In this issue of EBioMedicine, Chen and colleagues investigated the association between urate, the anionic form of uric acid, and blood pressure (BP), by studying three groups of genetically engineered mice with different levels of urate, and by reanalysing data from a clinical trial using inosine to increase urate levels in Parkinson's disease (PD) [1,2].
Urate is the enzymatic end-product of purine metabolism in apes and humans, and is traditionally thought to be a cardiovascular risk factor, contributing to chronic inflammation within the endothelium and, ultimately, to its dysfunction with subsequently higher BP [3,4]. However, higher urate is not necessarily a cause of hypertension, nor its consequence, and could be merely an association. Based on this, authors acquired BP measurements from three complementary lines of genetically engineered mice: urate oxidase (UOx) conditional knockout (cKO), global KO (gKO), and transgenic (Tg) mice with mildly elevated, markedly elevated, and substantially reduced serum urate, respectively. These knockout models were specifically selected to mimic the evolutional mutations in UOx gene, making them as much “humanized” as an animal model could possibly be. Also, authors re-analysed data from the SURE-PD, a phase 2 clinical trial aiming at evaluating safety of inosine in increasing urate levels in early PD. [1] Results consistently did not support any positive association between long-term urate elevation and BP variations in neither animal models nor generally-healthy early PD. [2] Biological and clinical relevance of these findings go far beyond this study, and will impact on basic and clinical research on neurodegenerative diseases, where urate-elevating strategies have been tested.
Urate accounts for 60% plasma antioxidant capacity and acts as a scavenger of free radicals, exerting neuroprotective effects on animal models of brain/spinal cord injury, multiple sclerosis (MS), and stroke [4,5]. Further neuroprotectant evidence comes from epidemiological studies showing lower levels of urate being associated with a higher risk of developing amyotrophic lateral sclerosis (ALS) [5], multiple sclerosis (MS) [6], multiple system atrophy (MSA) [7], and PD. [4] Not least, clinical observational studies found lower levels of urate being associated with worse outcomes in MS [8], MSA [7], PD [4,9], and stroke [10]. Based on this, urate-elevating strategies have been tested for safety and efficacy in phase 2 and, more recently, phase 3 clinical trials (Table 1). Most of these studies have used an urate precursor, inosine, that is taken orally and rapidly metabolized to urate [5]. Overall, phase 2 clinical trials proved inosine safe in elevating plasma and CSF urate in the long term, and did not support any association between elevated urate and any cardiovascular comorbidity (e.g., hypertensive, hyperglycaemic, dyslipidaemic and obesity components of metabolic syndrome) [1,6]. Encouraging clinical results were shown in a phase 2/3 clinical trial (URICO-ICTUS) where the combination of intravenous urate with thrombolysis in acute ischemic stroke resulted in improved clinical outcomes, especially in woman and in patients more vulnerable to oxidative stress and reperfusion injury (e.g., hyperglycaemia at stroke onset) [10]. Further clinical results are expected from the ongoing phase 3 clinical trial in PD (SURE-PD3), potentially leading to the first disease-modifying therapy for PD.
Table 1.
Urate in clinical trials.
Table shows ongoing and completed clinical trials using treatment with uric acid or with urate-elevating strategies. For each trial, phase, intervention(s), primary and secondary outcomes, sample size, year of start and current status, and ClinicalTrials.gov reference are reported.
| Conditions | Phase | Interventions | Primary outcome | Secondary outcomes | Sample size | Year at start | Reference |
|---|---|---|---|---|---|---|---|
| Acute Ischemic Stroke | 2/3 | Uric acid or Placebo | Degree of disability after stroke | Other clinical outcomes | 421 | 2011-completed | ClinicalTrials.gov/show/NCT00860366 |
| Radiological outcomes | |||||||
| ALS | 1 | Inosine | Safety Tolerability | Blood outcomes | 32 | 2015-completed | ClinicalTrials.gov/show/NCT02288091 |
| Radiological outcomes | |||||||
| 2 | Inosine or Placebo | Safety Tolerability | 30 | 2017-ongoing | ClinicalTrials.gov/show/NCT03168711 | ||
| Healthy | 1 | Inosine | Pharmacokinetics | Safety /Tolerability | 18 | 2015-completed | ClinicalTrials.gov/show/NCT02614469 |
| 1 | Uric acid or Rasburicase | Change in inflammatory markers | 97 | 2009-completed | ClinicalTrials.gov/show/NCT01323335 | ||
| 1 | Montmorency cherry concentrate | Change in uric acid | Change in inflammatory markers | 12 | 2012-completed | ClinicalTrials.gov/show/NCT01825070 | |
| MSA | 2 | Inosine or Placebo | Change in uric acid | Rate of clinical decline | 80 | 2018-ongoing | ClinicalTrials.gov/show/NCT03403309 |
| Safety/Tolerability | |||||||
| PD | 2 | Inosine or Placebo | Safety /Tolerability | Change in uric acid | 75 | 2009-completed | ClinicalTrials.gov/show/NCT00833690 |
| 3 | Inosine or Placebo | Rate of clinical decline | Safety /Tolerability | 270 | 2016-ongoing | ClinicalTrials.gov/show/NCT02642393 | |
| Other clinical outcomes | |||||||
| Patient reported outcomes | |||||||
| RRMS | 2 | Inosine | n.r. | n.r. | 30 | 2001-completed | ClinicalTrials.gov/show/NCT00067327 |
ALS: Amyotrophic Lateral Sclerosis; MSA: Multiple System Atrophy; PD: Parkinson Disease; RRMS: Relapsing-Remitting Multiple Sclerosis; n.r.: not reported.
In the future, basic scientists might consider using animal models as described by Chen and colleagues to study consequences of urate elevation on motor/behavioural tasks, though an effect is not necessarily implied considering that the urate pathway is rather specific of hominoids, and, possibly, relates to more developed cerebral function [4]. Also, it is worth noting that PD patients included in the SURE-PD were at early stage with neither severe neurological symptoms nor cardiovascular comorbidities [1]. Thus, generalizability of these findings should be examined on more heterogenous cohorts where a number of variables should be considered (e.g., physical exercise, medication, concomitant cardiovascular diseases and diet).
In conclusion, we feel we need to thank Chen and colleagues for their elegant study, providing basic and clinical scientists with evidence suggesting there is little risk of increasing blood pressure while applying urate-elevating strategies, that, thus, could be further moved towards treatment of neurodegenerative diseases.
Acknowledgements, funding and conflict of interest
The authors declare no conflict of interest.
Martina Petruzzo has nothing to disclose. Marcello Moccia has received research grants from ECTRIMS-MAGNIMS and Merck.
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