Resveratrol ameliorates brain injury via the TGF‑β‑mediated ERK signaling pathway in a rat model of cerebral hemorrhage

Zhao,Riguang; Zhao,Kun; Su,Hongjun; Zhang,Peng; Zhao,Na

doi:10.3892/etm.2019.7939

Resveratrol ameliorates brain injury via the TGF‑β‑mediated ERK signaling pathway in a rat model of cerebral hemorrhage

Authors:
- Riguang Zhao
- Kun Zhao
- Hongjun Su
- Peng Zhang
- Na Zhao
View Affiliations

Affiliations: Baodi Clinical College of Tianjin Medical University, Tianjin Baodi Hospital, Tianjin 301800, P.R. China, College of Basic Medicine, Shanghai Jiao Tong University, Shanghai 240001, P.R. China
Published online on: August 26, 2019 https://doi.org/10.3892/etm.2019.7939
Pages: 3397-3404
Copyright: © Zhao 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

Brain injury is the most common intracranial injury in human cerebrovascular disease, which may lead to ischemic stroke. Resveratrol induces ameliorative effects in the treatment of certain human diseases by regulating different signaling pathways. The present study assessed the therapeutic effects of resveratrol and its potential mechanism of action in the neurons from rats with ischemia/reperfusion‑induced cerebral hemorrhage. The rat model of cerebral hemorrhage was established and reverse transcription‑quantitative polymerase chain reaction, western blotting, immunohistochemistry and terminal deoxynucleotidyl‑transferase‑mediated dUTP nick end labeling assays were subsequently performed to assess the therapeutic effects of resveratrol. The results demonstrated that treatment with resveratrol (10 mg/kg/day) decreased cerebral water content, hippocampal cell apoptosis and cerebral infarct volume compared with the PBS‑treated group. Resveratrol treatment also increased neuronal cell viability, improved neurological function and blood brain barrier disruption compared with the PBS group following 21 days of treatment. The administration of resveratrol was demonstrated to decrease the levels of certain inflammatory factors, including ionized calcium binding adaptor molecule 1 and myeloperoxidase, in rats with cerebral hemorrhage. The results revealed that treatment with resveratrol regulated neuronal apoptosis by downregulating the transforming growth factor‑β (TGF‑β)‑mediated extracellular signal‑regulated kinase (ERK) signaling pathway. In conclusion, these results indicate that resveratrol decreases ischemia/reperfusion‑induced neuronal apoptosis by downregulating the TGF‑β‑mediated ERK pathway in a rat model of cerebral hemorrhage and may serve as a potential agent for the treatment of cerebral hemorrhage.

View Figures

View References

1	Al-Mufti F, Amuluru K, Changa A, Lander M, Patel N, Wajswol E, Al-Marsoummi S, Alzubaidi B, Singh IP, Nuoman R and Gandhi C: Traumatic brain injury and intracranial hemorrhage-induced cerebral vasospasm: A systematic review. Neurosurgical focus. 43:E142017. View Article : Google Scholar : PubMed/NCBI
2	Shoamanesh A, Kwok CS, Lim PA and Benavente OR: Postthrombolysis intracranial hemorrhage risk of cerebral microbleeds in acute stroke patients: A systematic review and meta-analysis. Int J Stroke. 8:348–356. 2013. View Article : Google Scholar : PubMed/NCBI
3	Bugeme M and Mukuku O: Neuropsychiatric manifestations revealing cerebral subarachnoid hemorrhage caused by electrification accident about a case and review of literature. Pan AfrMed J. 18:2012014.(In French).
4	Wang X, Gao XD, Gao B, Jia LL, Yang MF, Zhang YB and Sun BL: Cerebral lymphatic blockage aggravates apoptosis of cortical neurons after subarachnoid hemorrhage in rats in vivo. Sheng Li Xue Bao. 62:109–114. 2010.(In Chinese). PubMed/NCBI
5	Jeong SI, Shin JA, Cho S, Kim HW, Lee JY, Kang JL and Park EM: Resveratrol attenuates peripheral and brain inflammation and reduces ischemic brain injury in aged female mice. Neurobiol Aging. 44:74–84. 2016. View Article : Google Scholar : PubMed/NCBI
6	Li H, Yan Z, Zhu J, Yang J and He J: Neuroprotective effects of resveratrol on ischemic injury mediated by improving brain energy metabolism and alleviating oxidative stress in rats. Neuropharmacology. 60:252–258. 2011. View Article : Google Scholar : PubMed/NCBI
7	Zou P, Liu X, Li G and Wang Y: Resveratrol pretreatment attenuates traumatic brain injury in rats by suppressing NLRP3 inflammasome activation via SIRT1. Mol Med Rep. 17:3212–3217. 2018.PubMed/NCBI
8	Karalis F, Soubasi V, Georgiou T, Nakas CT, Simeonidou C, Guiba-Tziampiri O and Spandou E: Resveratrol ameliorates hypoxia/ischemia-induced behavioral deficits and brain injury in the neonatal rat brain. Brain Res. 1425:98–110. 2011. View Article : Google Scholar : PubMed/NCBI
9	Logan TT, Villapol S and Symes AJ: TGF-β superfamily gene expression and induction of the Runx1 transcription factor in adult neurogenic regions after brain injury. PLoS One. 8:e592502013. View Article : Google Scholar : PubMed/NCBI
10	Sugawara T, Jadhav V, Ayer R and Zhang J: Simvastatin attenuates cerebral vasospasm and improves outcomes by upregulation of PI3K/Akt pathway in a rat model of subarachnoid hemorrhage. Acta Neurochir Suppl. 102:391–394. 2008. View Article : Google Scholar : PubMed/NCBI
11	Aguilar-Alonso P, Vera-Lopez O, Brambila-Colombres E, Segura-Badilla O, Avalos-López R, Lazcano-Hernández M and Navarro-Cruz AR: Evaluation of oxidative stress in cardiomyocytes during the aging process in rats treated with resveratrol. Oxid Med Cell Longev. 2018:13904832018. View Article : Google Scholar : PubMed/NCBI
12	Gamberini MT, Rodrigues DS, Rodrigues D and Pontes VB: Effects of the aqueous extract of Pimpinella anisum L. seeds on exploratory activity and emotional behavior in rats using the open field and elevated plus maze tests. J Ethnopharmacol. 168:45–49. 2015. View Article : Google Scholar : PubMed/NCBI
13	Vatter H, Weidauer S, Konczalla J, Dettmann E, Zimmermann M, Raabe A, Preibisch C, Zanella FE and Seifert V: Time course in the development of cerebral vasospasm after experimental subarachnoid hemorrhage: Clinical and neuroradiological assessment of the rat double hemorrhage model. Neurosurgery. 58:1190–1197; discussion 1190–1197. 2006. View Article : Google Scholar : PubMed/NCBI
14	Hijioka M, Matsushita H, Hisatsune A, Isohama Y and Katsuki H: Therapeutic effect of nicotine in a mouse model of intracerebral hemorrhage. J Pharmacol Exp Ther. 338:741–749. 2011. View Article : Google Scholar : PubMed/NCBI
15	Hong H, Kim CJ, Kim JD and Seo JH: β-glucan reduces exercise-induced stress through downregulation of c-Fos and c-Jun expression in the brains of exhausted rats. Mol Med Rep. 9:1660–1666. 2014. View Article : Google Scholar : PubMed/NCBI
16	Chen H, Guan B, Chen X, Chen X, Li C, Qiu J, Yang D, Liu KJ, Qi S and Shen J: Baicalin attenuates blood-brain barrier disruption and hemorrhagic transformation and improves neurological outcome in ischemic stroke rats with delayed t-PA treatment: Involvement of ONOO(−)-MMP-9 pathway. Transl Stroke Res. 9:515–529. 2017. View Article : Google Scholar : PubMed/NCBI
17	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
18	Li R, Wu Y, Zou S, Wang X, Li Y, Xu K, Gong F, Liu Y, Wang J, Liao Y, et al: NGF attenuates high glucose-induced ER stress, preventing schwann cell apoptosis by activating the PI3K/Akt/GSK3β and ERK1/2 pathways. Neurochem Res. 42:3005–3018. 2017. View Article : Google Scholar : PubMed/NCBI
19	Hausmann R, Biermann T, Wiest I, Tubel J and Betz P: Neuronal apoptosis following human brain injury. Int J Legal Med. 118:32–36. 2004. View Article : Google Scholar : PubMed/NCBI
20	Zhou XM, Zhou ML, Zhang XS, Zhuang Z, Li T, Shi JX and Zhang X: Resveratrol prevents neuronal apoptosis in an early brain injury model. J Surg Res. 189:159–165. 2014. View Article : Google Scholar : PubMed/NCBI
21	Song J, Cho KJ, Cheon SY, Kim SH, Park KA, Lee WT and Lee JE: Apoptosis signal-regulating kinase 1 (ASK1) is linked to neural stem cell differentiation after ischemic brain injury. Exp Mol Med. 45:e692013. View Article : Google Scholar : PubMed/NCBI
22	Ai Z, Li C, Li L and He G: Resveratrol inhibits beta-amyloid-induced neuronal apoptosis via regulation of p53 acetylation in PC12 cells. Mol Med Rep. 11:2429–2434. 2015. View Article : Google Scholar : PubMed/NCBI
23	Chen X, Liu J, Feng WK, Wu X and Chen SY: MiR-125b protects against ethanol-induced apoptosis in neural crest cells and mouse embryos by targeting Bak 1 and PUMA. Exp Neurol. 271:104–111. 2015. View Article : Google Scholar : PubMed/NCBI
24	Taylor RA, Chang CF, Goods BA, Hammond MD, Mac Grory B, Ai Y, Steinschneider AF, Renfroe SC, Askenase MH, McCullough LD, et al: TGF-β1 modulates microglial phenotype and promotes recovery after intracerebral hemorrhage. J Clin Invest. 127:280–292. 2017. View Article : Google Scholar : PubMed/NCBI
25	Anderson CN and Tolkovsky AM: A role for MAPK/ERK in sympathetic neuron survival: Protection against a p53-dependent, JNK-independent induction of apoptosis by cytosine arabinoside. J Neurosci. 19:664–673. 1999. View Article : Google Scholar : PubMed/NCBI