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Review
. 2023 Dec 4;101(23):1068-1074.
doi: 10.1212/WNL.0000000000207825.

Uric Acid: A Translational Journey in Cerebroprotection That Spanned Preclinical and Human Data

Enrique C Leira  1 , Anna M Planas  1 , Anil K Chauhan  1 , Angel Chamorro  2
Affiliations
Review

Uric Acid: A Translational Journey in Cerebroprotection That Spanned Preclinical and Human Data

Enrique C Leira et al. Neurology. .

Abstract

Uric acid (UA) is a strong endogenous antioxidant that neutralizes the toxicity of peroxynitrite and other reactive species on the neurovascular unit generated during and after acute brain ischemia. The realization that a rapid reduction of UA levels during an acute ischemic stroke was associated with a worse stroke outcome paved the way to investigate the value of exogenous UA supplementation to counteract the progression of redox-mediated ischemic brain damage. The long translational journey for UA supplementation recently reached a critical milestone when the results of the multicenter NIH stroke preclinical assessment network (SPAN) were reported. In a novel preclinical paradigm, 6 treatment candidates including UA supplementation were selected and tested in 6 independent laboratories following predefined criteria and strict methodological rigor. UA supplementation was the only intervention in SPAN that exceeded the prespecified efficacy boundary with male and female animals, young mice, young rats, aging mice, obese mice, and spontaneously hypertensive rats. This unprecedented achievement will allow UA to undergo clinical testing in a pivotal clinical trial through a NIH StrokeNet thrombectomy endovascular platform created to assess new treatment strategies in patients treated with mechanical thrombectomy. UA is a particularly appealing adjuvant intervention for mechanical thrombectomy because it targets the microcirculatory hypoperfusion and oxidative stress that limits the efficacy of this therapy. This descriptive review aims to summarize the translational development of UA supplementation, highlighting those aspects that likely contributed to its success. It includes having a well-defined target and mechanism of action, and an approach that simultaneously integrated rigorous preclinical assessment, with epidemiologic and preliminary human intervention studies. Validation of the clinical value of UA supplementation in a pivotal trial would confirm the translational value of the SPAN paradigm in preclinical research.

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Conflict of interest statement

E.C. Leira has received salary support from the National Institute of Neurological Disorders and Stroke as co-PI of SPAN at the University of Iowa. A.M. Planas reports no relevant disclosure relevant to this manuscript. A.K. Chauhan has received salary support from the National Institute of Neurological Disorders and Stroke as co-PI of SPAN at the University of Iowa. A. Chamorro has a patent in UA use in mechanical thrombectomy and stocks in Freeox biotech. Go to Neurology.org/N for full disclosures.

Figures

Figure 1
Figure 1. Graphical Depiction of the Translational Journey of UA Supplementation as an Adjuvant Cerebroprotectant
MT = mechanical thrombectomy; RCT = randomized controlled trial; rtPA = recombinant tissue plasminogen activator; STAIR = Stroke Therapy Academic Industry Roundtable; UA = uric acid.
Figure 2
Figure 2. Mechanistic Role of UA in the Current Reperfusion Scenario
After a large vessel occlusion, the microcirculation is also impaired due in part to peroxynitrite generation in capillary pericytes. UA during thrombectomy scavenges peroxynitrite and other reactive species resulting in improved flow in the microcirculation and improved tissue perfusion and cerebroprotection. Created with BioRender.com. rtPA = recombinant tissue plasminogen activator; UA = uric acid.
See this image and copyright information in PMC

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