Uric Acid Stroke Cerebroprotection Transcended Sex, Age, and Comorbidities in a Multicenter Preclinical Trial

Rakesh B Patel^#¹, Mariia Kumskova^#¹, Hanish Kodali², Ivan Budnik¹, Vitalii Kuznetsov³, Aditi Jain¹, Abhishek Jha¹, Daniel Thedens⁴, Nirav Dhanesha¹, Brijesh Sutariya¹, Karisma A Nagarkatti⁵, Jessica Lamb⁵, Pradip Kamat⁶, Yanrong Shi⁷, Brooklyn Avery⁷, Takahiko Imai⁸, Xuyan Jin⁸, Anjali Chauhan⁹, Ligia S B Boisserand¹⁰, Mohammad B Khan⁶, Krishnan Dhandapani⁶, Basavaraju G Sanganahalli¹¹, Lauren H Sansing¹⁰, David C Hess⁶, Raymond C Koehler⁷, Louise D McCullough⁹, Jaroslaw Aronowski⁹, Cenk Ayata⁸, Márcio A Diniz², Patrick D Lyden^{5

12}, Anna M Planas^{13

14}, Angel Chamorro^{15

14

16}, Anil K Chauhan¹, Enrique C Leira^{15

17

18}; SPAN Investigators

Affiliations

¹ Division of Hematology, Oncology and Blood & Marrow Transplantation, Department of Internal Medicine, Carver College of Medicine (R.B.P., M.K., I.B., A. Jain, A. Jha, N.D., B.S., A.K.C.), University of Iowa, Iowa City.
² Department of Population Health Science and Policy, Icahn School of Medicine, Mount Sinai, New York, NY (H.K., M.A.D.).
³ ABR Labs LLC, Jacksonville, FL (V.K.).
⁴ Department of Radiology, Carver College of Medicine (D.T.), University of Iowa, Iowa City.
⁵ Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine (K.A.N., J.L., P.D.L.), University of Southern California, Los Angeles.
⁶ Department of Neurology, Medical College of Georgia, Augusta University (P.K., M.B.K., K.D., D.C.H.).
⁷ Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD (Y.S., B.A., R.C.K.).
⁸ Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston (T.I., X.J., C.A.).
⁹ Department of Neurology, McGovern Medical School, University of Texas HSC, Houston (A. Chauhan, L.D.M., J.A.).
¹⁰ Department of Neurology, Yale University School of Medicine, New Haven, CT (L.S.B.B., L.H.S.).
¹¹ Departments of Radiology and Biomedical Imaging, Yale University, New Haven, CT (B.G.S.).
¹² Department of Neurology, Keck School of Medicine (P.D.L.), University of Southern California, Los Angeles.
¹³ Institute of Biomedical Research of Barcelona (IIBB), Spanish National Research Council (CSIC) (A.M.P.).
¹⁴ August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain (A.M.P., A. Chamorro).
¹⁵ Department of Neurology, Carver College of Medicine (A. Chamorro, E.C.L.), University of Iowa, Iowa City.
¹⁶ Department of Neurology, Hospital Clinic, University of Barcelona, Spain (A. Chamorro).
¹⁷ Department of Neurosurgery, Carver College of Medicine (E.C.L.), University of Iowa, Iowa City.
¹⁸ Department of Epidemiology, College of Public Health (E.C.L.), University of Iowa, Iowa City.

^# Contributed equally.

PMID: 40091742
PMCID: PMC11932773 (available on 2026-04-01)
DOI: 10.1161/STROKEAHA.124.048748

Multicenter Study

Uric Acid Stroke Cerebroprotection Transcended Sex, Age, and Comorbidities in a Multicenter Preclinical Trial

Rakesh B Patel et al. Stroke. 2025 Apr.

. 2025 Apr;56(4):965-973.

doi: 10.1161/STROKEAHA.124.048748. Epub 2025 Mar 17.

Authors

Affiliations

¹ Division of Hematology, Oncology and Blood & Marrow Transplantation, Department of Internal Medicine, Carver College of Medicine (R.B.P., M.K., I.B., A. Jain, A. Jha, N.D., B.S., A.K.C.), University of Iowa, Iowa City.
² Department of Population Health Science and Policy, Icahn School of Medicine, Mount Sinai, New York, NY (H.K., M.A.D.).
³ ABR Labs LLC, Jacksonville, FL (V.K.).
⁴ Department of Radiology, Carver College of Medicine (D.T.), University of Iowa, Iowa City.
⁵ Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine (K.A.N., J.L., P.D.L.), University of Southern California, Los Angeles.
⁶ Department of Neurology, Medical College of Georgia, Augusta University (P.K., M.B.K., K.D., D.C.H.).
⁷ Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD (Y.S., B.A., R.C.K.).
⁸ Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston (T.I., X.J., C.A.).
⁹ Department of Neurology, McGovern Medical School, University of Texas HSC, Houston (A. Chauhan, L.D.M., J.A.).
¹⁰ Department of Neurology, Yale University School of Medicine, New Haven, CT (L.S.B.B., L.H.S.).
¹¹ Departments of Radiology and Biomedical Imaging, Yale University, New Haven, CT (B.G.S.).
¹² Department of Neurology, Keck School of Medicine (P.D.L.), University of Southern California, Los Angeles.
¹³ Institute of Biomedical Research of Barcelona (IIBB), Spanish National Research Council (CSIC) (A.M.P.).
¹⁴ August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain (A.M.P., A. Chamorro).
¹⁵ Department of Neurology, Carver College of Medicine (A. Chamorro, E.C.L.), University of Iowa, Iowa City.
¹⁶ Department of Neurology, Hospital Clinic, University of Barcelona, Spain (A. Chamorro).
¹⁷ Department of Neurosurgery, Carver College of Medicine (E.C.L.), University of Iowa, Iowa City.
¹⁸ Department of Epidemiology, College of Public Health (E.C.L.), University of Iowa, Iowa City.

^# Contributed equally.

PMID: 40091742
PMCID: PMC11932773 (available on 2026-04-01)
DOI: 10.1161/STROKEAHA.124.048748

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.

Keywords: intention to treat analysis; ischemic stroke; middle cerebral artery; sex; uric acid.

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Conflict of interest statement

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.

References

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Uric Acid Stroke Cerebroprotection Transcended Sex, Age, and Comorbidities in a Multicenter Preclinical Trial

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Uric Acid Stroke Cerebroprotection Transcended Sex, Age, and Comorbidities in a Multicenter Preclinical Trial

Authors

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Abstract

Conflict of interest statement

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