The aim of this study was to investigate whether uric acid (UA) might exert neuroprotection via activating the nuclear factor erythroid 2‐related factor 2 (Nrf2) pathway and regulating neurotrophic factors in the cerebral cortices after transient focal cerebral ischemia/reperfusion (FCI/R) in rats. UA was intravenously injected through the tail vein (16 mg/kg) 30 min after the onset of reperfusion in rats subjected to middle cerebral artery occlusion for 2 h. Neurological deficit score was performed to analyze neurological function at 24 h after reperfusion. Terminal deoxynucleotidyl transferase‐mediated dNTP nick end labeling (TUNEL) staining and hematoxylin and eosin (HE) staining were used to detect histological injury of the cerebral cortex. Malondialdehyde (MDA), the carbonyl groups, and 8‐hydroxyl‐2 ^′‐deoxyguanosine (8‐OHdG) levels were employed to evaluate oxidative stress. Nrf2 and its downstream antioxidant protein, heme oxygenase‐ (HO‐) 1,were detected by western blot. Nrf2 DNA‐binding activity was observed using an ELISA‐based measurement. Expressions of BDNF and NGF were analyzed by immunohistochemistry. Our results showed that UA treatment significantly suppressed FCI/R‐induced oxidative stress, accompanied by attenuating neuronal damage, which subsequently decreased the infarct volume and neurological deficit. Further, the treatment of UA activated Nrf2 signaling pathway and upregulated BDNF and NGF expression levels. Interestingly, the aforementioned effects of UA were markedly inhibited by administration of brusatol, an inhibitor of Nrf2. Taken together, the antioxidant and neuroprotective effects afforded by UA treatment involved the modulation of Nrf2‐mediated oxidative stress and regulation of BDNF and NGF expression levels. Thus, UA treatment could be of interest to prevent FCI/R injury.

Hypercholesterolemia and carotid atherosclerosis contribute to the etiology of stroke. However, there has been a lack of appropriate comorbid animal models incorporating some of the ubiquitous characteristics that precede strokes. Curcumin is a natural active polyphenolic compound extracted from the rhizoma of Curcuma longa L. which possesses comprehensive bioactivities. The present study aimed to evaluate whether neurobehavioral deficits, neuroendocrine-immune dysregulations and cerebral microcirculation dysfunction, are part of the initial stages of cerebral ischemia in individuals suffering from carotid atherosclerosis resulting from a high cholesterol diet (HCD) and if they could be tested using a comorbid animal model. Furthermore, the utility of this model will be examined following the administration of curcumin. Adult wild-type SD rats were fed a regular diet or HCD and supplemented with either vehicle or curcumin for 4 weeks. Carotid injury was induced by an air-drying endothelial denudation method at the end of the second week. Plasma cholesterol, carotid pathomorphology, neurobehavioral tests, and neuroendocrine-immune parameters were measured. We found higher plasma levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein-cholesterol (LDL-C), intima and media (I/M) ratio, but lower high-density lipoprotein-cholesterol (HDL-C), spatial learning and memory capacity impairment, elevated NPY expression in the hypothalamus, increased plasma concentration of leptin, upregulated TNF-α, IL-1β, and CRP in the circulation as well as TNF-α and IL-1β in the cerebral cortex, plus enhanced ICAM-1, VCAM-1, and E-selectin in cerebral microvessels in HCD-fed model rats. All these alterations were ameliorated by curcumin. These results suggest that a comorbid rat model was effectively developed by HCD and carotid injury.