Generic placeholder image

Current Pharmaceutical Design


ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

General Research Article

Endogenous BMP-4/ROS/COX-2 Mediated IPC and Resveratrol Alleviated Brain Damage

Author(s): Ying Yan, Fei Tong* and Jianer Chen*

Volume 25, Issue 9, 2019

Page: [1030 - 1039] Pages: 10

DOI: 10.2174/1381612825666190506120611

open access plus


The objective of the study was to examine the therapeutic role of combined ischemic preconditioning (IPC) and resveratrol (RES) on brain ischemia/reperfusion injury (BI/RI) by modulating endogenous bone morphogenetic protein-4 (BMP-4)/reactive oxygen species (ROS)/cyclooxygenase-2 (COX-2) in rats. Sprague Dawley (SD) rats were pretreated with 20 mg/kg RES (20 mg/kg RES was administered once a day via intraperitoneal injection 7 days prior to the I/R procedure) and IPC (equal volumes of saline were administered once a day by intraperitoneal injection over 7 days, and the bilateral common carotid arteries were separated for clamp 5 minutes followed by 5 minutes of reperfusion prior to the I/R procedure), and then subjected to 2 hours of ischemia and 22 hours of reperfusion. Blood and cerebral tissues were collected, cerebral pathological injuries and infarct sizes were investigated, serum interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) levels were measured, the activities of superoxide dismutase (SOD) and ROS were calculated, the contents of methane dicarboxylic aldehyde (MDA), IL-6, TNF-α and hemodynamic change were estimated, and expression levels of b-cell lymphoma-2 (Bcl-2), bcl-2-associated x (Bax), BMP-4 and COX-2 were assessed in cerebral tissues. IPC, RES and a combination of IPC and RES preconditioning ameliorated the pathological damage and infarct sizes, reduced cerebral oxidative stress damage, alleviated inflammatory damage, restrained apoptosis, and downregulated the expression levels of BMP-4 and COX-2 compared with those of the ischemia/reperfusion (I/R) group. This study suggested a combined strategy that could enhance protection against BI/RI in clinical brain disease.

Keywords: IPC, RES, Bcl-2, Bax, BMP-4/ROS/COX-2, tumor necrosis.

Cui HX, Chen JH, Li JW, Cheng FR, Yuan K. Protection of anthocyanin from myrica rubra against cerebral ischemia-reperfusion injury via modulation of the TLR4/NF-κB and NLRP3 pathways. Molecules 2018; 23(7): E1788. []. [PMID: 30036952].
Li H, Yan Z, Zhu J, Yang J, He J. Neuroprotective effects of resveratrol on ischemic injury mediated by improving brain energy metabolism and alleviating oxidative stress in rats. Neuropharmacology 2011; 60(2-3): 252-8. []. [PMID: 20868700].
Mohagheghi F, Khalaj L, Ahmadiani A, Rahmani B. Gemfibrozil pretreatment affecting antioxidant defense system and inflammatory, but not Nrf-2 signaling pathways resulted in female neuroprotection and male neurotoxicity in the rat models of global cerebral ischemia-reperfusion. Neurotox Res 2013; 23(3): 225-37. []. [PMID: 22773136].
Nassar NN, Abdelsalam RM, Abdel-Rahman AA, Abdallah DM. Possible involvement of oxidative stress and inflammatory mediators in the protective effects of the early preconditioning window against transient global ischemia in rats. Neurochem Res 2012; 37(3): 614-21. []. [PMID: 22113727].
Park HS, Han KH, Shin JA, Park JH, Song KY, Kim DH. The neuroprotective effects of carnosine in early stage of focal ischemia rodent model. J Korean Neurosurg Soc 2014; 55(3): 125-30. []. [PMID: 24851146].
Prabhakar O. Cerebroprotective effect of resveratrol through antioxidant and anti-inflammatory effects in diabetic rats. Naunyn Schmiedebergs Arch Pharmacol 2013; 386(8): 705-10. []. [PMID: 23612842].
Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 1986; 74(5): 1124-36. []. [PMID: 3769170].
Hu YQ, Chen W, Yan MH, Lai JJ, Tang N, Wu L. Ischemic preconditioning protects brain from ischemia/reperfusion injury by attenuating endoplasmic reticulum stress-induced apoptosis through PERK pathway. Eur Rev Med Pharmacol Sci 2017; 21(24): 5736-44. []. [PMID: 29272010].
Ma ZF, Chen W, Cao CC, Chen X. Ischemic preconditioning attenuates brain injury induced by ischemia/reperfusion during moderate hypothermia low-flow procedures. Int J Neurosci 2014; 124(11): 824-33. []. [PMID: 24433123].
Kizmazoglu C, Aydin HE, Sevin IE, Kalemci O, Yüceer N, Atasoy MA. Neuroprotective Effect of Resveratrol on Acute Brain Ischemia Reperfusion Injury by Measuring Annexin V, p53, Bcl-2 Levels in Rats. J Korean Neurosurg Soc 2015; 58(6): 508-12. []. [PMID: 26819684].
Juhasz B, Varga B, Gesztelyi R, Kemeny-Beke A, Zsuga J, Tosaki A. Resveratrol: a multifunctional cytoprotective molecule. Curr Pharm Biotechnol 2010; 11(8): 810-8. []. [PMID: 20874691].
Juhasz B, Varga B, Gesztelyi R, Kemeny-Beke A, Zsuga J, Tosaki A. Resveratrol: a multifunctional cytoprotective molecule. Curr Pharm Biotechnol 2010; 11(8): 810-8. []. [PMID: 20874691].
Zhang F, Liu J, Shi JS. Anti-inflammatory activities of resveratrol in the brain: role of resveratrol in microglial activation. Eur J Pharmacol 2010; 636(1-3): 1-7. []. [PMID: 20361959].
Yeh DY, Fu YH, Yang YC, Wang JJ. Resveratrol alleviates lung ischemia and reperfusion-induced pulmonary capillary injury through modulating pulmonary mitochondrial metabolism. Transplant Proc 2014; 46(4): 1131-4. []. [PMID: 24815145].
Cheng L, Jin Z, Zhao R, Ren K, Deng C, Yu S. Resveratrol attenuates inflammation and oxidative stress induced by myocardial ischemia-reperfusion injury: role of Nrf2/ARE pathway. Int J Clin Exp Med 2015; 8(7): 10420-8. [PMID: 26379832].
Bienholz A, Mae Pang R, Guberina H, et al. Resveratrol Does Not Protect from Ischemia-Induced Acute Kidney Injury in an in Vivo Rat Model. Kidney Blood Press Res 2017; 42(6): 1090-103. []. [PMID: 29207388].
Erkasap S, Erkasap N, Bradford B, et al. The effect of leptin and resveratrol on JAK/STAT pathways and Sirt-1 gene expression in the renal tissue of ischemia/reperfusion induced rats. Bratisl Lek Listy 2017; 118(8): 443-8. []. [PMID: 29050480].
Seong H, Ryu J, Yoo WS, et al. Resveratrol Ameliorates Retinal Ischemia/Reperfusion Injury in C57BL/6J Mice via Downregulation of Caspase-3. Curr Eye Res 2017; 42(12): 1650-8. []. [PMID: 28985092].
Nakamura K, Kageyama S, Ke B, et al. Sirtuin 1 attenuates inflammation and hepatocellular damage in liver transplant ischemia/Reperfusion: From mouse to human. Liver Transpl 2017; 23(10): 1282-93. []. [PMID: 28719070].
Bennet D, Kim S. Effects of agmatine and resveratrol on RGC-5 cell behavior under light stimulation. Environ Toxicol Pharmacol 2014; 38(1): 84-97. []. [PMID: 24929477].
Fang L, Gao H, Zhang W, Zhang W, Wang Y. Resveratrol alleviates nerve injury after cerebral ischemia and reperfusion in mice by inhibiting inflammation and apoptosis. Int J Clin Exp Med 2015; 8(3): 3219-26. [PMID: 26064211].
Jia JY, Tan ZG, Liu M, Jiang YG. Apurinic/apyrimidinic endonuclease 1 (APE1) contributes to resveratrol-induced neuroprotection against oxygen-glucose deprivation and re-oxygenation injury in HT22 cells: Involvement in reducing oxidative DNA damage. Mol Med Rep 2017; 16(6): 9786-94. []. [PMID: 29039534].
He Q, Li Z, Wang Y, Hou Y, Li L, Zhao J. Resveratrol alleviates cerebral ischemia/reperfusion injury in rats by inhibiting NLRP3 inflammasome activation through Sirt1-dependent autophagy induction. Int Immunopharmacol 2017; 50: 208-15. []. [PMID: 28683365].
Chen D, Zhao M, Mundy GR. Bone morphogenetic proteins. Growth Factors 2004; 22(4): 233-41. []. [PMID: 15621726].
Upton PD, Long L, Trembath RC, Morrell NW. Functional characterization of bone morphogenetic protein binding sites and Smad1/5 activation in human vascular cells. Mol Pharmacol 2008; 73(2): 539-52. []. [PMID: 17989347].
Lee J, Stavropoulos A, Susin C, Wikesjö UME. Periodontal regeneration: focus on growth and differentiation factors. Dent Clin North Am 2010; 54(1): 93-111. []. [PMID: 20103474].
Vukicevic S, Paralkar VM, Cunningham NS, Gutkind JS, Reddi AH. Autoradiographic localization of osteogenin binding sites in cartilage and bone during rat embryonic development. Dev Biol 1990; 140(1): 209-14. []. [PMID: 2358119].
Haidar ZS, Hamdy RC, Tabrizian M. Delivery of recombinant bone morphogenetic proteins for bone regeneration and repair. Part A: Current challenges in BMP delivery. Biotechnol Lett 2009; 31(12): 1817-24. []. [PMID: 19690804].
Gu GL, Yang QY, Zeng RL, Xu XL. The association between BMP4 gene polymorphism and its serum level with the incidence of LVH in hypertensive patients. J Transl Med 2015; 13: 14. []. [PMID: 25591903].
Tong F, Dong B, Chai R, et al. Simvastatin nanoparticles attenuated intestinal ischemia/reperfusion injury by downregulating BMP4/COX-2 pathway in rats. Int J Nanomedicine 2017; 12: 2477-88. []. [PMID: 28408819].
Csiszar A, Labinskyy N, Jo H, Ballabh P, Ungvari Z. Differential proinflammatory and prooxidant effects of bone morphogenetic protein-4 in coronary and pulmonary arterial endothelial cells. Am J Physiol Heart Circ Physiol 2008; 295(2): H569-77. []. [PMID: 18539760].
Xiao L, Dong JH, Jin S, et al. Hydrogen sulfide improves endothelial dysfunction via downregulating BMP4/COX-2 pathway in rats with hypertension. Oxid Med Cell Longev 2016; 20168128957. []. [PMID: 27642495].
Farmer DG, Shen XD, Amersi F, et al. CD62 blockade with P-Selectin glycoprotein ligand-immunoglobulin fusion protein reduces ischemia-reperfusion injury after rat intestinal transplantation. Transplantation 2005; 79(1): 44-51. []. [PMID: 15714168].
Shu X, Zhang J, Wang Q, Xu Z, Yu T. Glutamine decreases intestinal mucosal injury in a rat model of intestinal ischemia-reperfusion by downregulating HMGB1 and inflammatory cytokine expression. Exp Ther Med 2016; 12(3): 1367-72. []. [PMID: 27588057].
Luan Q, Pan L, He D, Gong X, Zhou H. SC79, the AKT Activator Protects Cerebral Ischemia in a Rat Model of Ischemia/Reperfusion Injury. Med Sci Monit 2018; 24: 5391-7. []. [PMID: 30074018].
Tsuchidate R, He QP, Smith ML, Siesjö BK. Regional cerebral blood flow during and after 2 hours of middle cerebral artery occlusion in the rat. J Cereb Blood Flow Metab 1997; 17(10): 1066-73. []. [PMID: 9346431].
Wang B, Wang P, Kang J, et al. Effects of dl-3n-butyphthalide on learning, memory and hippocampal NR2B expression in mice with vascular dementia. Zhongguo Xin Yao Zazhi 2008; 17: 43-6.
Kader A, Frazzini VI, Solomon RA, Trifiletti RR. Nitric oxide production during focal cerebral ischemia in rats. Stroke 1993; 24(11): 1709-16. []. [PMID: 7694393].
Rosenberg GA. Ischemic brain edema. Prog Cardiovasc Dis 1999; 42(3): 209-16. []. [PMID: 10598921].
Yang G, Schielke G, Gong C. Expression of TNF2αand ICAM21 after focal cerebral ischemia in IL2β converting enzyme deficient mice. J Cereb Blood Flow Metab 1999; 19: 1109-17. []. [PMID: 10532635].
Zhang X, Xue X, Xian L, Guo Z, Ito Y, Sun W. Potential neuroprotection of protodioscin against cerebral ischemia-reperfusion injury in rats through intervening inflammation and apoptosis. Steroids 2016; 113: 52-63. []. [PMID: 27343977].
Ahmad M, Dar NJ, Bhat ZS, et al. Inflammation in ischemic stroke: mechanisms, consequences and possible drug targets. CNS Neurol Disord Drug Targets 2014; 13(8): 1378-96. []. [PMID: 25345517].
Simonyi A, Wang Q, Miller RL, et al. Polyphenols in cerebral ischemia: novel targets for neuroprotection. Mol Neurobiol 2005; 31(1-3): 135-47. []. [PMID: 15953817].
Salehiabar M, Nosrati H, Javani E, et al. Production of biological nanoparticles from bovine serum albumin as controlled release carrier for curcumin delivery. Int J Biol Macromol 2018; 115: 83-9. []. [PMID: 29653171].
Kobra R, Mostafa M, Hamed N, et al. Methotrexate-conjugated mPEG–PCL copolymers: a novel approach for dual triggered drug delivery. New J Chem 2018; 42: 5937-45. [].

© 2022 Bentham Science Publishers | Privacy Policy