Carthamin yellow improves cerebral ischemia‑reperfusion injury by attenuating inflammation and ferroptosis in rats

Guo,Huihui; Zhu,Lili; Tang,Pingping; Chen,Dong; Li,Yancai; Li,Jianbing; Bao,Chao

doi:10.3892/ijmm.2021.4885

Carthamin yellow improves cerebral ischemia‑reperfusion injury by attenuating inflammation and ferroptosis in rats

Authors:
- Huihui Guo
- Lili Zhu
- Pingping Tang
- Dong Chen
- Yancai Li
- Jianbing Li
- Chao Bao
View Affiliations

Affiliations: Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210029, P.R. China, Department of Acupuncture, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210029, P.R. China
Published online on: February 11, 2021 https://doi.org/10.3892/ijmm.2021.4885
Article Number: 52
Copyright: © Guo et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Carthamin yellow (CY), a flavonoid compound extracted from safflower, has been reported to attenuate cardiac ischemia and reperfusion injury. However, whether CY could ameliorate ischemic stroke is not completely understood. In the present study, the preventive effects of CY on experimental ischemic stroke were investigated using middle cerebral artery occlusion (MCAO) model rats. Neurological scores, brain edema, infarct area and microtubule‑associated protein 2 (MAP‑2) immunoreactivity were assessed to evaluate the effects of CY on ischemic brain injury. The involvement of inflammation and ferroptosis were examined to investigate the mechanism underlying the effects of CY. The results demonstrated that 2‑week CY treatment attenuated the neurological deficit score, brain water content and infarct area, and increased MAP‑2 immunoreactivity in the cortex in MCAO model rats. CY administration also deactivated the cortex NF‑κB/NLR family pyrin domain containing 3 inflammasome signaling pathway, and decreased serum TNF‑α, IL‑1β and IL‑6 concentrations. Moreover, CY treatment inhibited Fe²⁺ and reactive oxygen species accumulation, and reversed acyl‑CoA synthetase long‑chain family member 4, transferrin receptor 1, glutathione peroxidase 4 and ferritin heavy chain 1 protein expression levels in the brain. The levels of glutathione, superoxide dismutase and malondialdehyde in the serum were also reversed by CY treatment. Collectively, the results of the present study demonstrated that CY protected rats against ischemic stroke, which was associated with mitigation of inflammation and ferroptosis.

View Figures

View References

1	Cao G, Jiang N, Hu Y, Zhang Y, Wang G, Yin M, Ma X, Zhou K, Qi J, Yu B and Kou J: Ruscogenin attenuates cerebral ischemia-induced blood-brain barrier dysfunction by suppressing TXNIP/NLRP3 inflammasome activation and the MAPK pathway. Int J Mol Sci. 17:14182016. View Article : Google Scholar :
2	So PW, Ekonomou A, Galley K, Brody L, Sahuri-Arisoylu M, Rattray I, Cash D and Bell JD: Intraperitoneal delivery of acetate-encapsulated liposomal nanoparticles for neuroprotection of the penumbra in a rat model of ischemic stroke. Int J Nanomedicine. 14:1979–1991. 2019. View Article : Google Scholar : PubMed/NCBI
3	Anrather J and Iadecola C: Inflammation and stroke: An overview. Neurotherapeutics. 13:661–670. 2016. View Article : Google Scholar : PubMed/NCBI
4	Alim I, Caulfield JT, Chen Y, Swarup V, Geschwind DH, Ivanova E, Seravalli J, Ai Y, Sansing LH, Ste Marie EJ, et al: Selenium drives a transcriptional adaptive program to block ferroptosis and treat stroke. Cell. 177:1262–1279.e25. 2019. View Article : Google Scholar : PubMed/NCBI
5	Zahid A, Li B, Kombe AJK, Jin T and Tao J: Pharmacological inhibitors of the NLRP3 inflammasome. Front Immunol. 10:25382019. View Article : Google Scholar : PubMed/NCBI
6	Negash AA, Olson RM, Griffin S and Gale M Jr: Modulation of calcium signaling pathway by hepatitis C virus core protein stimulates NLRP3 inflammasome activation. PLoS Pathog. 15:e10075932019. View Article : Google Scholar : PubMed/NCBI
7	Fann DY, Lim YA, Cheng YL, Lok KZ, Chunduri P, Baik SH, Drummond GR, Dheen ST, Sobey CG, Jo DG, et al: Evidence that NF-κB and MAPK signaling promotes NLRP inflammasome activation in neurons following ischemic stroke. Mol Neurobiol. 55:1082–1096. 2018. View Article : Google Scholar
8	Wu H, Tang C, Tai LW, Yao W, Guo P, Hong J, Yang X, Li X, Jin Z, Ke J and Wang Y: Flurbiprofen axetil attenuates cerebral ischemia/reperfusion injury by reducing inflammation in a rat model of transient global cerebral ischemia/reperfusion. Biosci Rep. 38:BSR201715622018. View Article : Google Scholar : PubMed/NCBI
9	Jiang T, Wu M, Zhang Z, Yan C, Ma Z, He S, Yuan W, Pu K and Wang Q: Electroacupuncture attenuated cerebral ischemic injury and neuroinflammation through α7nAChR-mediated inhibition of NLRP3 inflammasome in stroke rats. Mol Med. 25:222019. View Article : Google Scholar
10	Wang L, Liu Y, Du T, Yang H, Lei L, Guo M, Ding HF, Zhang J, Wang H, Chen X and Yan C: ATF3 promotes erastin-induced ferroptosis by suppressing system Xc. Cell Death Differ. 27:662–675. 2020. View Article : Google Scholar
11	Bai T, Lei P, Zhou H, Liang R, Zhu R, Wang W, Zhou L and Sun Y: Sigma-1 receptor protects against ferroptosis in hepatocellular carcinoma cells. J Cell Mol Med. 23:7349–7359. 2019. View Article : Google Scholar : PubMed/NCBI
12	Doll S, Proneth B, Tyurina YY, Panzilius E, Kobayashi S, Ingold I, Irmler M, Beckers J, Aichler M, Walch A, et al: ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat Chem Biol. 13:91–98. 2017. View Article : Google Scholar :
13	Lei G, Zhang Y, Koppula P, Liu X, Zhang J, Lin SH, Ajani JA, Xiao Q, Liao Z, Wang H and Gan B: The role of ferroptosis in ionizing radiation-induced cell death and tumor suppression. Cell Res. 30:146–162. 2020. View Article : Google Scholar : PubMed/NCBI
14	Feng H, Schorpp K, Jin J, Yozwiak CE, Hoffstrom BG, Decker AM, Rajbhandari P, Stokes ME, Bender HG, Csuka JM, et al: Transferrin receptor is a specific ferroptosis marker. Cell Rep. 30:3411–3423.e7. 2020. View Article : Google Scholar : PubMed/NCBI
15	Lu J, Liu X, Tian Y, Li H, Ren Z, Liang S, Zhang G, Zhao C, Li X, Wang T, et al: Moxibustion exerts a neuroprotective effect through antiferroptosis in Parkinson's disease. Evid Based Complement Alternat Med. 2019:27354922019. View Article : Google Scholar : PubMed/NCBI
16	Tuo QZ, Lei P, Jackman KA, Li XL, Xiong H, Li XL, Liuyang ZY, Roisman L, Zhang ST, Ayton S, et al: Tau-mediated iron export prevents ferroptotic damage after ischemic stroke. Mol Psychiatry. 22:1520–1530. 2017. View Article : Google Scholar : PubMed/NCBI
17	Guan X, Li X, Yang X, Yan J, Shi P, Ba L, Cao Y and Wang P: The neuroprotective effects of carvacrol on ischemia/reperfusion-induced hippocampal neuronal impairment by ferroptosis mitigation. Life Sci. 235:1167952019. View Article : Google Scholar : PubMed/NCBI
18	Lu QY, Ma JQ, Duan YY, Sun Y, Yu S, Li B and Zhang GM: Carthamin yellow protects the heart against ischemia/reperfusion injury with reduced reactive oxygen species release and inflammatory response. J Cardiovasc Pharmacol. 74:228–234. 2019. View Article : Google Scholar : PubMed/NCBI
19	Chen B, Wang HT, Yu B, Zhang JD and Feng Y: Carthamin yellow inhibits matrix degradation and inflammation induced by LPS in the intervertebral disc via suppression of MAPK pathway activation. Exp Ther Med. 14:1614–1620. 2017. View Article : Google Scholar : PubMed/NCBI
20	Sun R, Song Y, Li S, Ma Z, Deng X, Fu Q, Qu R and Ma S: Levo-tetrahydropalmatine attenuates neuron apoptosis induced by cerebral ischemia-reperfusion injury: Involvement of c-Abl activation. J Mol Neurosci. 65:391–399. 2018. View Article : Google Scholar : PubMed/NCBI
21	Yang Y, Hu Z, Du X, Davies H, Huo X and Fang M: miR-16 and fluoxetine both reverse autophagic and apoptotic change in chronic unpredictable mild stress model rats. Front Neurosci. 11:4282017. View Article : Google Scholar : PubMed/NCBI
22	Chen S, Dong Z, Cheng M, Zhao Y, Wang M, Sai N, Wang X, Liu H, Huang G and Zhang X: Homocysteine exaggerates microglia activation and neuroinflammation through microglia localized STAT3 overactivation following ischemic stroke. J Neuroinflammation. 14:1872017. View Article : Google Scholar : PubMed/NCBI
23	Fluri F, Schuhmann MK and Kleinschnitz C: Animal models of ischemic stroke and their application in clinical research. Drug Des Devel Ther. 9:3445–3454. 2015.PubMed/NCBI
24	Guo P, Jin Z, Wu H, Li X, Ke J, Zhang Z and Zhao Q: Effects of irisin on the dysfunction of blood-brain barrier in rats after focal cerebral ischemia/reperfusion. Brain Behav. 9:e014252019. View Article : Google Scholar : PubMed/NCBI
25	Terai K, Matsuo A, McGeer EG and McGeer PL: Enhancement of immunoreactivity for NF-kappa B in human cerebral infarctions. Brain Res. 739:343–349. 1996. View Article : Google Scholar : PubMed/NCBI
26	Gumy LF, Katrukha EA, Grigoriev I, Jaarsma D, Kapitein LC, Akhmanova A and Hoogenraad CC: MAP2 defines a pre-axonal filtering zone to regulate KIF1-versus KIF5-dependent cargo transport in sensory neurons. Neuron. 94:347–362.e7. 2017. View Article : Google Scholar
27	He F, Dai R, Zhou X, Li X, Song X, Yan H, Meng Q, Yang C and Lin Q: Protective effect of 4-Methoxy benzyl alcohol on the neurovascular unit after cerebral ischemia reperfusion injury. Biomed Pharmacother. 118:1092602019. View Article : Google Scholar
28	Xu SY, Hu YF, Li WP, Wu YM, Ji Z, Wang SN, Li K and Pan SY: Intermittent hypothermia is neuroprotective in an in vitro model of ischemic stroke. Int J Biol Sci. 10:873–881. 2014. View Article : Google Scholar : PubMed/NCBI
29	Lambertsen KL, Finsen B and Clausen BH: Post-stroke inflammation-target or tool for therapy? Acta Neuropathol. 137:693–714. 2019. View Article : Google Scholar
30	Hoesel B and Schmid JA: The complexity of NF-κB signaling in inflammation and cancer. Mol Cancer. 12:862013. View Article : Google Scholar
31	Yu X, Lan P, Hou X, Han Q, Lu N, Li T, Jiao C, Zhang J, Zhang C and Tian Z: HBV inhibits LPS-induced NLRP3 inflammasome activation and IL-1β production via suppressing the NF-κB pathway and ROS production. J Hepatol. 66:693–702. 2017. View Article : Google Scholar
32	Zeng J, Chen Y, Ding R, Feng L, Fu Z, Yang S, Deng X, Xie Z and Zheng S: Isoliquiritigenin alleviates early brain injury after experimental intracerebral hemorrhage via suppressing ROS- and/or NF-κB-mediated NLRP3 inflammasome activation by promoting Nrf2 antioxidant pathway. J Neuroinflammation. 14:1192017. View Article : Google Scholar
33	Ye Y, Jin T, Zhang X, Zeng Z, Ye B, Wang J, Zhong Y, Xiong X and Gu L: Meisoindigo protects against focal cerebral ischemia-reperfusion injury by inhibiting NLRP3 inflammasome activation and regulating microglia/macrophage polarization via TLR4/NF-κB signaling pathway. Front Cell Neurosci. 13:5532019. View Article : Google Scholar
34	Zhang S, Jiang L, Che F, Lu Y, Xie Z and Wang H: Arctigenin attenuates ischemic stroke via SIRT1-dependent inhibition of NLRP3 inflammasome. Biochem Biophys Res Commun. 493:821–826. 2017. View Article : Google Scholar : PubMed/NCBI
35	Weiland A, Wang Y, Wu W, Lan X, Han X, Li Q and Wang J: Ferroptosis and its role in diverse brain diseases. Mol Neurobiol. 56:4880–4893. 2019. View Article : Google Scholar :
36	Lu J, Xu F and Lu H: LncRNA PVT1 regulates ferroptosis through miR-214-mediated TFR1 and p53. Life Sci. 260:1183052020. View Article : Google Scholar : PubMed/NCBI