Ferulic Acid Methyl Ester Attenuates Cerebral Ischemia-Reperfusion Injury in Rats by Modulating PI3K/HIF-1α/VEGF Signaling Pathway

Overview

Journal J Inflamm Res

Publisher Dove Medical Press

Date 2024 Sep 3

PMID 39224659

Authors

Peijie Zhou

Shangshang Yu

Xuan Wang

Xiaofei Zhang

Dongyan Guo

Chongbo Zhao

Jiangxue Cheng

Jing Wang

Jing Sun

Affiliations

Soon will be listed here.

Abstract

Background: Cerebral ischaemia-reperfusion injury (CIRI) could worsen the inflammatory response and oxidative stress in brain tissue. According to previous studies, ferulic acid methyl ester (FAME), as the extract with the strongest comprehensive activity in the traditional Chinese medicine Huang Hua oil dot herb, has significant anti-oxidative stress and neuroprotective functions, and can effectively alleviate CIRI, but its mechanism of action is still unclear.

Methods: Firstly, the pharmacological effects of FAME were investigated by in vitro oxidative stress and inflammatory experiments. Secondly, evaluate the therapeutic effects of FAME in the treatment of CIRI by brain histopathological staining and cerebral infarct area by replicating the in vivo MACO model. Thirdly, RNA-Seq and network pharmacology were utilized to predict the possible targets and mechanisms of FAME for CIRI at the molecular level. Finally, the expression of key target proteins, as well as the key regulatory relationships were verified by molecular docking visualization, Western Blotting and immunohistochemistry.

Results: The results of in vitro experiments concluded that FAME could significantly reduce the content of TNF-α, IL-1β and ROS, inhibiting COX-2 and iNOS protein expression in cells(p<0.01). FAME was demonstrated to have anti-oxidative stress and anti-inflammatory effects. The results of in vivo experiments showed that after the administration of FAME, the area of cerebral infarction in rats with CIRI was reduced, the content of Bcl-2 and VEGF was increased(p<0.05). Network pharmacology and RNA-Seq showed that the alleviation of CIRI by FAME may be through PI3K-AKT and HIF-1 signaling pathway. Enhanced expression of HIF-1α, VEGF, p-PI3K, p-AKT proteins in the brain tissues of rats in the FAME group was verified by molecular docking and Western Blotting.

Conclusion: FAME possesses significant anti-inflammatory and anti-oxidative stress activities and alleviates CIRI through the PI3K/HIF-1α/VEGF signaling pathway.

References

Liu N, Jiang Y, Huang T, Hou J, Liu J . [A network pharmacology approach to explore mechanisms of Buyang Huanwu decoction for treatment of cerebral infarction]. Zhongguo Zhong Yao Za Zhi. 2018; 43(11):2190-2198. DOI: 10.19540/j.cnki.cjcmm.20180418.001. View

Song F, Fan B, Sun J . [Explore compatibility mechanism of Xingnaojing injection in treating cerebral infarction based on network pharmacology]. Zhongguo Zhong Yao Za Zhi. 2018; 43(7):1366-1372. DOI: 10.19540/j.cnki.cjcmm.20180115.011. View

Cheng S, Chen C, Wang L . Gelsemine Exerts Neuroprotective Effects on Neonatal Mice with Hypoxic-Ischemic Brain Injury by Suppressing Inflammation and Oxidative Stress via Nrf2/HO-1 Pathway. Neurochem Res. 2022; 48(5):1305-1319. DOI: 10.1007/s11064-022-03815-6. View

Lv W, Jiang J, Xu Y, Chen Z, Wang Z, Xing A . Re-Exploring the Inflammation-Related Core Genes and Modules in Cerebral Ischemia. Mol Neurobiol. 2023; 60(6):3439-3451. DOI: 10.1007/s12035-023-03275-1. View

Lv H, Ren H, Wang L, Chen W, Ci X . Lico A Enhances Nrf2-Mediated Defense Mechanisms against t-BHP-Induced Oxidative Stress and Cell Death via Akt and ERK Activation in RAW 264.7 Cells. Oxid Med Cell Longev. 2015; 2015:709845. PMC: 4630662. DOI: 10.1155/2015/709845. View

Cao J, Tang Z, Song J, Yao J, Sheng X, Su Z . HIF‑1α protects PC12 cells from OGD/R‑induced cell injury by regulating autophagy flux through the miR‑20a‑5p/KIF5A axis. Acta Neurobiol Exp (Wars). 2022; 82(3):358-372. DOI: 10.55782/ane-2022-034. View

Mo Y, Sun Y, Liu K . Autophagy and inflammation in ischemic stroke. Neural Regen Res. 2020; 15(8):1388-1396. PMC: 7059569. DOI: 10.4103/1673-5374.274331. View

Buch P, Sharma T, Airao V, Vaishnav D, Mani S, Rachamalla M . Geraniol protects hippocampal CA1 neurons and improves functional outcomes in global model of stroke in rats. Chem Biol Drug Des. 2023; 102(3):523-535. DOI: 10.1111/cbdd.14260. View

Chen X, Li P, Huang R, Zhang J, Ouyang X, Tan D . Ulinastatin affects focal cerebral ischemia-reperfusion injury via SOCS1-mediated JAK2/STAT3 signalling pathway. Clin Exp Pharmacol Physiol. 2022; 50(1):107-116. DOI: 10.1111/1440-1681.13731. View

10.

Cheng J, Zhang S, Fan A, Li Y, Xu P, Huang J . An immune-related gene signature for the prognosis of human bladder cancer based on WGCNA. Comput Biol Med. 2022; 151(Pt A):106186. DOI: 10.1016/j.compbiomed.2022.106186. View

11.

Ren L, Wang Y, Zhang W, Zhou R, Zhao M, Tang Z . Triculata A, a novel compound from (D. Don) J. F. Macbr. with biological properties. Nat Prod Res. 2020; 35(21):3729-3737. DOI: 10.1080/14786419.2020.1736059. View

12.

Semenza G . Hypoxia-inducible factor 1: regulator of mitochondrial metabolism and mediator of ischemic preconditioning. Biochim Biophys Acta. 2010; 1813(7):1263-8. PMC: 3010308. DOI: 10.1016/j.bbamcr.2010.08.006. View

13.

Li P, Zhai X, Wang J, Zhu X, Zhao L, You S . Two Ferulic Acid Derivatives Inhibit Neuroinflammatory Response in Human HMC3 Microglial Cells via NF-B Signaling Pathway. Molecules. 2023; 28(5). PMC: 10004133. DOI: 10.3390/molecules28052080. View

14.

Pei H, Du R, He Z, Yang Y, Wu S, Li W . Protection of a novel velvet antler polypeptide PNP1 against cerebral ischemia-reperfusion injury. Int J Biol Macromol. 2023; 247:125815. DOI: 10.1016/j.ijbiomac.2023.125815. View

15.

Jurcau A, Ardelean I . Molecular pathophysiological mechanisms of ischemia/reperfusion injuries after recanalization therapy for acute ischemic stroke. J Integr Neurosci. 2021; 20(3):727-744. DOI: 10.31083/j.jin2003078. View

16.

Longa E, Weinstein P, Carlson S, Cummins R . Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke. 1989; 20(1):84-91. DOI: 10.1161/01.str.20.1.84. View

17.

Wang W, Wang Y, Guo Q, Li H, Wang Z, Li J . Valerian essential oil for treating insomnia the serotonergic synapse pathway. Front Nutr. 2022; 9:927434. PMC: 9387164. DOI: 10.3389/fnut.2022.927434. View

18.

Yang J, Mukda S, Chen S . Diverse roles of mitochondria in ischemic stroke. Redox Biol. 2018; 16:263-275. PMC: 5854930. DOI: 10.1016/j.redox.2018.03.002. View

19.

Wen S, Unuma K, Funakoshi T, Aki T, Uemura K . Cocaine induces vascular smooth muscle cells proliferation via DRP1-mediated mitochondrial fission and PI3K/HIF-1α signaling. Biochem Biophys Res Commun. 2023; 676:30-35. DOI: 10.1016/j.bbrc.2023.07.020. View

20.

Zhao Y, Zhang X, Chen X, Wei Y . Neuronal injuries in cerebral infarction and ischemic stroke: From mechanisms to treatment (Review). Int J Mol Med. 2021; 49(2). PMC: 8711586. DOI: 10.3892/ijmm.2021.5070. View