Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2018 Nov 18:2018:6069150.
doi: 10.1155/2018/6069150. eCollection 2018.

Uric Acid Protects against Focal Cerebral Ischemia/Reperfusion-Induced Oxidative Stress via Activating Nrf2 and Regulating Neurotrophic Factor Expression

Bai-Liu Ya  1 , Qian Liu  2 , Hong-Fang Li  3 , Hong-Ju Cheng  1 , Ting Yu  1 , Lin Chen  4 , You Wang  4 , Li-Li Yuan  4 , Wen-Juan Li  5 , Wen-Yan Liu  1 , Bo Bai  1
Affiliations

Uric Acid Protects against Focal Cerebral Ischemia/Reperfusion-Induced Oxidative Stress via Activating Nrf2 and Regulating Neurotrophic Factor Expression

Bai-Liu Ya et al. Oxid Med Cell Longev. .

Abstract

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.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Effect of UA on the infarct volume, neurological deficit, and brain water content in rats. (a) Representative TTC-stained coronal sections. (b) Quantification of infarct volume; data are means ± SE (n = 10). (c) Neurological deficit scores; data are medians ± interquartile range (n = 10). Box plots show the interquartile range (25% to 75%) as the box, median as the horizontal line in the box, and the 95% range as the whiskers. (d) Brain water content; data are means ± SE (n = 12). ФФP < 0.01 vs. the sham group; ∗P < 0.05, ∗∗P < 0.01 vs. the vehicle-treated I/R group; #P < 0.05, ##P < 0.01 vs. the UA-treated I/R group.
Figure 2
Figure 2
Effect of UA on neuronal injury in cerebral cortices in rats. (a) Representative photomicrographs of HE staining. Scale bar in all panels = 50 μm. (b) Quantification of surviving neuronal cells. (c) Representative photomicrographs of TUNEL staining. Scale bar in all panels = 50 μm. (d) Quantification of apoptotic cells. (e) Schematic diagram of coronal brain section. Black rectangle in the ischemic ipsilateral parietal cortex of penumbra represents the region selected for histology. Data are means ± SE (n = 3). ФФP < 0.01 vs. the sham group; ∗∗P < 0.01 vs. the vehicle-treated I/R group; ##P < 0.01 vs. the UA-treated I/R group.
Figure 3
Figure 3
Effect of UA on oxidative injury in cerebral cortices in rats. (a) Quantification of MDA; data are means ± SE (n = 12). (b, c) Representative blot of protein oxidation. Quantification of carbonyl group bands; data are means ± SE (n = 4). (d) Representative photomicrographs of 8-OHdG immunostaining. Scale bar in all panels = 50 μm. (e) Quantification of 8-OHdG-positive cells; data are means ± SE (n = 3). (f) Schematic diagram of coronal brain section. The black rectangle in the ischemic ipsilateral parietal cortex of the penumbra represents the region selected for histology. ФФP < 0.01 vs. the sham group; ∗∗P < 0.01 vs. the vehicle-treated I/R group; #P < 0.05, ##P < 0.01 vs. the UA-treated I/R group.
Figure 4
Figure 4
Effect of UA on Nrf2 protein distribution, HO-1 protein expression, and Nrf2 DNA-binding activity in cerebral cortices in rats. (a, b) Representative western blot of nuclear Nrf2. Quantification of nuclear Nrf2 normalized with histone H3. (c, d) Representative western blot of cytosolic Nrf2 and HO-1. Quantification of cytosolic Nrf2 and HO-1 normalized with β-actin. (e) Nuclear Nrf2 DNA-binding activity. Data are means ± SE (n = 4). ∗P < 0.05, ∗∗P < 0.01 vs. the vehicle-treated I/R group; #P < 0.05, ##P < 0.01 vs. the UA-treated I/R group.
Figure 5
Figure 5
Effect of UA on the expression of BDNF and NGF in cerebral cortices in rats. (a) Representative photomicrographs of BDNF immunostaining. Scale bar in all panels = 50 μm. (b) Quantification of BDNF positive cells. (c) Representative photomicrographs of NGF immunostaining. Scale bar in all panels = 50 μm. (d) Quantification of NGF positive cells. (e) Schematic diagram of coronal brain section. The black rectangle in the ischemic ipsilateral parietal cortex of the penumbra represents the region selected for histology. Data are means ± SE (n = 3). ФФP < 0.01 vs. the sham group; ∗∗P < 0.01 vs. the vehicle-treated I/R group; #P < 0.05 vs. the UA-treated I/R group.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Moskowitz M. A., Lo E. H., Iadecola C. The science of stroke: mechanisms in search of treatments. Neuron. 2010;67(2):181–198. doi: 10.1016/j.neuron.2010.07.002. - DOI - PMC - PubMed
    1. Chen H., Yoshioka H., Kim G. S., et al. Oxidative stress in ischemic brain damage: mechanisms of cell death and potential molecular targets for neuroprotection. Antioxidants & Redox Signaling. 2011;14(8):1505–1517. doi: 10.1089/ars.2010.3576. - DOI - PMC - PubMed
    1. Janyou A., Wicha P., Jittiwat J., Suksamrarn A., Tocharus C., Tocharus J. Dihydrocapsaicin attenuates blood brain barrier and cerebral damage in focal cerebral ischemia/reperfusion via oxidative stress and inflammatory. Scientific Reports. 2017;7(1, article 10556) doi: 10.1038/s41598-017-11181-5. - DOI - PMC - PubMed
    1. Pundik S., Xu K., Sundararajan S. Reperfusion brain injury: focus on cellular bioenergetics. Neurology. 2012;79(13, Supplement 1):S44–S51. doi: 10.1212/WNL.0b013e3182695a14. - DOI - PubMed
    1. Suzuki T., Yamamoto M. Molecular basis of the Keap1–Nrf2 system. Free Radical Biology & Medicine. 2015;88(Part B):93–100. doi: 10.1016/j.freeradbiomed.2015.06.006. - DOI - PubMed

MeSH terms

LinkOut - more resources