Uric Acid: A Translational Journey in Cerebroprotection That Spanned Preclinical and Human Data.

Uric acid (UA) is a strong endogenous antioxidant that neutralizes the toxicity of peroxynitrite and other reactive species on the neurovascular unit generated during and after acute brain ischemia. The realization that a rapid reduction of UA levels during an acute ischemic stroke was associated with a worse stroke outcome paved the way to investigate the value of exogenous UA supplementation to counteract the progression of redox-mediated ischemic brain damage. The long translational journey for UA supplementation recently reached a critical milestone when the results of the multicenter NIH stroke preclinical assessment network (SPAN) were reported. In a novel preclinical paradigm, 6 treatment candidates including UA supplementation were selected and tested in 6 independent laboratories following predefined criteria and strict methodological rigor. UA supplementation was the only intervention in SPAN that exceeded the prespecified efficacy boundary with male and female animals, young mice, young rats, aging mice, obese mice, and spontaneously hypertensive rats. This unprecedented achievement will allow UA to undergo clinical testing in a pivotal clinical trial through a NIH StrokeNet thrombectomy endovascular platform created to assess new treatment strategies in patients treated with mechanical thrombectomy. UA is a particularly appealing adjuvant intervention for mechanical thrombectomy because it targets the microcirculatory hypoperfusion and oxidative stress that limits the efficacy of this therapy. This descriptive review aims to summarize the translational development of UA supplementation, highlighting those aspects that likely contributed to its success. It includes having a well-defined target and mechanism of action, and an approach that simultaneously integrated rigorous preclinical assessment, with epidemiologic and preliminary human intervention studies. Validation of the clinical value of UA supplementation in a pivotal trial would confirm the translational value of the SPAN paradigm in preclinical research.

Treatment with Uric Acid Reduces Infarct and Improves Neurologic Function in Female Mice After Transient Cerebral Ischemia.

BACKGROUND: 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 human stroke patients in Spain as an adjuvant treatment to mechanical thrombectomy. Before clinical trials can be initiated in the United States, however, confirmation of efficacy in alternative preclinical models is required in accordance with stroke therapy academic industry roundtable-RIGOR criteria. To date, preclinical efficacy has only been established in the acute setting in male rodents. METHODS: To address this need, we subjected 7- to 9-week old ovariectomized female mice 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. A separate lab randomly assigned animals to vehicle versus uric acid infusion, which was initiated immediately after 45 minutes of reperfusion. Poststroke analysis of infarction size and neurologic function were conducted by investigators blind to treatment group, with a 7-day primary endpoint and a 3-day intermediary analysis at 1and. RESULTS: Infarct size and neurologic function at 7 days poststroke were significantly improved in uric acid-treated animals, relative to vehicle. CONCLUSION: Efficacy of uric acid in preclinical models of stroke is now expanded to include female mice analyzed at a later time point than has been investigated previously. These results support stroke therapy academic industry roundtable-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.

The NIHSS supplementary motor scale: a valid tool for multidisciplinary recovery trials.

BACKGROUND: There is a growing interest in therapies that may augment motor recovery that could be initiated in the acute stroke unit and maintained through the rehabilitation period. Homogenization of the currently fragmented stroke clinicometrics is necessary before such multidisciplinary trials can be conducted. The supplementary motor scale of the NIH Stroke Scale (SMS-NIHSS) is a simple and reliable scale for assessing proximal and distal motor function in the upper and lower extremities. We hypothesized that the currently underutilized SMS-NIHSS is a valid tool for assessing motor recovery with prognosticative value. METHODS: We performed an analysis of SMS-NIHSS scores recorded in 1,281 patients enrolled in the Trial of ORG 10172 in Acute Stroke Treatment (TOAST). We plotted the probability of a favorable outcome (FO) and very favorable outcome (VFO) at 3 months based on the baseline SMS-NIHSS scores. In order to better study the relationship between SMS-NIHSS and 3-month functional outcome, we performed multivariate logistic regression analyses using both FO and VFO as outcome measures. Analyses were adjusted for potential confounders such as age, sex, side of the lesion, time from symptom onset to emergency room arrival, temperature, systolic blood pressure, blood glucose level and treatment group assignment (ORG 10172 vs. placebo). We also calculated the Spearman correlation coefficient between the SMS-NIHSS, Barthel Index (BI) and Glasgow Outcome Score (GOS) obtained at the 3-month visit. RESULTS: The mean SMS-NIHSS scores were 8.18 at baseline and 4.68 at 3 months. The SMS-NIHSS scores showed a gradual improvement during the first 3 months after stroke. There was a linear relationship between the baseline SMS-NIHSS scores and the probability of an FO or VFO at 3 months. The SMS-NIHSS baseline score was an independent predictor of FO (OR = 0.86; 95% CI 0.84-0.87; p < 0.0001) and VFO (OR = 0.85; 95% CI 0.84-0.87; p < 0.0001) at 3 months after adjusting for confounders. The degree of improvement in the SMS-NIHSS scores from baseline to 3 months was also independently associated with FO and VFO (p < 0.0001). At 3 months, SMS-NIHSS scores showed a strong correlation with the BI (r = -0.70; p < 0.0001) and GOS (r = 0.73; p < 0.0001). CONCLUSIONS: The SMS-NIHSS is a valid scale for assessing motor recovery with prognosticative value, and may be sensitive to changes during recovery. Given that the SMS-NIHSS is an extension of the widely accepted NIHSS, it could be easily implemented in trials conducted in a variety of clinical research settings, including acute stroke hospitals and rehabilitation units.