Forsythiaside A protects against focal cerebral ischemic injury by mediating the activation of the Nrf2 and endoplasmic reticulum stress pathways

Ma,Tao; Shi,Ya‑Ling; Wang,Yan‑Ling

doi:10.3892/mmr.2019.10312

Forsythiaside A protects against focal cerebral ischemic injury by mediating the activation of the Nrf2 and endoplasmic reticulum stress pathways

Authors:
- Tao Ma
- Ya‑Ling Shi
- Yan‑Ling Wang
View Affiliations

Affiliations: Department of Neurology, Xintai Municipal People's Hospital, Xintai, Shandong 271200, P.R. China, Department of Neurology, The First Hospital of Xi'an, Xi'an, Shaanxi 710002, P.R. China, Department of Neurology, Cangzhou People's Hospital, Cangzhou, Hebei 061000, P.R. China
Published online on: May 30, 2019 https://doi.org/10.3892/mmr.2019.10312
Pages: 1313-1320

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

Ischemic stroke is a common type of stroke with a high mortality and morbidity rate. Preventing and controlling cerebral ischemic injury is particularly important. Forsythiaside A (FA) has been reported to have anti‑inflammatory and antioxidant activities. The aim of the present study was to explore the impact of FA on middle cerebral artery occlusion (MCAO)‑induced cerebral ischemic injury in rats. The results indicated that FA markedly increased the percent survival and decreased the neurological deficit score in rats with cerebral ischemic injury. Furthermore, cell apoptosis was significantly inhibited by FA administration, which was accompanied by decreased caspase‑3 and caspase‑9 expression. A marked increase in the expression levels of nuclear factor‑erythroid 2‑related factor 2 (Nrf2), NAD(P)H quinone dehydrogenase 1 and glutathione‑s‑transferase was detected in FA‑treated rats. In addition, treatment with FA reduced malonaldehyde expression, and enhanced the expression of superoxide dismutase and glutathione. Furthermore, endoplasmic reticulum (ER) stress was vastly alleviated by FA treatment, as evidenced by the increased expression of B‑cell lymphoma 2, apoptosis regulator and the downregulated expression of phosphorylated (phospho)‑protein kinase RNA‑like ER kinase (PERK)/PERK, phospho‑inositol‑requiring enzyme 1 (IRE1α)/IRE1α and CCAAT‑enhancer‑binding proteins homologous protein. Taken together, the present study demonstrated that FA attenuated cerebral ischemic damage via mediation of the activation of Nrf2 and ER stress pathways. These data may provide ideas for novel treatment strategies of cerebral ischemic damage.

View Figures

View References

1	Hong KS and Saver JL: Quantifying the value of stroke disability outcomes: WHO global burden of disease project disability weights for each level of the modified rankin scale. Stroke. 40:3828–3833. 2009. View Article : Google Scholar : PubMed/NCBI
2	Laskowitz DT, Bennett ER, Durham RJ, Volpi JJ, Wiese JR, Frankel M, Shpall E, Wilson JM, Troy J and Kurtzberg J: Allogeneic umbilical cord blood infusion for adults with ischemic stroke: Clinical outcomes from a Phase 1 Safety Study. Stem Cells Transl Med. 521–529. 2018. View Article : Google Scholar : PubMed/NCBI
3	Mayor D and Tymianski M: Neurotransmitters in the mediation of cerebral ischemic injury. Neuropharmacology. 134:178–188. 2018. View Article : Google Scholar : PubMed/NCBI
4	Napier S: Review of caplan's stroke: A clinical approach, 4th edition, by louis R. caplan. Neurodiagn J. 57:100–101. 2017. View Article : Google Scholar
5	Badhiwala JH, Nassiri F, Alhazzani W, Selim MH, Farrokhyar F, Spears J, Kulkarni AV, Singh S, Alqahtani A, Rochwerg B, et al: Endovascular thrombectomy for acute ischemic stroke: A meta-analysis. JAMA. 314:1832–1843. 2015. View Article : Google Scholar : PubMed/NCBI
6	Gori AM, Giusti B, Piccardi B, Nencini P, Palumbo V, Nesi M, Nucera A, Pracucci G, Tonelli P, Innocenti E, et al: Inflammatory and metalloproteinases profiles predict three-month poor outcomes in ischemic stroke treated with thrombolysis. J Cereb Blood Flow Metab. 37:3253–3261. 2017. View Article : Google Scholar : PubMed/NCBI
7	Pan CW, Zhou GY, Chen WL, Zhuge L, Jin LX, Zheng Y, Lin W and Pan ZZ: Protective effect of forsythiaside A on lipopolysaccharide/d-galactosamine-induced liver injury. Int Immunopharmacol. 26:80–85. 2015. View Article : Google Scholar : PubMed/NCBI
8	Qian J, Ma X, Xun Y and Pan L: Protective effect of forsythiaside A on OVA-induced asthma in mice. Eur J Pharmacol. 812:250–255. 2017. View Article : Google Scholar : PubMed/NCBI
9	Deng L, Pang P, Zheng K, Nie J, Xu H, Wu S, Chen J and Chen X: Forsythoside a controls influenza a virus infection and improves the prognosis by inhibiting virus replication in Mice. Molecules. 21(pii): E5242016. View Article : Google Scholar : PubMed/NCBI
10	Cheng Y, Liang X, Feng L, Liu D, Qin M, Liu S, Liu G and Dong M: Effects of phillyrin and forsythoside A on rat cytochrome P450 activities in vivo and in vitro. Xenobiotica. 47:297–303. 2017.PubMed/NCBI
11	Kim JM, Kim S, Kim DH, Lee CH, Park SJ, Jung JW, Ko KH, Cheong JH, Lee SH and Ryu JH: Neuroprotective effect of forsythiaside against transient cerebral global ischemia in gerbil. Eur J Pharmacol. 660:326–333. 2011. View Article : Google Scholar : PubMed/NCBI
12	Huang XP, Ding H, Lu JD, Tang YH, Deng BX and Deng CQ: Autophagy in cerebral ischemia and the effects of traditional Chinese medicine. J Integr Med. 13:289–296. 2015. View Article : Google Scholar : PubMed/NCBI
13	Khoshnam SE, Winlow W, Farzaneh M, Farbood Y and Moghaddam HF: Pathogenic mechanisms following ischemic stroke. Neurol Sci. 38:1167–1186. 2017. View Article : Google Scholar : PubMed/NCBI
14	Lopez MS, Dempsey RJ and Vemuganti R: Resveratrol neuroprotection in stroke and traumatic CNS injury. Neurochem Int. 89:75–82. 2015. View Article : Google Scholar : PubMed/NCBI
15	Galehdar Z, Swan P, Fuerth B, Callaghan SM, Park DS and Cregan SP: Neuronal apoptosis induced by endoplasmic reticulum stress is regulated by ATF4-CHOP-mediated induction of the Bcl-2 homology 3-only member PUMA. J Neurosc. 30:16938–16948. 2010. View Article : Google Scholar
16	Guo H, Li MJ, Liu QQ, Guo LL, Ma MM, Wang SX, Yu B and Hu LM: Danhong injection attenuates ischemia/reperfusion-induced brain damage which is associating with Nrf2 levels in vivo and in vitro. Neurochem Res. 39:1817–1824. 2014. View Article : Google Scholar : PubMed/NCBI
17	Guo H, Adah D, James PB, Liu Q, Li G, Ahmadu P, Chai L, Wang S, Liu Y and Hu L: Xueshuantong injection (Lyophilized) attenuates cerebral ischemia/Reperfusion injury by the activation of Nrf2-VEGF pathway. Neurochem Res. 43:1096–1103. 2018. View Article : Google Scholar : PubMed/NCBI
18	Longa EZ, Weinstein PR, Carlson S and Cummins R: Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke. 20:84–91. 1989. View Article : Google Scholar : PubMed/NCBI
19	Prasai PK, Shrestha B, Orr AW and Pattillo CB: Decreases in GSH:GSSG activate vascular endothelial growth factor receptor 2 (VEGFR2) in human aortic endothelial cells. Redox Biol. 19:22–27. 2018. View Article : Google Scholar : PubMed/NCBI
20	Cao L, Waldon D, Teffera Y, Roberts J, Wells M, Langley M and Zhao Z: Ratios of biliary glutathione disulfide (GSSG) to glutathione (GSH): A potential index to screen drug-induced hepatic oxidative stress in rats and mice. Anal Bioanal Chem. 405:2635–2642. 2013. View Article : Google Scholar : PubMed/NCBI
21	Vanden Berghe T, Linkermann A, Jouan-Lanhouet S, Walczak H and Vandenabeele P: Regulated necrosis: The expanding network of non-apoptotic cell death pathways. Nat Rev Mol Cell Biol. 15:135–147. 2014. View Article : Google Scholar : PubMed/NCBI
22	Galluzzi L, Bravo-San Pedro JM, Vitale I, Aaronson SA, Abrams JM, Adam D, Alnemri ES, Altucci L, Andrews D, Annicchiarico-Petruzzelli M, et al: Essential versus accessory aspects of cell death: Recommendations of the NCCD 2015. Cell Death Differ. 22:58–73. 2015. View Article : Google Scholar : PubMed/NCBI
23	Vandenabeele P, Galluzzi L, Vanden Berghe T and Kroemer G: Molecular mechanisms of necroptosis: An ordered cellular explosion. Nat Rev Mol Cell Biol. 11:700–714. 2010. View Article : Google Scholar : PubMed/NCBI
24	Savitskaya MA and Onishchenko GE: Mechanisms of apoptosis. Biochemistry (Mose). 80:1393–1405. 2015. View Article : Google Scholar
25	Shin HS, Park SY, Song HG, Hwang E, Lee DG and Yi TH: The androgenic alopecia protective effects of forsythiaside-A and the molecular regulation in a mouse model. Phytother Res. 29:870–876. 2015. View Article : Google Scholar : PubMed/NCBI
26	Song QJ, Weng XG, Cai DJ, Zhang W and Wang JF: Forsythoside a inhibits BVDV replication via TRAF2-dependent CD28-4-1BB signaling in bovine PBMCs. PLoS One. 11:e01627912016. View Article : Google Scholar : PubMed/NCBI
27	Jiang S, Deng C, Lv J, Fan C, Hu W, Di S, Yan X, Ma Z, Liang Z and Yang Y: Nrf2 weaves an elaborate network of neuroprotection against stroke. Mol Neurobiol. 54:1440–1455. 2017. View Article : Google Scholar : PubMed/NCBI
28	Liu X, Liu J, Zhao S, Zhang H, Cai W, Cai M, Ji X, Leak RK, Gao Y, Chen J and Hu X: Interleukin-4 is essential for microglia/macrophage M2 polarization and long-term recovery after cerebral ischemia. Stroke. 47:498–504. 2016. View Article : Google Scholar : PubMed/NCBI
29	Oh YS and Jun HS: Effects of glucagon-like peptide-1 on oxidative stress and Nrf2 signaling. Int J Mol Sci. 19(pii): E262017. View Article : Google Scholar : PubMed/NCBI
30	Meng J, Lv Z, Qiao X, Li X, Li Y, Zhang Y and Chen C: The decay of redox-stress response capacity is a substantive characteristic of aging: Revising the redox theory of aging. Redox Biol. 11:365–374. 2017. View Article : Google Scholar : PubMed/NCBI
31	Wang Y, Zhao H, Lin C, Ren J and Zhang S: Forsythiaside a exhibits anti-inflammatory effects in LPS-stimulated BV2 microglia cells through activation of Nrf2/HO-1 signaling pathway. Neurochem Res. 41:659–665. 2016. View Article : Google Scholar : PubMed/NCBI
32	Wang HM, Wang LW, Liu XM, Li CL, Xu SP and Farooq AD: Neuroprotective effects of forsythiaside on learning and memory deficits in senescence-accelerated mouse prone (SAMP8) mice. Pharmacol Biochem Behav. 105:134–141. 2013. View Article : Google Scholar : PubMed/NCBI
33	Huang C, Lin Y, Su H and Ye D: Forsythiaside protects against hydrogen peroxide-induced oxidative stress and apoptosis in PC12 cell. Neurochem Res. 40:27–35. 2015. View Article : Google Scholar : PubMed/NCBI
34	Ramezani A, Nahad MP and Faghihloo E: The role of Nrf2 transcription factor in viral infection. J Cell Biochem. 119:6366–6382. 2018. View Article : Google Scholar : PubMed/NCBI
35	Bottino-Rojas V, Talyuli OAC, Carrara L, Martins AJ, James AA, Oliveira PL and Paiva-Silva GO: The redox-sensing gene Nrf2 affects intestinal homeostasis, insecticide resistance, and Zika virus susceptibility in the mosquito Aedes aegypti. J Biol Chem. 293:9053–9063. 2018. View Article : Google Scholar : PubMed/NCBI
36	Tanaka N, Ikeda Y, Ohta Y, Deguchi K, Tian F, Shang J, Matsuura T and Abe K: Expression of Keap1-Nrf2 system and antioxidative proteins in mouse brain after transient middle cerebral artery occlusion. Brain Res. 1370:246–253. 2011. View Article : Google Scholar : PubMed/NCBI
37	Lou J, Cao G, Li R, Liu J, Dong Z and Xu L: β-caryophyllene attenuates focal cerebral ischemia-reperfusion injury by Nrf2/HO-1 pathway in Rats. Neurochem Res. 41:1291–1304. 2016. View Article : Google Scholar : PubMed/NCBI
38	Zhang Y, Fan L, Li H, Wang X, Xu W, Chu K and Lin Y: Gualou guizhi granule protects against oxidative injury by activating Nrf2/ARE pathway in rats and PC12 cells. Neurochem Res. 43:1003–1009. 2018. View Article : Google Scholar : PubMed/NCBI
39	Zitka O, Skalickova S, Gumulec J, Masarik M, Adam V, Hubalek J, Trnkova L, Kruseova J, Eckschlager T and Kizek R: Redox status expressed as GSH:GSSG ratio as a marker for oxidative stress in paediatric tumour patients. Oncol Lett. 4:1247–1253. 2012. View Article : Google Scholar : PubMed/NCBI
40	Noctor G and Foyer CH: ASCORBATE AND GLUTATHIONE: Keeping active oxygen under control. Ann Rev Plant Physiol Plant Mol Biol. 49:249–279. 1998. View Article : Google Scholar
41	Sentellas S, Morales-Ibanez O, Zanuy M and Alberti JJ: GSSG/GSH ratios in cryopreserved rat and human hepatocytes as a biomarker for drug induced oxidative stress. Toxicol in vitro. 28:1006–1015. 2014. View Article : Google Scholar : PubMed/NCBI
42	Chai YC, Ashraf SS, Rokutan K, Johnston RB Jr and Thomas JA: S-thiolation of individual human neutrophil proteins including actin by stimulation of the respiratory burst: Evidence against a role for glutathione disulfide. Arch Biochem Biophys. 310:273–281. 1994. View Article : Google Scholar : PubMed/NCBI
43	Bravo R, Parra V, Gatica D, Rodriguez AE, Torrealba N, Paredes F, Wang ZV, Zorzano A, Hill JA, Jaimovich E, et al: Endoplasmic reticulum and the unfolded protein response: dynamics and metabolic integration. Int Rev Cell Mol Biol. 301:215–290. 2013. View Article : Google Scholar : PubMed/NCBI
44	Chen D, Dixon BJ, Doycheva DM, Li B, Zhang Y, Hu Q, He Y, Guo Z, Nowrangi D, Flores J, et al: IRE1α inhibition decreased TXNIP/NLRP3 inflammasome activation through miR-17-5p after neonatal hypoxic-ischemic brain injury in rats. J Neuroinflammation. 15:322018. View Article : Google Scholar : PubMed/NCBI
45	Schroder M and Kaufman RJ: ER stress and the unfolded protein response. Mutat Res. 569:29–63. 2005. View Article : Google Scholar : PubMed/NCBI
46	Malhi H and Kaufman RJ: Endoplasmic reticulum stress in liver disease. J Hepatol. 54:795–809. 2011. View Article : Google Scholar : PubMed/NCBI