• Badiaa Aklil Université Des Frères Mentouri-Constantine, Département de Biologie Animale, Laboratoire d’Obtention de Substances Thérapeutiques (L.O.S.T), 25000 Constantine, Algeria
  • Sakina Zerizer Université Des Frères Mentouri-Constantine, Département de Biologie Animale, Laboratoire d’Obtention de Substances Thérapeutiques (L.O.S.T), 25000 Constantine, Algeria
  • Zahia Kabouche Université Des Frères Mentouri-Constantine, Département de Biologie Animale, Laboratoire d’Obtention de Substances Thérapeutiques (L.O.S.T), 25000 Constantine, Algeria


Objective : Hyperhomocysteinemia (HHcy), oxidative stress and decreased antioxidant capacities lead to several clinical manifestations and particularly, cardiovascular and liver diseases.  Our aim in this study was to investigate the protective effect of Argania spinosa crude exctract against high methionine diet  induced  HHcy ,  oxidative stress and damages in the aorta, and  heart of mice.

Materials and methods: Adult male Mus Musculus were systematically divided into four groups of similar mean body weights and fed for 21 days with control and experimental diets. The control group (F) was fed with white bread (0.50mg/mice), group (M) was fed with L-methionine (500mg/kg/day), group (MP) was fed with L-methionine (500mg/kg/day) plus A.spinosa crude extract (150mg/kg), and the group (P) was treated with A.spinosa crude extract (150mg/kg/day). The experimental diets were given in white bread (0.50mg/mice). After 3 weeks of treatments, homocysteine (Hcy) concentrations, hepatic antioxidant status and histological sections of aorta and heart were determined.

Results: Consumption of high methionine diet led to an increase in plasma Hcy , reduced the concentrations of GSH, and  the enzyme catalase. These were associated with the loss and degeneration of endothelium, fenestration and formation of foam cells of aorta, also the alteration of the cardiac muscle. However, administration of A.spinosa crude extract in combination  with methionine ameliorated all these changes.

Conclusion:  A.spinosa crude extract is effective in decreasing plasma Hcy level as induced by methionine enriched diet in mice,   and improves the antioxidants defense.

Keywords: Homocysteine, Argania spinosa, Antioxidant enzymes, Methionine, Oxidative stress, Cardiovascular diseases.


Download data is not yet available.


1. Selicharova I, Korinek M, Demianova Z, Chrudinova M, Mladkova J, Jiracek J. Effects of hyperhomocysteinemia and betaine-homocysteine S-methyltransferase inhibition on hepatocyte metabolites and the proteome. Biochim Biophysica Acta 2013;1834:1596–606.
2. Agoston-Coldea L, Mocan T, Gatfosse M, Lupu S, Dumitrascu DL. Plasma homocysteine and the severity of heart failure in patients with previous myocardial infarction. Cardiol J 2011;18:55–62.
3. Wang X, Cui L, Joseph J, Jiang B, Pimental D, Handy DE. Homocysteine induces cardiomyocyte dysfunction and apoptosis through p38 MAPK mediated increase in oxidant stress. J Mol Cell Cardiol 2012;52:753–60.
4. Faraci FM, Lentz SR. Hyperhomocysteinemia, oxidative stress, and cerebral vascular dysfunction. Stroke 2004;35:345-7.
5. Clarke R, Daly L, Robinson K. Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med 1999;324:1149–55.
6. Adinolfi LE, Ingrosso D, Cesaro G, Cimmino A, D’Anto M, Capasso R, et al. Hyperhomocysteinemia and the MTHFR C677T polymorphism promote steatosis and fibrosis in chronic hepatitis C patients. Hepatology 2005;41:995–1003.
7. Roblin X, Pofelski J, Zarski JP. Steatosis, chronic hepatitis virus C infection and homocysteine. Gastroenterol Clin Biol 2007;31:415–20.
8. Glushchenko AV, Jacobsen DW. Molecular targeting of proteins by L-homocysteine: mechanistic implications for vascular disease. Antioxid Redox Signal 2007;9:1883–98.
9. Hogg N. The effect of cysteine on the auto-oxidation of homocysteine. Free Radical Biol Med 1999;27:28-33.
10. Stipanuk MH. Sulfur amino acid metabolism: pathways for production and removal of homocysteine and cysteine. Annu Rev Nutr 2004;24:539-77.
11. Eberhardt RT, Forgione MA, Cap A, Leopold JA, Rudd MA, Trolliet M, et al. Endothelial dysfunction in a murine model of mild hyperhomocysteinemia. J Clin Invest 2000;106:483–91.
12. Zhang R, Ma J, Xia M, Zhu H, Ling W. Mild hyperhomocysteinemia induced by feeding rats diets rich in methionine or deficient in folate promotes early atherosclerotic inflammatory processes. J Nutr 2004;134:825–30.
13. Afaf A, Sayed S. Lipid profile and levels of homocysteine and total antioxidant capacity in plasma of rats with experimental thyroid disorders. J Basic Appl Zool 2015;72:173–8.
14. Jacobsen DW. Hyperhomocysteinemia and oxidative stress: time for a reality check? Arterioscler Thromb Vascular Biol 2000;20:1182–4.
15. Landmesser U, Dikalov S, Price SR, McCann L, Fukai T, Holland SM, et al. Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension. J Clin Invest 2003;111:1201–9.
16. Cha JY, Repa J. The liver X receptor (LXR) and hepatic lipogenesis: the carbohydrate-response element-binding protein is a target gene of LXR. J Biol Chem 2007;282:743-51.
17. Denechaud PD, Bossard P, Lobaccaro JM, Millatt L, Staels B, Girard J. ChREBP, but not LXRs, is required for the induction of glucose-regulated genes in mouse liver. J Clin Invest 2008;118:956-64.
18. Dentin R, Benhamed F, Hainault I, Fauveau V, Foufelle F, Dyck JR. Liver-specifi c Inhibition of ChREBP improves hepatic steatosis and insulin resistance in ob/ob mice. Diabetes 2006;55:2159-70.
19. Charrouf Z, Guillaume D. Ethnoeconomical, ethnomedical, and phytochemical study of Argania spinosa (L.) Skeels. J Ethnopharmacol 1999;67:7–14.
20. Necib Y, Bahi A, Zerizer S. Argan oil (Argania spinosa L) Provides protection against mercuric chloride induced oxidative stress in rat Albinos Wistar. Int J Basic Appl Sci 2013;2:73-80.
21. Cherki M, Berrougui H, Drissi A, Adlouni A, Khalil A. Argan oil: which benefits on cardiovascular diseases? Pharmacol Res 2006;54:1–5.
22. Bradford MA. Rapid and sensitive method for the quantities of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976;72:248-54.
23. Weckbercker G, Cory JG. Ribonucleotide reductase activity and growth of glutathione-depended mouse leukaemia L 1210 cells in vitro. Cancer Lett 1988;40:257-64.
24. Aebi H. Catalase: methods for enzymatic analysis. Acadamic Press 1974;2:674‐ 84.
25. Curro M, Gugliandolo A, Gangemi C, Risitano R, Ientile R, Caccamo D. Toxic effects of mildly elevated homocysteine concentrations in neuronal-like cells. Neurochem Res 2014;39:1485–95.
26. Faeh D, Chiolero A, Paccaud F. Homocysteine as a risk factor for cardiovascular disease: should we (still) worry about it? Swiss Med Wkly 2006;136:745–56.
27. Baszczuk A, Kopczynski Z. Hyperhomocysteinemia in patients with cardiovascular disease. Postepy Hig Med Dosw 2014;68:579.
28. Mudd SH. Hypermethioninemias of genetic and non-genetic origin: a review. J Med Genet C Semin Med Genet 2011;157:3–32.
29. Viggianoa A, Viggianoa E, Mondaa M, Ingrossob D, Pernac AF, Luca BD. Methionine-enriched diet decreases hippocampal antioxidant defences and impairs spontaneous behaviour and long-termpotentiation in rats. Brain Res 2012;1471:66-74.
30. Yamada H, Akahoshi N, Kamata S, Hagiya Y, Hishiki T, Nagahata Y, et al. Methionine excess in diet induces acute lethal hepatitis in mice lacking cystathionine γ-lyase, an animal model of cystathioninuria. Free Radical Biol Med 2012;52:1716-26.
31. Kirac D, Negis Y, Ozer NK. Vitamin E attenuates homocysteine and cholesterol induced damage in rat aorta. Cardiovascular Pathol 2013;22:465–72.
32. Welch GN, Upchurch GR, Farivar RS, Pigazzi A, Vu K, Brecher P. Homocysteine-induced nitric oxide production in vascular smooth muscle cells by NF-kappaB dependent transcriptional activation of Nos2. Proc Assoc Am Physicians 1998;110:22–31.
33. Stipanuk MH, Dominy JE, Lee JI, Coloso RM. Mammalian cysteine metabolism: new insights into the regulation of cysteine metabolism. J Nutr 2006;136:1652S-59S.
34. Milton NGN. Homocysteine inhibits hydrogen peroxide breakdown by catalase. Open Enzyme Inhibition J 2008;1:34–41.
35. Góth L, Rass P, Pay A. Catalase enzyme mutations and their association with diseases. Mol Diagn 2004;8:141-9.
36. Ho YS, Xiong Y, Ma W, Spector A, Ho DS. Mice lacking catalase develop normally but show differential sensitivity to oxidant tissue injury. J Biol Chem 2004;279:32804-12.
37. Margoliash E, Novogrodsky A. A study of the inhibition of catalase by 3-amino-1:2:4:-triazole. Biochem J 1958;68:468-75.
38. Putnam CD, Arvai AS, Bourne Y, Tainer JA. Active and inhibited human catalase structures: ligand and NADPH binding and catalytic mechanism. J Mol Biol 2000;296:295-309.
39. Milton NGN. Amyloid-ß binds catalase with high affinity and inhibits hydrogen peroxide breakdown. Biochem J 1999;344:293-6.
40. Benmebarek A, Zerizer S, Laggoune S, Kabouche Z. Effect of Stachys mialhesi de Noé on the inflammation induced by hyperhomocysteinemia in cardiovascular diseases. Scholar Res Library 2013;5:212-23.
41. Gallai V, Caso V, Paciaroni M, Cardaioli G, Arning E, Bottiglieri T, et al. Mild hyperhomocysteinemia: a possible risk factor for cervical artery dissection. Stroke 2001;32:714–8.
42. Papatheodorou L, Weiss N. Vascular oxidant stress and inflammation in hyperhomocysteinemia. Antioxid Redox Signal 2007;9:1941–58.
43. Lamda S, Aggoun C, Naimi D. The effects of homocysteine on plasma biochemical parameters and aortic matrix metalloproteinases activities. Innov Acad Sci 2014;7:975-491.
44. Pacher P, Beckman JS, Liaudet L. Nitric oxide and peroxynitrite in health and disease. Physiol Rev 2007;87:315–424.
45. Cooke JP, Dzau VJ. Nitric oxide synthase: role in the genesis of vascular disease. Annu Rev Med 1997;48:489–509.
46. Kanani PM, Sinkey CA, Browning RL, Allaman M, Knapp HR, Haynes WG. Role of oxidant stress in endothelial dysfunction produced by experimental hyperhomocysteinemia in humans. Circulation 1999;100:1161–8.
47. Rolland PH, Friggi A, Barlatier A. Hyperhomocysteinemia-induced vascular damage in the minipig. Captopril-hydrochlorothiazide combination prevents elastic alterations. Circulation 1995;91:1161–74.
48. Zulli A, Hare DL. High dietary methionine plus cholesterol stimulates early atherosclerosis and late fibrous cap development which is associated with a decrease in GRP78 positive plaque cells. Int J Exp Pathol 2009;90:311–20.
49. Raghuveer G, Sinkey CA, Chenard C, Stumbo P, Haynes WG. Effect of vitamin E on resistance vessel endothelial dysfunction induced by methionine. Am J Cardiol 2001;88:285–90.
50. Barbato JC, Catanescu O, Murray K, DiBello PM, Jacobsen DW. Targeting of metallothionein by L-homocysteine: a novel mechanism for disruption of zinc and redox homeostasis. Arterioscler Thromb Vasc Biol 2007;27:49–54.
51. Hamelet J, Demuth K, Dairou J, Ledru A, Paul JL, Dupret JM. Effects of catechin on homocysteine metabolism in hyperhomocysteinemic mice. Biochem Biophys Res Commun 2007;355:221–7.
52. Yalc S, Unlucerci Y, Giris M, Olgac V, Dogru-Abbasoglu S, Uysal M. Oxidative and nitrosative stress and apoptosis in the liver of rats fed on high methionine diet: protective effect of taurine. J Nutr 2009;25:436–44.
53. Meng MD, Weina MD, Ph D, Jingyu BS, Jijun BS, Jianquan MD. Quercetin reduces serum homocysteine level in rats fed a methionine-enriched Diet. J Nutr 2013;29:661–6.
54. Masella R, Giovannini C, Vari R, Di Benedetto R, Coni E, Volpe R. Effect of dietary virgin olive oil phenols on low-density lipoprotein oxidation in hyperlipidemic patients. Lipids 2001;36:1195–202.
55. Ketterer B. Glutathione-S-transferase and prevention of cellular free radical damage. Free Radical Resear 1998;28:647-58.
56. Benajiba N, Morel S, De Leiris J, Boucher F, Charrouf Z, Mokhtar N. The effect of argan oil on heart function during ischemia and reperfusion. Therapie 2002;57:246-52.
57. Zerizer S, Naimi D. Homocysteine: an independent risk factor in the atherogenic process. Egyptian Pharm J 2004;3:110-4.
58. Zerizer S, Zaher K, Boutaghane N, Laggoune S, Kabouche Z. Comparative effect of Chrysanthemum Macrocarpum and Stachys Mialhesi on the rat's aorta exposed to homocysteine with B Vitamins. Scottish J Arts Soc Sciences Scientific Studies 2008;6:2047-1278.
59. Kale MA, Bindu SM, Khadkikar P. Role of antioxidants and nutrition in oxidative stress: a review. Int J Appl Pharm 2015;7:975-7058.
60. kumar SV, Saritha G, Fareedullah Md. Role of antioxidants and oxidative stress in cardiovascular diseases. A Biol Res 2010;1:158-73.
61. Duffy SJ, Vita JA. Effects of phenolics on vascular endothelial function. Curr Opin Lipidol 2003;14:21–7.
405 Views | 753 Downloads
How to Cite
Aklil, B., S. Zerizer, and Z. Kabouche. “THE PROTECTIVE EFFECTS OF ARGANIA SPINOSA SEEDS AGAINST HYPERHOMOCYSTENEMIA INDUCED BY HIGH METHIONINE DIET IN MICE”. International Journal of Pharmacy and Pharmaceutical Sciences, Vol. 9, no. 12, Dec. 2017, pp. 64-69, doi:10.22159/ijpps.2017v9i12.18275.
Original Article(s)