Uric Acid Stroke Cerebroprotection Transcended Sex, Age, and Comorbidities in a Multicenter Preclinical Trial
Abstract
BACKGROUND:
Past failures in translating stroke cerebroprotection provoked calls for a more rigorous methodological approach, leading to the stroke preclinical assessment network SPAN (Stroke Preclinical Assessment Network), where uric acid (UA) treatment exceeded a prespecified efficacy boundary for the primary functional outcome. Still, successful translation to humans requires confirmation of the effect of UA across key biological variables relevant to patients with stroke.
METHODS:
We measured the effects of intravenous UA treatment (16 mg/kg) versus intravenous saline in groups of animals enrolled in the SPAN network with diverse comorbidities, sex, and age. The masked study drug or placebo was administered during reperfusion in rodents undergoing a transient middle cerebral artery filament occlusion. The primary outcome was the modified corner test index at day 30 poststroke, and numerous secondary outcomes were collected. A modified intention-to-treat population was used in the analysis. We tested for any interactions with sex, age, and comorbidities (obesity-induced hyperglycemia and hypertension).
RESULTS:
In total, 710 animals were randomized to receive either intravenous UA or saline. After accounting for procedural dropouts and exclusions from treatment, a total of 687 animals were qualified and analyzed, including 458 assigned to UA and 229 to intravenous saline control. UA-treated animals exhibited a better primary functional outcome at day 30 (probability, 0.56 [95% CI, 0.52–0.60]; P=0.006). UA-treated animals also had a better corner test index at day 7 (probability, 0.55 [95% CI, 0.5–0.59]; P=0.035) and a higher survival rate at day 30 (hazard ratio, 1.41 [95% CI, 1.08–1.83]; P=0.011). Brain morphometry at day 2 and 30 was comparable between the treatment groups. The improved functional outcome and survival in UA-treated animals were preserved across different species, sexes, ages, and comorbidities.
CONCLUSIONS:
UA provides ischemic stroke cerebroprotection across key relevant biological variables, making it a promising intervention to be further tested in human clinical trials.
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© 2025 American Heart Association, Inc.
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History
Received: 26 July 2024
Revision received: 6 December 2024
Accepted: 21 January 2025
Published online: 17 March 2025
Published in print: April 2025
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Disclosures
Dr Lyden reports compensation from the National Institutes of Health Clinical Center for other services and compensation from Apex Innovations and EMD Serono for consultant services. Dr Chamorro owns a patent for the use of uric acid in stroke patients treated with thrombectomy and reports shares from FreeOx Biotech SL. Dr Hess reports compensation from Gentibio Inc for consultant services; a patent for the use of the Metropolitan Area Planning Council (MAPC) in neurological diseases licensed to Athersys; and grants from the National Institutes of Health. Dr Ayata reports grants from the Takeda Pharmaceutical Company; consulting for BioAxone Biosciences, Scientific Advisory Board at Neurelis, and Clinical Advisory Board at Omniox. Dr Leira reports grants from the American Stroke Association. Dr Diniz reports grants from the National Institutes of Health. The other authors report no conflicts.
Funding Information
NIH: U01NS113388,R35 HL139926
NIH: U01NS113388
NIH: U24NS113452
NIH: U01NS113445
NIH: U01NS113444,R01NS102583,R01NS105894
NIH: R01 NS099455,1UO1NS113356,and R01NS112511
NIH: U01 NS113443
NIH: U01NS113451
Supported by the National Institutes of Health funding to the University of Iowa (U01NS113388, R35HL139926, Dr Chauhan and U01NS113388, Dr Leira), the University of Southern California (U24NS113452, Dr Lyden), the Yale University School of Medicine (U01NS113445, Dr Sansing), the Johns Hopkins University (U01NS113444, R01NS102583, and R01NS105894, Dr Koehler), the Augusta University (R01NS099455, U01NS113356, and R01NS112511, Dr Hess), the Massachusetts General Hospital (U01NS113443, Dr Ayata), the University of Texas (U01NS113451, Dr McCullough and Dr Aronowski).
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