Faculty, Staff and Student Publications

Language

English

Publication Date

10-7-2025

Journal

Journal of the American Heart Association

DOI

10.1161/JAHA.124.040914

PMID

40996065

PMCID

PMC12684482

PubMedCentral® Posted Date

9-25-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Background: The Stroke Preclinical Assessment Network tested 6 therapeutic interventions initiated at the time of reperfusion after focal ischemic stroke in young mice, aging mice, obese mice, and spontaneously hypertensive rats. This randomized, controlled trial was conducted across 6 sites with concealed treatment and blinded neurobehavior assessments. The trial had an adaptive design with preset levels of efficacy and futility interrogated after each of 4 stages. The primary outcome was turning preference on the corner test at 1 month. The PARP (poly(ADP-ribose) polymerase) inhibitor, veliparib, was considered futile after the second stage when pooling all animal models (n=231 veliparib; n=344 placebo).

Methods: A secondary analysis was performed to evaluate veliparib treatment on primary and secondary outcomes in individual subgroup models.

Results: Intravenous injection of veliparib at reperfusion failed to show a benefit on the corner test at 7 or 30 days of recovery in young mice, obese mice, or spontaneously hypertensive rats. However, in aging mice (15-18 months old), veliparib significantly improved performance on the corner test at 7 (P=0.007) and 30 (P=0.03) days and reduced foot-faults on the grid walk test at 7 (P=0.024) and 30 (P=0.008) days. These effects were independent of sex. Treatment had no effect on magnetic resonance imaging-determined lesion volume. The survival was similar with placebo and veliparib treatments across subgroups, although mortality was high in aging mice.

Conclusions: Veliparib improved functional outcome in aging mice. Because ischemic stroke predominantly occurs in the aging population, further research into the benefit of PARP inhibitors in aged animal models of stroke is warranted.

Keywords

Animals, Poly(ADP-ribose) Polymerase Inhibitors, Benzimidazoles, Rats, Inbred SHR, Mice, Male, Disease Models, Animal, Rats, Risk Factors, Mice, Inbred C57BL, Ischemic Stroke, Stroke, Behavior, Animal, Age Factors, aging, middle cerebral artery occlusion, obesity, poly(ADP‐ribose) polymerase, preclinical trial, spontaneously hypertensive rat, veliparib

Published Open-Access

yes

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