Hexane extracts of Polygonum multiflorum improve tissue and functional outcome following focal cerebral ischemia in mice

Lee,Soo Vin; Choi,Kyung Ha; Choi,Young Whan; Hong,Jin Woo; Baek,Jin Ung; Choi,Byung Tae; Shin,Hwa Kyoung

doi:10.3892/mmr.2014.1943

Hexane extracts of Polygonum multiflorum improve tissue and functional outcome following focal cerebral ischemia in mice

Authors:
- Soo Vin Lee
- Kyung Ha Choi
- Young Whan Choi
- Jin Woo Hong
- Jin Ung Baek
- Byung Tae Choi
- Hwa Kyoung Shin
View Affiliations

Affiliations: School of Korean Medicine, Pusan National University, Yangsan, Gyeongnam 626-870, Republic of Korea, College of Natural Resources and Life Sciences, Pusan National University, Gyeongnam 627-706, Republic of Korea
Published online on: February 11, 2014 https://doi.org/10.3892/mmr.2014.1943
Pages: 1415-1421

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

Polygonum multiflorum is a traditional Korean medicine that has been utilized widely in East Asian countries as a longevity agent. Clinical studies have demonstrated that Polygonum multiflorum improves hypercholesterolemia, coronary heart disease, neurosis and other diseases commonly associated with aging. However, scientific evidence defining the protective effects and mechanisms of Polygonum multiflorum against ischemic stroke is incomplete. In the present study, we investigated the cerebrovascular protective effects of Polygonum multiflorum against ischemic brain injury using an in vivo photothrombotic mouse model. To examine the underlying mechanism of action, we utilized an in vitro human brain microvascular endothelial cell (HBMEC) culture system. Hexane extracts (HEPM), ethyl acetate extracts (EAEPM) and methanol extracts (MEPM) of Polygonum multiflorum (100 mg/kg) were administered intraperitoneally 30 min prior to ischemic insult. Focal cerebral ischemia was induced in C57BL/6J mice and endothelial nitric oxide synthase knockout (eNOS KO) mice by photothrombotic cortical occlusion. We evaluated the infarct volume, as well as neurological and motor function, 24 h after ischemic brain injury. Following ischemic insult, HEPM induced a significant reduction in infarct volume and subsequent neurological deficits, compared with EAEPM and MEPM. HEPM significantly decreased infarct size and improved neurological and motor function, which was not observed in eNOS KO mice, suggesting that this cerebroprotective effect is primarily an eNOS-dependent mechanism. In vitro, HEPM effectively promoted NO production, however these effects were inhibited by the NOS inhibitor, L-NAME and the PI3K/Akt inhibitor, LY-294002. Furthermore, HEPM treatment resulted in increased phosphorylation-dependent activation of Akt and eNOS in HBMEC, suggesting that HEPM increased NO production via phosphorylation-dependent activation of Akt and eNOS. In conclusion, HEPM prevents cerebral ischemic damage through an eNOS-dependent mechanism, and thus may have clinical applications as a protective agent against neurological injury in stroke.

View Figures

View References

1	Roger VL, Go AS, Lloyd-Jones DM, et al: Heart disease and stroke statistics - 2011 update: a report from the American Heart Association. Circulation. 123:e18–e209. 2011. View Article : Google Scholar : PubMed/NCBI
2	Allen CL and Bayraktutan U: Risk factors for ischaemic stroke. Int J Stroke. 3:105–116. 2008. View Article : Google Scholar : PubMed/NCBI
3	Endres M, Laufs U, Liao JK and Moskowitz MA: Targeting eNOS for stroke protection. Trends Neurosci. 27:283–289. 2004. View Article : Google Scholar : PubMed/NCBI
4	Dimmeler S, Fleming I, Fisslthaler B, Hermann C, Busse R and Zeiher AM: Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature. 399:601–605. 1999. View Article : Google Scholar : PubMed/NCBI
5	Limbourg FP, Huang Z, Plumier JC, et al: Rapid nontranscriptional activation of endothelial nitric oxide synthase mediates increased cerebral blood flow and stroke protection by corticosteroids. J Clin Invest. 110:1729–1738. 2002. View Article : Google Scholar
6	Xiao PG, Xing ST and Wang LW: Immunological aspects of Chinese medicinal plants as antiageing drugs. J Ethnopharmacol. 38:167–175. 1993.PubMed/NCBI
7	Liu Z, Liu Y, Chao Z, Song Z, Wang C and Lu A: In vitro antioxidant activities of maillard reaction products produced in the steaming process of Polygonum multiflorum root. Nat Prod Commun. 6:55–58. 2011.PubMed/NCBI
8	Yang PY, Almofti MR, Lu L, et al: Reduction of atherosclerosis in cholesterol-fed rabbits and decrease of expressions of intracellular adhesion molecule-1 and vascular endothelial growth factor in foam cells by a water-soluble fraction of Polygonum multiflorum. J Pharmacol Sci. 99:294–300. 2005. View Article : Google Scholar
9	Um MY, Choi WH, Aan JY, Kim SR and Ha TY: Protective effect of Polygonum multiflorum Thunb on amyloid beta-peptide 25–35 induced cognitive deficits in mice. J Ethnopharmacol. 104:144–148. 2006.PubMed/NCBI
10	Chan YC, Wang MF and Chang HC: Polygonum multiflorum extracts improve cognitive performance in senescence accelerated mice. Am J Chin Med. 31:171–179. 2003. View Article : Google Scholar : PubMed/NCBI
11	Wang T, Gu J, Wu PF, et al: Protection by tetrahydroxystilbene glucoside against cerebral ischemia: involvement of JNK, SIRT1, and NF-kappaB pathways and inhibition of intracellular ROS/RNS generation. Free Radic Biol Med. 47:229–240. 2009. View Article : Google Scholar : PubMed/NCBI
12	Sun FL, Zhang L, Zhang RY and Li L: Tetrahydroxystilbene glucoside protects human neuroblastoma SH-SY5Y cells against MPP⁺-induced cytotoxicity. Eur J Pharmacol. 660:283–290. 2011. View Article : Google Scholar : PubMed/NCBI
13	Lee JK, Park MS, Kim YS, et al: Photochemically induced cerebral ischemia in a mouse model. Surg Neurol. 67:620–625. 2007. View Article : Google Scholar : PubMed/NCBI
14	Li X, Blizzard KK, Zeng Z, DeVries AC, Hurn PD and McCullough LD: Chronic behavioral testing after focal ischemia in the mouse: functional recovery and the effects of gender. Exp Neurol. 187:94–104. 2004. View Article : Google Scholar : PubMed/NCBI
15	Chen T, Liu W, Chao X, et al: Salvianolic acid B attenuates brain damage and inflammation after traumatic brain injury in mice. Brain Res Bull. 84:163–168. 2011. View Article : Google Scholar : PubMed/NCBI
16	Kojima H, Sakurai K, Kikuchi K, et al: Development of a fluorescent indicator for nitric oxide based on the fluorescein chromophore. Chem Pharm Bull (Tokyo). 46:373–375. 1998. View Article : Google Scholar : PubMed/NCBI
17	Fisslthaler B and Fleming I: Activation and signaling by the AMP-activated protein kinase in endothelial cells. Circ Res. 105:114–127. 2009. View Article : Google Scholar : PubMed/NCBI
18	Chan YC, Wang MF, Chen YC, Yang DY, Lee MS and Cheng FC: Long-term administration of Polygonum multiflorum Thunb. reduces cerebral ischemia-induced infarct volume in gerbils. Am J Chin Med. 31:71–77. 2003.PubMed/NCBI
19	Jang JY, Kim HN, Kim YR, et al: Hexane extract from Polygonum multiflorum attenuates glutamate-induced apoptosis in primary cultured cortical neurons. J Ethnopharmacol. 145:261–268. 2013. View Article : Google Scholar : PubMed/NCBI
20	Dudzinski DM and Michel T: Life history of eNOS: partners and pathways. Cardiovasc Res. 75:247–260. 2007. View Article : Google Scholar : PubMed/NCBI
21	Huang Z, Huang PL, Ma J, et al: Enlarged infarcts in endothelial nitric oxide synthase knockout mice are attenuated by nitro-L-arginine. J Cereb Blood Flow Metab. 16:981–987. 1996. View Article : Google Scholar : PubMed/NCBI
22	Huang HC, Chu SH and Chao PD: Vasorelaxants from Chinese herbs, emodin and scoparone, possess immunosuppressive properties. Eur J Pharmacol. 198:211–213. 1991. View Article : Google Scholar : PubMed/NCBI
23	Xu XL, Huang YJ, Chen XF, Lin DY and Zhang W: 2,3,4′,5-tetrahydroxystilbene-2-O-β-D-glucoside inhibits proliferation of vascular smooth muscle cells: involvement of NO/cGMP/PKG pathway. Phytother Res. 26:1068–1074. 2012.
24	Zhang W, Xu XL, Wang YQ, Wang CH and Zhu WZ: Effects of 2,3,4′,5-tetrahydroxystilbene 2-O-beta-D-glucoside on vascular endothelial dysfunction in atherogenic-diet rats. Planta Med. 75:1209–1214. 2009.
25	Fulton D, Gratton JP and Sessa WC: Post-translational control of endothelial nitric oxide synthase: why isn’t calcium/calmodulin enough? J Pharmacol Exp Ther. 299:818–824. 2001.
26	MacRitchie AN, Jun SS, Chen Z, et al: Estrogen upregulates endothelial nitric oxide synthase gene expression in fetal pulmonary artery endothelium. Circ Res. 81:355–362. 1997. View Article : Google Scholar : PubMed/NCBI