We are proposing exogenous supplementation of Uric acid (UA) as our endorsed neuroprotective agent for SPAN. The choice was based on supportive evidence that includes efficacy in different pre-clinical models of ischemia, combined with an excellent human safety record and preliminary efficacy data. Growing preclinical and clinical data suggest that replenishing serum UA levels may result in significant clinical benefits, particularly in patients with a higher oxidative/nitrosative burden, such as those who recanalize after receiving MT 5 . During ischemia and reperfusion, different molecular changes converge to produce damaging concentrations of reactive oxygen species (ROS) and reactive nitrogen species (RNS). The ROS and RNS trigger cellular responses ranging from subtle modulations of cell signaling to devastating oxidative and nitrosative brain injury. UA is the most potent endogenous scavenger of peroxynitrite and hydroxyl radicals (ˉOH) in humans. UA contributes up to 60% of the total plasma antioxidant activity. Endogenous UA levels rapidly drop following AIS6 and are inadequate to counteract the redox-mediated challenge. Our laboratory tested the long-term effect of UA in ovariectomized female mice after 45 minutes of MCAO ischemia and reperfusion using the most rigorous methodology to prevent biases7. Our study added to the growing body of preclinical evidence for UA.

Furthermore, there is growing evidence of efficacy of UA in human stroke patients.  In an enriched analysis of the URICO-ICTUS trial, 45 patients with proximal vessel occlusions treated with mechanical thrombectom, UA treatment was associated with excellent functional outcome: 67% of patients who received UA and 48% of the patients who received placebo had an “excellent” outcome at 90 days 9. The mortality, rates of symptomatic cerebral bleeding and gout attacks, were similar in both treatment groups. These results provide encouraging evidence of preliminary efficacy and safety of UA in patients successfully reperfused with MT, which further supports the candidacy of UA as a very competitive agent in future trials of neuroprotection with adequate reperfusion.

Uric Acid (UA): Mechanism

• Peroxynitrite and hydroxyl radicals surge in ischemia-reperfusion
• Secondary mitochondrial dysfunction, excitotoxicity, lipid peroxidation, and inflammation
• UA is the most potent endogenous scavenger of peroxynitrite and hydroxyl radicals in humans
• During acute cerebral ischemia endogenous UA  are rapidly depleted
• Acute UA supplementation counteracts free-radical surge

Quality of Pre-Clinical Evidence: Uric Acid

Quality of Human Data (URICO-ICTUS trial)

All Patients treated with rtPA (n=411)

Patients treated with rtPA + MT (n=45)