Uric acid therapy for vasculoprotection in acute ischemic stroke

Abstract

Uric acid (UA) is a product of the catabolism of purine nucleotides, the principal constituents of DNA, RNA, and cellular energy stores, such as adenosine triphosphate. The main properties of UA include scavenging of hydroxyl radicals, superoxide anion, hydrogen peroxide, and peroxynitrite that make this compound to be the most potent antioxidant in the human plasma. As the result of two silencing mutations in the gene of the hepatic enzyme uricase which degrades UA to allantoin, humans have higher levels of UA than most mammals. However, these levels rapidly decrease following an acute ischemic stroke (AIS), and this decrement has been associated to worse stroke outcomes. This review highlights the safety and potential clinical value of UA therapy in AIS, particularly in patients more exposed to redox-mediated mechanism following the onset of ischemia, such as women, hyperglycemic patients, or patients treated with mechanical thrombectomy. The clinical findings are supported by preclinical data gathered in different laboratories, and in assorted animal species which include male and female individuals or animals harboring comorbidities frequently encountered in patients with AIS, such as hyperglycemia or hypertension. A remarkable finding in these studies is that UA targets its main effects in the brain vasculature since available evidence suggests that does not seem to cross the blood–brain barrier. Altogether, the available data with UA therapy extend the importance of vasculoprotection for effective neuroprotection at the bedside and reinforce the role of endothelial cells after brain ischemia for an increased survival of the whole neurovascular unit.

Serum ICAM-1 as a Predictor of Prognosis in Patients with Acute Ischemic Stroke

“…Animal studies have demonstrated the causal relationship between systemic inflammation and AIS neurological damage and poor prognosis [ 29 ]. The underlying mechanisms of systemic inflammation affecting the poor prognosis of AIS include neutrophil infiltration, blood-brain barrier (BBB) destruction, and cerebral ischemia-reperfusion injury [ 30 , 31 ]. Animal experiments showed that reducing leukocyte infiltration could reduce the neurological damage of AIS and delay disease progression [ 32 ].…”

Gout Is Not Just Arthritis: Abnormal Cortical Thickness and Structural Covariance Networks in Gout

“…Previous studies have found that, compared with those in other animals, higher concentrations of uric acid in humans may stimulate the cerebral cortex to obtain more brain volume and better intelligence performance ( 49 ). The antioxidant, vasculoprotective, and neuroprotective effects of uric acid have also been proven to be effective in treating some neurological diseases ( 6 , 50 , 51 ). However, whole brain structural mapping in gout patient has not been done before.…”

The Next Step in the Treatment of Stroke

“…Uric Acid is a product of the catabolism of purine nucleotides and contributes up to 60% of the plasma antioxidant activity: scavenging hydroxyl radicals, superoxide anions, hydrogen peroxide, and peroxynitrite (103). In MCAO mouse models, uric acid treatment reduced infarct volume, ROS production, and neurological deficits (104,105).…”

“…For example, in a rat MCAO model, uric acid treatment reduced MCA wall thickening and increased lumen expansion (106). Mechanistically, uric acid treatment increases the expression Kruppel-like factor 2 and reduces the expression of VEGF-A, thereby maintaining BBB integrity (103). In the URICO-ICTUS trial, a multicenter, randomized, double blind, phase 2b/3 trial, patients that received uric acid in combination with alteplase (<4.5 h) did not improve outcomes at 90 days, but in a sensitivity analyses, a borderline significance was seen in patients with uric acid treatment who experienced an ordinal shift in mRS, decreasing their residual disability by a median of 1 point on the mRS compared to the placebo group (107).…”