Study on mechanism of ursolic acid ameliorating cerebral ischemia-reperfusion injury by inhibiting NLRP3-mediated microglia pyroptosis

doi:10.3877/cma.j.issn.2095-5782.2024.03.006

Abstract

Abstract:

Objective

To elucidate the mechanism of ursolic acid (UA) ameliorating cerebral ischemia-reperfusion injury.

Methods

An oxygen-glucose deprivation/reoxygenation (OGD/R) model in BV-2 microglia cells was established. Cell Counting Kit-8 (CCK-8) assay was used to measure cell viability. Western blot and immunofluorescence were conducted to measure pyroptotic protein levels. RT-qPCR was used to measure NOD-like receptor thermal protein domain associated protein 3 (NLRP3), Interleukin (IL)-1β, and IL-18 mRNA levels. ELISA was utilized to measure IL-1β and IL-18 concentration. The mice transient middle cerebral artery occlusion (tMCAO) model was established. UA was administered intragastrically after reperfusion. Neurological deficits were evaluated by Zea-Longa scoring criteria. Neuronal damage was assessed through TUNEL staining.

Results

UA promoted cell survival in OGD/R-challenged BV-2 cells. UA inhibited OGD/R-induced NLRP3 inflammasome activation and pyroptosis-related cytokines release in BV-2 cells. UA reduced mortality rates, Zea-Longa score, and neuronal damage in MCAO mice.

Conclusion

UA may exert neuroprotective effects by inhibiting NLRP3 inflammasome-mediated microglia pyroptosis.

Key words: Cerebral ischemia-reperfusion injury, Ursolic acid, Microglia, Pyroptosis, Neuroinflammation

Junbin Liu, Xiaoting Zhang, Jingpei Guo, Jiani Liu, Benshuai Yu, Ke Zhang, Bin Zhou. Study on mechanism of ursolic acid ameliorating cerebral ischemia-reperfusion injury by inhibiting NLRP3-mediated microglia pyroptosis[J]. Chinese Journal of Interventional Radiology(Electronic Edition), 2024, 12(03): 221-227.

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References 22

[1]	Campbell BCV, De Silva DA, Macleod MR, et al. Ischaemic stroke[J]. Nat Rev Dis Primers, 2019, 5(1): 70.
[2]	Tu WJ, Wang LD. China stroke surveillance report 2021[J]. Mil Med Res, 2023, 10(1): 33.
[3]	王陇德, 彭斌, 张鸿祺, 等. 《中国脑卒中防治报告2020》概要[J]. 中国脑血管病杂志, 2022, 19(2): 136-44.
[4]	Macrez R, Ali C, Toutirais O, et al. Stroke and the immune system: from pathophysiology to new therapeutic strategies[J]. Lancet Neurol, 2011, 10(5): 471-480.
[5]	Bergsbaken T, Fink SL, Cookson BT. Pyroptosis: host cell death and inflammation[J]. Nat Rev Microbiol, 2009, 7(2): 99-109.
[6]	Schroder K, Tschopp J. The inflammasomes[J]. Cell, 2010, 140(6): 821-832.
[7]	Li W, Shen N, Kong L, et al. STING mediates microglial pyroptosis via interaction with NLRP3 in cerebral ischaemic stroke[J]. Stroke Vasc Neurol, 2024, 9(2): 153-164.
[8]	Shi J, Zhao Y, Wang K, et al. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death[J]. Nature, 2015, 526(7575): 660-665.
[9]	Kashyap D, Tuli HS, Sharma AK. Ursolic acid (UA): a metabolite with promising therapeutic potential[J]. Life Sci, 2016, 146: 201-213.
[10]	Nie Y, Liu Q, Zhang W, et al. Ursolic acid reverses liver fibrosis by inhibiting NOX4/NLRP3 inflammasome pathways and bacterial dysbiosis[J]. Gut Microbes, 2021, 13(1): 1972746.
[11]	Fu Y, Liu T, He S, et al. Ursolic acid reduces oxidative stress injury to ameliorate experimental autoimmune myocarditis by activating Nrf2/HO-1 signaling pathway[J]. Front Pharmacol, 2023, 14: 1189372.
[12]	Xu LL, Su HX, Li PB, et al. Ursolic Acid ameliorates myocardial ischaemia/reperfusion injury by improving mitochondrial function via immunoproteasome-PP2A-AMPK signalling[J]. Nutrients, 2023, 15(4): 1049.
[13]	Liu SJ, Guo BD, Gao QH, et al. Ursolic acid alleviates chronic prostatitis via regulating NLRP3 inflammasome-mediated Caspase-1/GSDMD pyroptosis pathway[J]. Phytother Res, 2024, 38(1): 82-97.
[14]	Yong HYF, Rawji KS, Ghorbani S, et al. The benefits of neuroinflammation for the repair of the injured central nervous system[J]. Cell Mol Immunol, 2019, 16(6): 540-546.
[15]	Long J, Sun Y, Liu S, et al. Targeting pyroptosis as a preventive and therapeutic approach for stroke[J]. Cell Death Discov, 2023, 9(1): 155.
[16]	Lei P, Li Z, Hua Q, et al. Ursolic acid alleviates neuroinflammation after intracerebral hemorrhage by mediating microglial pyroptosis via the NF-κB/NLRP3/GSDMD pathway[J]. Int J Mol Sci, 2023, 24(19): 14771.
[17]	DING R, LI H, LIU Y, et al. Activating cGAS-STING axis contributes to neuroinflammation in CVST mouse model and induces inflammasome activation and microglia pyroptosis[J]. J Neuroinflammation, 2022, 19(1): 137.
[18]	Deng Y, Li Z, Sun X, et al. TRIM29 (tripartite motif containing 29) alleviates NLRC4 (NLR family CARD domain containing protein 4) inflammasome related cerebral injury via promoting proteasomal degradation of NLRC4 in ischemic stroke[J]. Stroke, 2023, 54(5): 1377-1389.
[19]	Kim H, Seo JS, Lee SY, et al. AIM2 inflammasome contributes to brain injury and chronic post-stroke cognitive impairment in mice[J]. Brain Behav Immun, 2020, 87: 765-776.
[20]	Hill RA, Connolly JD. Triterpenoids[J]. Nat Prod Rep, 2020, 37(7): 962-998.
[21]	Yuan L, Zhang L, Yao N, et al. Upregulation of UGT1A1 expression by ursolic acid and oleanolic acid via the inhibition of the PKC/NF-κB signaling pathway[J]. Phytomedicine, 2021, 92: 153726.
[22]	Wang C, Gao Y, Zhang Z, et al. Ursolic acid protects chondrocytes, exhibits anti-inflammatory properties via regulation of the NF-κB/NLRP3 inflammasome pathway and ameliorates osteoarthritis[J]. Biomed Pharmacother, 2020, 130: 110568.

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