Uric Acid Treatment After Stroke Prevents Long-Term Middle Cerebral Artery Remodelling and Attenuates Brain Damage in Spontaneously Hypertensive Rats
- 206 Downloads
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−1) 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.
KeywordsHypertension Ischaemia-reperfusion Ischaemic stroke Vascular remodelling Oxidative stress Antioxidant
We are grateful to Núria Masip Salas, Marina Purroy Rodríguez and Cristina Ríos Delgado for helpful technical assistance, to the confocal microscopy facility of the Universitat Autònoma de Barcelona and to the joint nuclear magnetic resonance facility of the Universitat Autònoma de Barcelona and Centro de Investigación Biomédica en Red-Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN) (Cerdanyola del Vallès, Spain), Unit 25 of NANBIOSIS.
F.J-A. and E.V. conceived the study and designed the experiments; F.J-A., E.V., E.J-X., B.P., AP.D. and L.P-U. performed the experiments and analysed the data; F.J-A. prepared the article; AM.P., A.C. and J.M-F. provided critical analysis; and all authors edited and approved the manuscript.
This study was supported by Ministerio de Ciencia e Innovación [SAF2014-56111-R] to E.V., B.P. and F.J-A.; Generalitat de Catalunya [2017-SGR-645] to AM.P., A.C., E.V. and F.J-A.; and Instituto Carlos III [FIS PI13/0091, RIC RD12/0042/0006] to AP.D. Instituto de Salud Carlos III (Spain) co-funded by EU FEDER funds Redes Temáticas de Investigación Cooperativa Sanitaria RETICS-INVICTUS-RD16/019 to J.M-F./E.J-X and to A.C./AM.P.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
A.C. is inventor of the patent “Pharmaceutical composition for neuroprotective treatment in patients with ictus comprising citicoline and uric acid”.
All institutional and national guidelines for the care and use of laboratory animals were followed. All of the experiments were carried out under the Guidelines established by the Spanish legislation (RD 1201/2005) and according to the Guide for the Care and Use of Laboratory Animals, published by the US National Institutes of Health (NIH Publication 85-23, revised 1996). Experiments were approved by the Ethics Committee of the Universitat Autònoma de Barcelona and were carried out in compliance with the European legislation.
- 3.Powers WJ, Derdeyn CP, Biller J, Coffey CS, Hoh BL, Jauch EC, et al. 2015 American Heart Association/American Stroke Association focused update of the 2013 guidelines for the early management of patients with acute ischemic stroke regarding endovascular treatment: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. American Heart Association Stroke Council. Stroke 2015;46(10):3020–35.Google Scholar
- 11.Feng S, Yang Q, Liu M, Li W, Yuan W, Zhang S, et al. Edaravone for acute ischaemic stroke. Cochrane Database Syst Rev. 2011;12:CD007230.Google Scholar
- 19.Amaro S, Laredo C, Renú A, Llull L, Rudilosso S, Obach V, et al. Uric acid therapy prevents early ischemic stroke progression: a tertiary analysis of the URICO-ICTUS Trial (Efficacy Study of Combined Treatment With Uric Acid and r-tPA in Acute Ischemic Stroke). Stroke. 2016;47(11):2874–6.CrossRefGoogle Scholar
- 25.Dorrance AM. The effects of hypertension and stroke on the cerebral vasculature. V. Aiyagari, P.B. Gorelick (eds.). Hypertension and stroke. Clinical Hypertension and Vascular Diseases. 2016;81–108.Google Scholar
- 26.Jiménez-Altayó F, Martín A, Rojas S, Justicia C, Briones AM, Giraldo J, et al. Transient middle cerebral artery occlusion causes different structural, mechanical, and myogenic alterations in normotensive and hypertensive rats. Am J Physiol Heart Circ Physiol. 2007;293(1):H628–35.CrossRefGoogle Scholar
- 31.Albers GW, Goldstein LB, Hess DC, Wechsler LR, Furie KL, Gorelick PB, et al. Stroke Treatment Academic Industry Roundtable (STAIR) recommendations for maximizing the use of intravenous thrombolytics and expanding treatment options with intra-arterial and neuroprotective therapies. Stroke. 2011;42(9):2645–50.CrossRefGoogle Scholar
- 49.Jiménez-Altayó F, Caracuel L, Pérez-Asensio FJ, Martínez-Revelles S, Messeguer A, Planas AM, et al. Participation of oxidative stress on rat middle cerebral artery changes induced by focal cerebral ischemia: beneficial effects of 3,4-dihydro-6-hydroxy-7-methoxy-2,2-dimethyl-1(2H)-benzopyran (CR-6). J Pharmacol Exp Ther. 2009;331(2):429–36.CrossRefGoogle Scholar