takashi; Koike, Yu; Johnson, Todd A.; Kamitsuji, Shigeo; Kamatani, Naoyuki; Sobue, Gen

doi:10.1097/md.0000000000021576

Cited by 18 publications

(21 citation statements)

References 58 publications

(56 reference statements)

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“…Moreover, Watanabe and colleagues conducted an open-label, single-arm, multicenter trial to investigate the efficacy and safety of the co-administration of febuxostat, a xanthine oxidoreductase inhibitor, and inosine in PD patients [ 15 ]. Patients received febuxostat 20 mg and inosine 500 mg twice a day for 8 weeks, and the primary endpoint was the change in the MDS-UPDRS Part III score immediately prior to and after 57 days of treatment [ 15 ]. After treatment, serum hypoxanthine levels were significantly increased, and the MDS-UPDRS Part III score was significantly decreased [ 15 ].…”

Section: Inosine In Pdmentioning

confidence: 99%

“…Patients received febuxostat 20 mg and inosine 500 mg twice a day for 8 weeks, and the primary endpoint was the change in the MDS-UPDRS Part III score immediately prior to and after 57 days of treatment [ 15 ]. After treatment, serum hypoxanthine levels were significantly increased, and the MDS-UPDRS Part III score was significantly decreased [ 15 ]. Overall, these data indicate that the co-treatment of febuxostat and inosine could be safe and effective in improving symptoms in PD patients [ 15 ].…”

Section: Inosine In Pdmentioning

confidence: 99%

“…However, the eventual risk of urate nephropathy can be reduced by high fluid consumption and a potassium-rich alkaline diet [ 14 ]. Moreover, people with a homozygous deficiency for genetic xanthine oxidoreductase (XOR), who have low-to-no UA serum levels, show a total absence of central nervous symptoms [ 15 ]. On the other hand, it is known that urate can exert strong antioxidant properties and may have a potential neuroprotective effect, promoting neuronal function and integrity [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

“…On the other hand, it is known that urate can exert strong antioxidant properties and may have a potential neuroprotective effect, promoting neuronal function and integrity [ 13 ]. Several lines of evidence have shown that patients with neurodegenerative disorders tend to have low serum, CSF, or brain tissue UA levels [ 15 ]. Interestingly, urate levels have been associated with a decreased risk of developing PD and AD [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

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Inosine in Neurodegenerative Diseases: From the Bench to the Bedside

2022

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Neurodegenerative diseases, such as Alzheimer′s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), currently represent major unmet medical needs. Therefore, novel therapeutic strategies are needed in order to improve patients’ quality of life and prognosis. Since oxidative stress can be strongly involved in neurodegenerative diseases, the potential use of inosine, known for its antioxidant properties, in this context deserves particular attention. The protective action of inosine treatment could be mediated by its metabolite urate. Here, we review the current preclinical and clinical studies investigating the use of inosine in AD, PD, ALS, and MS. The most important properties of inosine seem to be its antioxidant action and its ability to raise urate levels and to increase energetic resources by improving ATP availability. Inosine appears to be generally safe and well tolerated; however, the possible formation of kidney stones should be monitored, and data on its effectiveness should be further explored since, so far, they have been controversial. Overall, inosine could be a promising potential strategy in the management of neurodegenerative diseases, and additional studies are needed in order to further investigate its safety and efficacy and its use as a complementary therapy along with other approved drugs.

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Section: Inosine In Pdmentioning

confidence: 99%

Section: Inosine In Pdmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Inosine in Neurodegenerative Diseases: From the Bench to the Bedside

2022

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“…Compensation by the hub, which is hierarchically located at the upper level of the disrupted lower network, may increase the energy requirements of the same region, and contribute to energy failure and accumulation of pathological proteins ( Saxena and Caroni, 2011 ; de Haan et al, 2012 ). Treatment with febuxostat and inosine increased blood hypoxanthine and ATP in healthy adults, and a preliminary trial in 30 patients with Parkinson’s disease demonstrated symptomatic improvement ( Watanabe et al, 2020 ).…”

Section: Possible Cellular Mechanisms Of Hub Vulnerability In the Aging Brain And Neurodegenerationmentioning

confidence: 99%

Characteristics of Neural Network Changes in Normal Aging and Early Dementia

Watanabe

Bagarinao

Maesawa

et al. 2021

Front. Aging Neurosci.

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To understand the mechanisms underlying preserved and impaired cognitive function in healthy aging and dementia, respectively, the spatial relationships of brain networks and mechanisms of their resilience should be understood. The hub regions of the brain, such as the multisensory integration and default mode networks, are critical for within- and between-network communication, remain well-preserved during aging, and play an essential role in compensatory processes. On the other hand, these brain hubs are the preferred sites for lesions in neurodegenerative dementias, such as Alzheimer’s disease. Disrupted primary information processing networks, such as the auditory, visual, and sensorimotor networks, may lead to overactivity of the multisensory integration networks and accumulation of pathological proteins that cause dementia. At the cellular level, the brain hub regions contain many synapses and require a large amount of energy. These regions are rich in ATP-related gene expression and had high glucose metabolism as demonstrated on positron emission tomography (PET). Importantly, the number and function of mitochondria, which are the center of ATP production, decline by about 8% every 10 years. Dementia patients often have dysfunction of the ubiquitin-proteasome and autophagy-lysosome systems, which require large amounts of ATP. If there is low energy supply but the demand is high, the risk of disease can be high. Imbalance between energy supply and demand may cause accumulation of pathological proteins and play an important role in the development of dementia. This energy imbalance may explain why brain hub regions are vulnerable to damage in different dementias. Here, we review (1) the characteristics of gray matter network, white matter network, and resting state functional network changes related to resilience in healthy aging, (2) the mode of resting state functional network disruption in neurodegenerative dementia, and (3) the cellular mechanisms associated with the disruption.

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Inosine attenuates rotenone‐induced Parkinson's disease in rats by alleviating the imbalance between autophagy and apoptosis

El‐Latif

Rabie

Sayed

et al. 2023

Drug Development Research

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Growing evidence points to impaired autophagy as one of the major factors implicated in the pathophysiology of Parkinson's disease (PD). Autophagy is a downstream target of adenosine monophosphate‐activated protein kinase (AMPK). Inosine has already demonstrated a neuroprotective effect against neuronal loss in neurodegenerative diseases, mainly due its anti‐inflammatory and antioxidant properties. We, herein, aimed at investigating the neuroprotective effects of inosine against rotenone‐induced PD in rats and to focus on the activation of AMPK‐mediated autophagy. Inosine successfully increased p‐AMPK/AMPK ratio in PD rats and improved their motor performance and muscular co‐ordination (assessed by rotarod, open field, and grip strength tests, as well as by manual gait analysis). Furthermore, inosine was able to mitigate the rotenone‐induced histopathological alterations and to restore the tyrosine hydroxylase immunoreactivity in PD rats' substantia nigra. Inosine‐induced AMPK activation resulted in an autophagy enhancement, as demonstrated by the increased striatal Unc‐S1‐like kinase1 and beclin‐1 expression, and also by the increment light chain 3II to light chain 3I ratio, along with the decline in striatal mammalian target of rapamycin and p62 protein expressions. The inosine‐induced stimulation of AMPK also attenuated neuronal apoptosis and promoted antioxidant activity. Unsurprisingly, these neuroprotective effects were antagonized by a preadministration of dorsomorphin (an AMPK inhibitor). In conclusion, inosine exerted neuroprotective effects against the rotenone‐induced neuronal loss via an AMPK activation and through the restoration of the imbalance between autophagy and apoptosis. These findings support potential application of inosine in PD treatment.

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Improved Parkinsons disease motor score in a single-arm open-label trial of febuxostat and inosine

Abstract: Supplemental Digital Content is available in the text

Cited by 18 publications

References 58 publications

Inosine in Neurodegenerative Diseases: From the Bench to the Bedside

Inosine in Neurodegenerative Diseases: From the Bench to the Bedside

Characteristics of Neural Network Changes in Normal Aging and Early Dementia

Inosine attenuates rotenone‐induced Parkinson's disease in rats by alleviating the imbalance between autophagy and apoptosis

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