Uric Acid Treatment After Stroke Prevents Long-Term Middle Cerebral Artery Remodelling and Attenuates Brain Damage in Spontaneously Hypertensive Rats

Abstract

Hypertension is the most important modifiable risk factor for stroke and is associated with poorer post-stroke outcomes. The antioxidant uric acid is protective in experimental normotensive ischaemic stroke. However, it is unknown whether this treatment exerts long-term protection in hypertension. We aimed to evaluate the impact of transient intraluminal middle cerebral artery (MCA) occlusion (90 min)/reperfusion (1-15 days) on brain and vascular damage progression in adult male Wistar-Kyoto (WKY; n = 36) and spontaneously hypertensive (SHR; n = 37) rats treated (i.v./120 min post-occlusion) with uric acid (16 mg kg) or vehicle (Locke's buffer). Ischaemic brain damage was assessed longitudinally with magnetic resonance imaging and properties of MCA from both hemispheres were studied 15 days after stroke. Brain lesions in WKY rats were associated with a transitory increase in circulating IL-18 and cerebrovascular oxidative stress that did not culminate in long-term MCA alterations. In SHR rats, more severe brain damage and poorer neurofunctional outcomes were coupled to higher cortical cerebral blood flow at the onset of reperfusion, a transient increase in oxidative stress and long-lasting stroke-induced MCA hypertrophic remodelling. Thus, stroke promotes larger brain and vascular damage in hypertensive rats that persists for long-time. Uric acid administered during early reperfusion attenuated short- and long-term brain injuries in both normotensive and hypertensive rats, an effect that was associated with abolishment of the acute oxidative stress response and prevention of stroke-induced long-lasting MCA remodelling in hypertension. These results suggest that uric acid might be an effective strategy to improve stroke outcomes in hypertensive subjects.

Stenosis coexists with compromised α1-adrenergic contractions in the ascending aorta of a mouse model of Williams-Beuren syndrome

“…Louis, MO, USA) were assessed by HPLC with fluorescence detection, as a quantitative measure of plasma superoxide anion levels, as described [37][38][39] . 2-EOH present in the samples was quantified by comparing with a calibration curve based on the reaction xanthine-xanthine oxidase from the method described by Michalski and cols 40 .…”

Preclinical Imaging Biomarkers for Postischaemic Neurovascular Remodelling

“…Functional imaging modalities, which reveal physiological changes in response to experimental interventions, mandate stable homeostasis. The administration of anaesthesia may influence key parameters, such as blood volume, flow, and oxygenation; therefore, these changes must be acknowledged and compensated for when administering anaesthetics, analgesics, fluids, body temperature control, blood pressure regulation, or artificial ventilation [27, 93–95]. Other considerations when using small animal models arise simply from their small size, which imposes the need for specialised equipment.…”

Uric acid therapy for vasculoprotection in acute ischemic stroke

“…UA therapy after I/R in normotensive rats also exerted long-term brain protective effects which were associated with attenuation of the short-term rise in both circulating levels of IL-18 and cerebrovascular oxidative stress. [67] Strikingly, UA treatment attenuated both short- and long-term brain damage in hypertensive rats, an effect associated with abolishment of the acute oxidative stress response and prevention of stroke-induced long-lasting MCA remodeling. Further, in BBB permeability assays, the permeability of UA was poor, suggesting that it did not cross the BBB by passive transport.…”

“…Indeed, UA plasma levels increased 10 min after intravenous (IV) UA administration, whereas UA levels in brain tissue were unaffected by UA infusion, suggesting that the main protective target of this compound was the brain vasculature. [67]…”