Antihypertensive Effect of Polyphenol-Rich Fraction of Azadirachta indica on Nω-Nitro-L-Arginine Methyl Ester-Induced Hypertension and Cardiorenal Dysfunction

Temidayo Olutayo Omóbòwálé; Ademola Adetokunbo Oyagbemi; Blessing Seun Ogunpolu; Olufunke Eunice Ola-Davies; Johnny Olufemi Olukunle; Ebunoluwa Racheal Asenuga; Temitayo Olabisi Ajibade; Olumuyiwa Abiola Adejumobi; Jeremiah Moyinoluwa Afolabi; Olufunke Olubunmi Falayi; Anofi Ashafa; Adeolu Alex Adedapo; Momoh Audu Yakubu

doi:10.1055/a-0635-0638

Drug Research, Table of Contents

Drug Res (Stuttg) 2019; 69(01): 12-22
DOI: 10.1055/a-0635-0638

Original Article

Antihypertensive Effect of Polyphenol-Rich Fraction of Azadirachta indica on Nω-Nitro-L-Arginine Methyl Ester-Induced Hypertension and Cardiorenal Dysfunction

Temidayo Olutayo Omóbòwálé

¹Department of Veterinary Medicine, Faculty of Veterinary Medicine, University of Ibadan, Ibadan, Nigeria

,

Ademola Adetokunbo Oyagbemi

²Department of Veterinary Physiology and Biochemistry, Faculty of Veterinary Medicine, University of Ibadan, Ibadan, Nigeria

,

Blessing Seun Ogunpolu

¹Department of Veterinary Medicine, Faculty of Veterinary Medicine, University of Ibadan, Ibadan, Nigeria

,

Olufunke Eunice Ola-Davies

²Department of Veterinary Physiology and Biochemistry, Faculty of Veterinary Medicine, University of Ibadan, Ibadan, Nigeria

,

Johnny Olufemi Olukunle

³Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine, Federal University of Agriculture, Abeokuta, Nigeria

,

Ebunoluwa Racheal Asenuga

⁴Department of Veterinary Physiology and Biochemistry, Faculty of Veterinary Medicine, University of Benin, Benin City, Nigeria

,

Temitayo Olabisi Ajibade

²Department of Veterinary Physiology and Biochemistry, Faculty of Veterinary Medicine, University of Ibadan, Ibadan, Nigeria

,

Olumuyiwa Abiola Adejumobi

¹Department of Veterinary Medicine, Faculty of Veterinary Medicine, University of Ibadan, Ibadan, Nigeria

,

Jeremiah Moyinoluwa Afolabi

¹Department of Veterinary Medicine, Faculty of Veterinary Medicine, University of Ibadan, Ibadan, Nigeria

,

Olufunke Olubunmi Falayi

⁵Department of Veterinary Pharmacology and Toxicology, Faculty of Veterinary Medicine, University of Ibadan, Ibadan, Nigeria

,

Anofi Ashafa

⁶Faculty of Natural and Agricultural Sciences, Qwaqwa Campus, University of the Free State, Phuthaditjaba, South Africa

,

Adeolu Alex Adedapo

⁴Department of Veterinary Physiology and Biochemistry, Faculty of Veterinary Medicine, University of Benin, Benin City, Nigeria

,

Momoh Audu Yakubu

⁷Department of Environmental & Interdisciplinary Sciences, College of Science, Engineering & Technology, Vascular Biology Unit, Center for Cardiovascular Diseases, COPHS, Texas Southern University, Houston, TX, USA

› Author Affiliations

Abstract

Azadirachta indica (AI) is a medicinal plant with reported antioxidant and cardio-protective properties. The use of plant-based polyphenols has become greatly increased in the last one decade. The present study investigated the protective effect of the polyphenol-rich fraction (PRF) of the methanol-extract of Azadirachta indica against N^ω-Nitro-L-Arginine Methyl Ester (L-NAME) induced hypertension and cardiorenal dysfunction in rats. Fifty (50) Wistar albino rats were grouped into five groups. Group A, the control, was administered potable water. Groups B-E received orally, 40 mg/kg of L-NAME only, 40 mg/kg of L-NAME and 100 mg/kg of AI extract, 40 mg/kg of L-NAME and 200 mg/kg of AI extract, and 40 mg/kg of L-NAME and 25 mg/kg of captopril, respectively for 21 days. The results of the present study revealed that L-NAME administration led to a significant increase in systolic blood pressure, diastolic blood pressure, and mean arterial blood pressure. Markers of oxidative stress (malondialdehyde,protein carbonyl) increased significantly while there was reduction in reduced glutathione level, activities of superoxide dismutase, glutathione peroxidase and glutathione-S-transferase as well nitric oxide bioavailability. Immunohistochemistry revealed higher expressions of nuclear factor kappa beta (NF-kB) and kidney injury molecule 1(Kim-1) and lower expressions of nuclear factor erythroid 2–related factor 2 (Nrf2) in hypertensive rats. Our results indicated that with PRF of AI restored high blood pressure, reduced markers of oxidative stress, normalized serum NO bioavailability and increased the expressions of Nrf2. Hence, PRF of Azadirachta indica could be used for the treatment of hypertension.

Key words

Azadirachta indica - hypertension - oxidative stress - renal damage - cell signaling

Full Text

References

References
1 Quam L, Smith R, Yach D. Rising to the global challenge of the chronic disease epidemic. Lancet 2006; 368: 1221-1223
2 Gu D, Reynolds K, Wu X. et al. InterASIA Collaborative Group, The International Collaborative Study of Cardiovascular Disease in ASIA (2002). Prevalence, awareness, treatment, and control of hypertension in China. Hypertension 2002; 40: 920-927
3 Roth GA, Huffman MD, Moran AE. et al. Global and regional patterns in cardiovascular mortality from 1990 to 2013. Circulation 2015; 132: 1667-1678
4 Binda D, Nicod L, Viollon-Abadie C. et al. Strain difference (WKY, SPRD) in the hepatic antioxidant status in rat and effect of hypertension (SHR, DOCA). Ex vivo and in vitro data. Mol Cell 218: 139-146
5 Chobanian AV, Bakris GL, Black HR. et al. JNC 7: Complete report-seventh report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Hypertension 2003; 42: 1206-1252
6 Tian D, Ling S, Chen G. et al. Hypertensive nephropathy treatment by heart-protecting musk pill: A study of anti-inflammatory therapy for target organ damage of hypertension. Int J Gen Med 2011; 4: 131-139
7 Mancia G, Fagard R, Narkiewicz K. et al. ESH/ESC guidelines for the management of arterial hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2013; 22: 193-278
8 Bartges JW, Willis AM, Polzin DJ. Hypertension and renal disease. Clin North Am Food Anim Pract 1996; 26: 1331-1345
9 Whitworth JA. World Health Organization, International Society of Hypertension Writing Group. World Health Organization (WHO)/International Society of Hypertension (ISH) statement on management of hypertension. J Hypertens 2003: 21: 1983–1992
10 Lloyd-Jones DM, Adams R, Carnethon M. et al. Heart disease and stroke statistics – 2009 update: A report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2009; 119: 480-486
11 Saravanakumar M, Raja B. Veratric acid, a phenolic acid attenuates blood pressure and oxidative stress in L-NAME induced hypertensive rats. Eur J Pharmacol 2011; 671: 87-94
12 Matsushita K, Morrell CN, Cambien B. et al. Nitric oxide regulates exocytosis by S-nitrosylation of N-ethylmaleimide-sensitive factor. Cell 2003; 115: 139-150
13 Morrell CN, Matsushita K, Chiles K. et al. Regulation of platelet granule exocytosis by S-nitrosylation. Proc. Natl. Acad. Sci. U.S.A 2005; 102: 3782-3787
14 Attia DM, Verhagen AMG, Stroes ES. et al. Vitamin E alleviates renal injury, but not hypertension, during chronic nitric oxide synthase inhibition in rats. Clin J Am Soc Nephrol 2001; 12: 2585-2593
15 Qian Z, Gelzer-Bell R, Yang SX. et al. Inducible nitric oxide synthase inhibition of weibel-palade body release in cardiac transplant rejection. Circulation 2001; 104: 2369-2375
16 Wagner DD. The Weibel-Palade body: The storage granule for von Willebrand factor and P-selectin. Thromb Haemost 1993; 70: 105-110
17 Manning Jr RD, Hu L, Mizelle HL. et al. Cardiovascular responses to long-term blockade of nitric oxide synthesis. Hypertension 1993; 22: 40-48
18 Henrion D, Dowell FJ, Levy BI. et al. In vitro alteration of aortic vascular reactivity in hypertension induced by chronic NG-nitro-L-arginine methyl ester. Hypertension 1996; 28: 361-366
19 Maneesai P, Prasarttong P, Bunbupha S. et al. Synergistic antihypertensive effect of Carthamus tinctorius L. extract and captopril in L-NAME-induced hypertensive rats via restoration of eNOS and AT1R expression. Nutrients 2016; 8: 122
20 Rauchová H, Pecháňová O, Kuneš J. et al. Chronic N-acetylcysteine administration prevents development of hypertension in Nω-nitro-L-arginine methyl ester-treated rats: The role of reactive oxygen species. Hypertens Res 2005; 28: 475-482
21 Jaarin K, Foong WD, Yeoh MH. et al. Mechanisms of the antihypertensive effects of Nigella sativa oil in L-NAME-induced hypertensive rats. Clinics 2015; 70: 751-757
22 World Health Organization. WHO traditional medicine strategy. 2002. 2005
23 Tilburt J, Kaptchuk T. Herbal medicine research and global health: An ethical analysis. Bull World Health Organ 2008; 577-656
24 Adedapo AD, Adeagbo AS, Adedapo AA. Use of botanical therapies among patients in secondary health facilities in southwest Nigeria: Implications for medical education. Recent Progress in Medicinal Plants 2012; 35: 293-304
25 Obiefuna I, Young R. Concurrent administration of aqueous Azadirachta indica (Neem) leaf extract with DOCA salt prevents the development of hypertension and accompanying electrocardiogram changes in the rat. Phytother Res 2005; 19: 792-795
26 Ogbuewu IP, Odoemenam VU, Obikaonu HO. et al. The growing importance of neem (Azadirachta indica A. Juss) in agriculture, industry, medicine and environment: A review. Res J Med Plant 2011; 5: 230-245
27 Omobowale TO, Oyagbemi AA, Oyewunmi OA. et al. Chemopreventive effect of methanolic extract of Azadirachta indica on experimental Trypanosoma brucei induced oxidative stress in dogs. Pharmacognosy Res 2015; 7: 249-258
28 Dwivedi VD, Tripathi IP, Mishra SK. In silico evaluation of inhibitory potential of triterpenoids from Azadirachta indica against therapeutic target of dengue virus, NS2B-NS3 protease. J Vector Borne Dis 2016; 53: 156-161
29 Rinaldi F, Hanieh PN, Longhi C. et al. Neem oil nanoemulsions: Characterisation and antioxidant activity. J Enzyme Inhib Med Chem 2017; 32: 1265-1273
30 Lu XF, Dai DM, Yu RM. et al. [Limonoids from seeds of Azadirachta indica and their cytotoxic activity]. Zhongguo Zhong Yao Za Zhi 2018; 43: 537-543
31 Habila N, Humphrey NC, Abel AS. Trypanocidal potentials of Azadirachta indica seeds against Trypanosoma evansi. Vet Parasitol 2011; 180: 173-178
32 Oyagbemi AA, Omobowale TO, Ochigbo GO. et al. Polyphenol-Rich Fraction of Parquetina nigrescens Mitigates Dichlorvos-Induced Cardiorenal Dysfunction Through Reduction in Cardiac Nitrotyrosine and Renal p38 Expressions in Wistar Rats. J Diet Suppl 2018; 15: 269-284
33 Misra HP, Fridovich I. The role of superoxide anoin in the autoxidation of epinephrine and a simple assay for superoxide dismutase. J Biol Chem 1972; 217: 3170-3175
34 Oyagbemi AA, Omobowale TO, Akinrinde AS. et al. Lack of reversal of oxidative damage in renal tissues of lead acetate-treated rats. Environ Toxicol 2015; 30: 1235-1243
35 Omobowale TO, Oyagbemi AA, Akinrinde AS. et al. Failure of recovery from lead induced hepatoxicity and disruption of erythrocyte antioxidant defence system in Wistar rats. Environ Toxicol Pharmacol 2014; 37: 1202-1211
36 Crespo E, Macías M, Pozo D. et al. Melatonin inhibits expression of the inducible NO synthase II in liver and lung and prevents endotoxemia in lipopolysaccharide-induced multiple organ dysfunction syndrome in rats. FASEB J 1999; 13: 1537-1546
37 Green LC, De Luzuriaga KR, Wagner DA. et al. Nitrate biosynthesis in man. Proc. Natl. Acad. Sci. U.S.A 1981; 78: 7764-7768
38 Beutler E, Duron O, Kelly BM. Improved method for the determination of blood glutathione. J Lab Clin Med 1963; 61: 882-888
39 Habig WH, Pabst MJ, Jakoby WB. Glutathione S-transferases. The first enzymatic step in mercapturic acid formation. J Biol Chem 1974; 249: 7130-7139
40 Ellman GL. Tissue sulfhydryl groups. Arch Biochem Biophys 1959; 82: 70-77
41 Varshney R, Kale R. Effects of calmodulin antagonists on radiation-induced lipid peroxidation in microsomes. Int J Radiat Biol 1990; 58: 733-743
42 Woff S. Ferrous ion oxidation in the presence of ferric ion indicator xylenol orange for measurement of hydrogen peroxides. Methods Enzymol 1994; 233: 182-189
43 Xia Y, Zweier JL. Measurement of myeloperoxidase in leukocyte-containing tissues. Anal Biochem 1997; 245: 93-96
44 Oyagbemi AA, Omobowale TO, Asenuga ER. et al. Sodium fluoride induces hypertension and cardiac complications through generation of reactive oxygen species and activation of nuclear factor kappa beta. Environ Toxicol 2017; 32: 1089-1101
45 Afkir S, Nguelefack TB, Aziz M. et al. Arbutus unedo prevents cardiovascular and morphological alterations in L-NAME-induced hypertensive rats: Part I: Cardiovascular and renal hemodynamic effects of Arbutus unedo in L-NAME-induced hypertensive rats. J Ethnopharmacol 2008; 116: 288-295
46 Schannwell CM, Hennersdorf MG, Strauer BE. Hypertension and cardiac failure Internist (Berl). 2007; 48: 909-920
47 Favero G, Paganelli C, Buffoli B et al. Endothelium and its alterations in cardiovascular diseases: Life style intervention. BioMed research international 2014 Feb 26 2014
48 Chalupsky K, Kračun D, Kanchev I. et al. Folic acid promotes recycling of tetrahydrobiopterin and protects against hypoxia-induced pulmonary hypertension by recoupling endothelial nitric oxide synthase. Antioxid Redox Signal 2015; 23: 1076-1091
49 Abdel-Wahhab MA, Abdel-Azim SH, El-Nekeety AA. Inula crithmoides extract protects against ochratoxin A-induced oxidative stress, clastogenic and mutagenic alterations in male rats. Toxicon 2008; 52: 566-573
50 Wu J, Saleh MA, Kirabo A. et al. Immune activation caused by vascular oxidation promotes fibrosis and hypertension. J Clin Invest 2016; 126: 50-67
51 Jones DP, Carlson JL, Mody VC. Redox state of glutathione in human plasma. Free Radic Biol Med 2000; 28: 625-635
52 Annadurai T, Muralidharan AR, Joseph T. et al. Antihyperglycemic and antioxidant effects of a flavanone, naringenin, in streptozotocin-nicotinamide-induced experimental diabetic rats. J Physiol Biochem 2012; 68: 307-318
53 Shodehinde SA, Oboh G. Antioxidant properties of aqueous extracts of unripe Musa paradisiaca on sodium nitroprusside induced lipid peroxidation in rat pancreas in vitro. Asian Pac J. Trop Biomed 2013; 3: 449-457
54 Cumaoglu A, Cevik C, Rackova L. et al. Effects of antioxidant stobadine on protein carbonylation, advanced oxidation protein products and reductive capacity of liver in streptozotocin-diabetic rats: Role of oxidative/nitrosative stress. Biofactors 2007; 30: 171-178
55 Negre-Salvayre A, Coatrieux C, Ingueneau C. et al. Advanced lipid peroxidation end products in oxidative damage to proteins. Potential role in diseases and therapeutic prospects for the inhibitors. Br J Pharmacol 2005; 153: 6-20
56 Zang KH, Rao Z, Zhang GQ. et al. Anticolitis activity of chinese herbal formula Yupingfeng powder via regulating colonic enterochromaffin cells and serotonin. Indian J Pharmacol 2015; 47: 632-637
57 Xu H, Cabezas-Rodriguez I, Qureshi AR. et al. Increased levels of modified advanced oxidation protein products are associated with central and peripheral blood pressure in peritoneal dialysis patients. Perit Dial Int 2015; 35: 460-470
58 Seelhammer TG, Maile MD, Heung M. et al. Kinetic estimated glomerular filtration rate and acute kidney injury in cardiac surgery patients. J Crit Care 2016; 31: 249-254
59 Pangjit K, Tantiphaipunwong P, Sajjapong W. et al. Iron-chelating, freeradical scavenging and anti-proliferative activities of Azadirachta indica. J Med Assoc Thai 2014; (Suppl. 04) S36-S43
60 Frantz S, Fraccarollo D, Wagner H. et al. Sustained activation of nuclear factor kappa B and activator protein 1 in chronic heart failure. Cardiovascular research 2003; 57: 749-756
61 Dornas WC, Cardoso LM, Silva M. et al. Oxidative stress causes hypertension and activation of nuclear factor-κB after high-fructose and salt treatments. Sci Rep 2017; 7: 46051
62 Baldwin Jr AS. The NF-kappa B and I kappa B proteins: New discoveries and insights. Annu Rev Immunol 1996; 14: 649-683
63 Humphreys BD, Xu F, Sabbisetti V. et al. Chronic epithelial kidney injury molecule-1 expression causes murine kidney fibrosis. J Clin Invest 2013; 123: 4023-4035