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

Enrique C Leira; Anna M Planas; Anil K Chauhan; Angel Chamorro

doi:10.1212/WNL.0000000000207825

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

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

Authors

Enrique C Leira¹, Anna M Planas¹, Anil K Chauhan¹, Angel Chamorro²

Affiliations

¹ From the Department of Neurology (E.L., A.C.), and Departments of Neurosurgery & Epidemiology (E.L.), University of Iowa, Iowa City; Institute of Biomedical Research of Barcelona (IIBB) (A.M.P.), Spanish National Research Council (CSIC); August Pi i Sunyer Biomedical Research Institute (IDIBAPS) (A.M.P., A.C.), Barcelona, Spain; Department of Internal Medicine (A.K.C.), University of Iowa, Iowa City; and Hospital Clinic (A.C.), University of Barcelona, Spain.
² From the Department of Neurology (E.L., A.C.), and Departments of Neurosurgery & Epidemiology (E.L.), University of Iowa, Iowa City; Institute of Biomedical Research of Barcelona (IIBB) (A.M.P.), Spanish National Research Council (CSIC); August Pi i Sunyer Biomedical Research Institute (IDIBAPS) (A.M.P., A.C.), Barcelona, Spain; Department of Internal Medicine (A.K.C.), University of Iowa, Iowa City; and Hospital Clinic (A.C.), University of Barcelona, Spain. achamorro@clinic.cat.

PMID: 37848338
PMCID: PMC10752646 (available on 2024-12-05)
DOI: 10.1212/WNL.0000000000207825

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.

Publication types

Review

MeSH terms

Animals
Brain Ischemia* / complications
Brain Ischemia* / drug therapy
Female
Humans
Ischemic Stroke* / drug therapy
Male
Mice
Microcirculation
Multicenter Studies as Topic
Rats
Stroke* / complications
Uric Acid

Substances

Uric Acid