Protective Effects of Sulphonated Formononetin in a Rat Model of Cerebral Ischemia and Reperfusion Injury

Abstract

Sodium formononetin-3′-sulphonate is a derivative of the plant isoflavone formononetin. The present study aimed to investigate the neuroprotective and angiogenesis effects of sodium formononetin-3′-sulphonate in vivo and in vitro. Treatment with sodium formononetin-3′-sulphonate (3, 7.5, 15, and 30 mg/kg, intravenous injection) could protect the brain from ischemia and reperfusion injury by improving neurological function, suppressing cell apoptosis, and increasing expression levels of vascular endothelial growth factor and platelet endothelial cell adhesion molecule 1 by middle cerebral artery occlusion. Treatment with sodium formononetin-3′-sulphonate (10 and 20 µg/mL) significantly increased cell migration, tube formation, and vascular endothelial growth factor and platelet endothelial cell adhesion molecule levels in human umbilical vein endothelial cells. Our results suggest that sodium formononetin-3′-sulphonate provides significant neuroprotective effects against cerebral ischemia and reperfusion injury in rats, and improves cerebrovascular angiogenesis in human umbilical vein endothelial cells. The protective mechanisms of sodium formononetin-3′-sulphonate may be attributed to the suppression of cell apoptosis and improved cerebrovascular angiogenesis by promoting vascular endothelial growth factor and platelet endothelial cell adhesion molecule expression.

Key words

angiogenesis - cerebral ischemia - platelet endothelial cell adhesion molecule-1 - sulphonated formononetin - vascular endothelial growth factor - Astragalus mongholicus - Fabaceae

• References

• 1 Chen YC, Wu JS, Yang ST, Huang CY, Chang C, Sun GY, Lin TN. Stroke, angiogenesis and phytochemicals. Front Biosci 2012; 4: 599-610
• 2 Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1995; 1: 27-31
• 3 Beck H, Plate KH. Angiogenesis after cerebral ischemia. Acta Neuropathol 2009; 117: 481-496
• 4 Carmeliet P. Angiogenesis in health and disease. Nat Med 2003; 9: 653-660
• 5 Dvorak HF, Brown LF, Detmar M, Dvorak AM. Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am J Pathol 1995; 146: 1029-1039
• 6 Muller WA, Berman ME, Newman PJ, DeLisser HM, Albelda SM. A heterophilic adhesion mechanism for platelet/endothelial cell adhesion molecule 1 (CD31). J Exp Med 1992; 175: 1401-1404
• 7 Delisser HM, Baldwin HS, Albelda SM. Platelet endothelial cell adhesion molecule 1 (PECAM-1/CD31): a multifunctional vascular cell adhesion molecule. Trends Cardiovasc Med 1997; 7: 203-210
• 8 Wu JH, Li Q, Wu MY, Guo DJ, Chen HL, Chen SL, Seto SW, Au AL, Poon CC, Leung GP, Lee SM, Kwan YW, Chan SW. Formononetin, an isoflavone, relaxes rat isolated aorta through endothelium-dependent and endothelium-independent pathways. J Nutr Biochem 2010; 21: 613-620
• 9 Yu D, Duan Y, Bao Y, Wei C, An L. Isoflavonoids from Astragalus mongholicus protect PC12 cells from toxicity induced by L-glutamate. J Ethnopharmacol 2005; 98: 89-94
• 10 Mu H, Bai YH, Wang ST, Zhu ZM, Zhang YW. Research on antioxidant effects and estrogenic effect of formononetin from Trifolium pratense (red clover). Phytomedicine 2009; 16: 314-319
• 11 Zhang S, Tang X, Tian J, Li C, Zhang G, Jiang W, Zhang Z. Cardioprotective effect of sulphonated formononetin on acute myocardial infarction in rats. Basic Clin Pharmacol Toxicol 2011; 108: 390-395
• 12 Kazda S, Towart R. Nimodipine: a new calcium antagonist drug with a preferential cerebrovascular action. Acta Neurochir (Wien) 1982; 63: 259-265
• 13 Du G, Zhu H, Yu P, Wang H, He J, Ye L, Fu F, Zhang J, Tian J. SMND-309 promotes angiogenesis in human umbilical vein endothelial cells through activating erythropoietin receptor/STAT3/VEGF pathways. Eur J Pharmacol 2013; 700: 173-180
• 14 Jaquet K, Krause K, Tawakol-Khodai M, Geidel S, Kuck KH. Erythropoietin and VEGF exhibit equal angiogenic potential. Microvasc Res 2002; 64: 326-333
• 15 Li ZG, Wang JF, Cheng JD, Liu YW, Xing HW, Wang Y, Chen YH. Regularity of hypoxia inducible factor 1 alpha expression in acute myocardial ischaemia in rats. Chin Med J (Engl) 2007; 120: 162-165
• 16 Zhang ZG, Zhang L, Jiang Q, Chopp M. Bone marrow-derived endothelial progenitor cells participate in cerebral neovascularization after focal cerebral ischemia in the adult mouse. Circ Res 2002; 90: 284-288
• 17 Krupinski J, Kaluza J, Kumar P, Kumar S, Wang J. Role of angiogenesis in patients with cerebral ischemic stroke. Stroke 1994; 25: 1794-1798
• 18 Zhang ZG, Wang C, Tian Z, Wang Q, Liu H, Zheng J, Suo Z. Formononetin-3′-sulfonate, prunetin-3′-sulfonate and its preparation method and pharmaceutical use. Chinese Patent ZL200710017326.5; 2007.
• 19 Jiang W, Fu F, Tian J, Zhu H, Hou J. Curculigoside A attenuates experimental cerebral ischemia injury in vitro and vivo . Neuroscience 2011; 192: 572-579
• 20 Chen J, Li Y, Wang L, Zhang Z, Lu D, Lu M, Chopp M. Therapeutic benefit of intravenous administration of bone marrow stromal cells after cerebral ischemia in rats. Stroke 2001; 32: 1005-1011
• 21 Swanson R, Morton MT, Tsao-Wu G, Savalos RA, Davidson C, Sharp FR. A semiautomated method for measuring brain infarct volume. J Cereb Blood Flow Metab 1990; 10: 290-293
• 22 Jaffe EA, Nachman RL, Becker CG, Minick CR. Culture of human endothelial cells derived from umbilical veins. Identification by morphologic and immunologic criteria. J Clin Invest 1973; 52: 2745-2756
• 23 Mehta SL, Manhas N, Raghubir R. Molecular targets in cerebral ischemia for developing novel therapeutics. Brain Res Rev 2007; 4: 34-66
• 24 Wang Y, Chen T, Han C, He D, Liu H, An H, Cai Z, Cao X. Lysosome-associated small Rab GTPase Rab7b negatively regulates TLR4 signaling in macrophages by promoting lysosomal degradation of TLR4. Blood 2007; 110: 962-971