Evidence suggests that spironolactone, a nonselective mineralocorticoid receptor (MR) antagonist, modulates alcohol seeking and consumption. Therefore, spironolactone may represent a novel pharmacotherapy for alcohol use disorder (AUD). In this study, we tested the effects of spironolactone in a mouse model of alcohol drinking (drinking-in-the-dark) and in a rat model of alcohol dependence (vapor exposure). We also investigated the association between spironolactone receipt for at least 60 continuous days and change in self-reported alcohol consumption, using the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C), in a pharmacoepidemiologic cohort study in the largest integrated healthcare system in the US. Spironolactone dose-dependently reduced the intake of sweetened or unsweetened alcohol solutions in male and female mice. No effects of spironolactone were observed on drinking of a non-alcohol-containing sweet solution, food or water intake, motor coordination, alcohol-induced ataxia, or blood alcohol levels. Spironolactone dose-dependently reduced operant alcohol self-administration in dependent and nondependent male and female rats. In humans, a greater reduction in alcohol consumption was observed among those who received spironolactone, compared to propensity-score matched individuals who did not receive spironolactone. The largest effects were among those who reported hazardous/heavy episodic alcohol consumption at baseline (AUDIT-C ≥ 8) and those exposed to ≥ 50 mg/day of spironolactone. These convergent findings across rodent and human studies demonstrate that spironolactone reduces alcohol use and support the hypothesis that this medication may be further studied as a novel pharmacotherapy for AUD.
Background & Purpose:
Exogenous administration of uric acid, a naturally occurring antioxidant that scavenges reactive oxygen species in vasculature, has shown protective efficacy in both rodent models of stroke and in human stroke patients in Spain as an adjuvant treatment to mechanical thrombectomy. In accordance with STAIR-RIGOR criteria, confirmation of efficacy in alternative preclinical models is required before clinical trials can be initiated in the United States. To date, preclinical efficacy has only been established in the acute setting in male rodents.
Methods:
Seven to nine week old ovariectomized female mice were subjected to filament-induced right middle cerebral artery ischemia and reperfusion, an established preclinical model of mechanical thrombectomy. Fidelity of the procedure was monitored by laser Doppler flowmetry in all animals. A separate lab randomly assigned animals to vehicle vs uric acid infusion, which was initiated immediately after 45 minutes of reperfusion. Post-stroke analysis of infarction size and neurological function were conducted by investigators blind to treatment group, with a 7 day primary endpoint and intermediary analysis at 1and 3 days.
Results:
Infarct size and neurological function at 7 days post-stroke was significantly improved in uric acid-treated animals, relative to vehicle.
Conclusions:
Efficacy of uric acid in preclinical models of stroke is now expanded to include female mice analyzed at a more chronic time point than has been investigated previously. These results supports STAIR-RIGOR driven determination of the suitability of acute administration of uric acid as an adjuvant to mechanical thrombectomy in clinical trials for patients with stroke.
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