Journal article
Uric Acid Stroke Cerebroprotection Transcended Sex, Age, and Comorbidities in a Multicenter Preclinical Trial
Stroke (1970), Vol.56(4), pp.965-973
04/2025
DOI: 10.1161/STROKEAHA.124.048748
PMCID: PMC11932773
PMID: 40091742
Abstract
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.
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).
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];
=0.006). UA-treated animals also had a better corner test index at day 7 (probability, 0.55 [95% CI, 0.5-0.59];
=0.035) and a higher survival rate at day 30 (hazard ratio, 1.41 [95% CI, 1.08-1.83];
=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.
UA provides ischemic stroke cerebroprotection across key relevant biological variables, making it a promising intervention to be further tested in human clinical trials.
Details
- Title: Subtitle
- Uric Acid Stroke Cerebroprotection Transcended Sex, Age, and Comorbidities in a Multicenter Preclinical Trial
- Creators
- Rakesh B Patel - University of IowaMariia Kumskova - University of IowaHanish Kodali - Icahn School of Medicine at Mount SinaiIvan Budnik - University of IowaVitalii Kuznetsov - ABR Labs LLC, Jacksonville, FL (V.K.)Aditi Jain - University of IowaAbhishek Jha - University of IowaDaniel Thedens - University of IowaNirav Dhanesha - University of IowaBrijesh Sutariya - University of IowaKarisma A Nagarkatti - University of Southern CaliforniaJessica Lamb - University of Southern CaliforniaPradip Kamat - Augusta UniversityYanrong Shi - Johns Hopkins UniversityBrooklyn Avery - Johns Hopkins UniversityTakahiko Imai - Massachusetts General HospitalXuyan Jin - Massachusetts General HospitalAnjali Chauhan - Department of Neurology, McGovern Medical School, University of Texas HSC, Houston (A. Chauhan, L.D.M., J.A.)Ligia S B Boisserand - Yale UniversityMohammad B Khan - Augusta UniversityKrishnan Dhandapani - Augusta UniversityBasavaraju G Sanganahalli - Yale UniversityLauren H Sansing - Yale UniversityDavid C Hess - Augusta UniversityRaymond C Koehler - Johns Hopkins UniversityLouise D McCullough - The University of Texas Health Science Center at HoustonJaroslaw Aronowski - The University of Texas Health Science Center at HoustonCenk Ayata - Harvard UniversityMárcio A Diniz - Icahn School of Medicine at Mount SinaiPatrick D Lyden - University of Southern CaliforniaAnna M Planas - Institut d'Investigacions Biomèdiques de BarcelonaAngel Chamorro - University of IowaAnil K Chauhan - University of IowaEnrique C Leira - University of IowaSPAN Investigators
- Resource Type
- Journal article
- Publication Details
- Stroke (1970), Vol.56(4), pp.965-973
- DOI
- 10.1161/STROKEAHA.124.048748
- PMID
- 40091742
- PMCID
- PMC11932773
- NLM abbreviation
- Stroke
- ISSN
- 0039-2499
- eISSN
- 1524-4628
- Publisher
- LIPPINCOTT WILLIAMS & WILKINS
- Grant note
- U01 NS113388 / NINDS NIH HHS U01 NS130587 / NINDS NIH HHS
- Language
- English
- Electronic publication date
- 03/17/2025
- Date published
- 04/2025
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Neurology; Radiology; Electrical and Computer Engineering; Hematology, Oncology, and Blood & Marrow Transplantation; Epidemiology; Iowa Neuroscience Institute; Neurosurgery; Internal Medicine
- Record Identifier
- 9984801842102771
Metrics
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