Uric Acid Neuroprotection Associated to IL-6/STAT3 Signaling Pathway Activation in Rat Ischemic Stroke

• Published in: Molecular neurobiology 2021, Vol.58 (1), p.408-423
• Main Authors: Aliena-Valero, Alicia, Rius-Pérez, Sergio, Baixauli-Martín, Júlia, Torregrosa, Germán, Chamorro, Ángel, Pérez, Salvador, Salom, Juan B.
• Format: Article
• Language: English
• Subjects: Animals; Antioxidants; Antioxidants - metabolism; Apoptosis; Apoptosis - drug effects; Bcl-2 protein; Biomedical and Life Sciences; Biomedicine; Body Weight - drug effects; Brain Edema - etiology; Brain Edema - pathology; Brain Edema - physiopathology; Brain Infarction - etiology; Brain Infarction - physiopathology; Caspase-3; Cell Biology; Cell death; Cerebral blood flow; Cytokines - genetics; Cytokines - metabolism; Edema; Gelatinase B; Gene Expression Regulation - drug effects; Infarction, Middle Cerebral Artery - complications; Infarction, Middle Cerebral Artery - physiopathology; Inflammation; Interleukin 6; Interleukin-6 - metabolism; Ischemia; Ischemic Stroke - etiology; Ischemic Stroke - metabolism; Ischemic Stroke - physiopathology; Lipid Peroxidation - drug effects; Male; Microglia; Neurobiology; Neurology; Neuroprotection; Neuroprotection - drug effects; Neurosciences; NF-κB protein; Original Article; Oxidative stress; Phosphorylation; Rats; Rats, Wistar; Reperfusion; Rodents; Signal transduction; Signal Transduction - drug effects; Stat3 protein; STAT3 Transcription Factor - metabolism; Stroke; Superoxide dismutase; Tissue inhibitor of metalloproteinase 1; Transcription factors; Uric acid; Uric Acid - administration & dosage; Uric Acid - pharmacology; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - metabolism
• ISSN: 0893-7648; 1559-1182
• DOI: 10.1007/s12035-020-02115-w

Despite the promising neuroprotective effects of uric acid (UA) in acute ischemic stroke, the seemingly pleiotropic underlying mechanisms are not completely understood. Recent evidence points to transcription factors as UA targets. To gain insight into the UA mechanism of action, we investigated its effects on pertinent biomarkers for the most relevant features of ischemic stroke pathophysiology: (1) oxidative stress (antioxidant enzyme mRNAs and MDA), (2) neuroinflammation (cytokine and Socs3 mRNAs, STAT3, NF-κB p65, and reactive microglia), (3) brain swelling ( Vegfa , Mmp9 , and Timp1 mRNAs), and (4) apoptotic cell death (Bcl-2, Bax, caspase-3, and TUNEL-positive cells). Adult male Wistar rats underwent intraluminal filament transient middle cerebral artery occlusion (tMCAO) and received UA (16 mg/kg) or vehicle (Locke’s buffer) i.v. at 20 min reperfusion. The outcome measures were neurofunctional deficit, infarct, and edema. UA treatment reduced cortical infarct and brain edema, as well as neurofunctional impairment. In brain cortex, increased UA: (1) reduced tMCAO-induced increases in Vegfa and Mmp9/Timp1 ratio expressions; (2) induced Sod2 and Cat expressions and reduced MDA levels; (3) induced Il6 expression, upregulated STAT3 and NF-κB p65 phosphorylation, induced Socs3 expression, and inhibited microglia activation; and (4) ameliorated the Bax/Bcl-2 ratio and induced a reduction in caspase-3 cleavage as well as in TUNEL-positive cell counts. In conclusion, the mechanism for morphological and functional neuroprotection by UA in ischemic stroke is multifaceted, since it is associated to activation of the IL-6/STAT3 pathway, attenuation of edematogenic VEGF-A/MMP-9 signaling, and modulation of relevant mediators of oxidative stress, neuroinflammation, and apoptotic cell death.