Journal of APPLIED BIOMEDICINE
ISSN 1214-0287 (on-line)
ISSN 1214-021X (printed)

Volume 5 (2007), No 2, p 105-113




Urtica dioica extract reduces platelet hyperaggregability in type 2 diabetes mellitus by inhibition of oxidant production, Ca2+ mobilization and protein tyrosine phosphorylation

Mohammed El Haouari, Isaac Jardin, Hasane Mekhfi, Juan A. Rosado, Gines M. Salido

Address: J. A. Rosado, Department of Physiology, University of Extremadura, Av. Universidad s/n. Caceres 10071, Spain
jarosado@unex.es

Received 21st March 2007.
Revised 23rd April 2007.
Published online 7th May 2007.

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SUMMARY
Platelet hyperaggregability is involved in the pathogenesis of type 2 diabetes mellitus. Thrombin-evoked platelet aggregation includes the activation of several intracellular pathways, including endogenous generation of reactive oxygen species (ROS), Ca2+ mobilization and protein tyrosine phosphorylation. Here we show that crude aqueous extract from Urtica dioica reduces thrombin-evoked aggregation in platelets from healthy donors and diabetics, in a concentration-dependent manner. U. dioica extract showed a potent antioxidant activity and prevented thrombin-evoked ROS generation in platelets from healthy and diabetic donors. Treatment with U. dioica extract reduced Ca2+ entry induced by thrombin or selective depletion of the two Ca2+ stores in platelets (without altering Ca2+ release), reduced protein tyrosine phosphorylation and reversed the abnormal Ca2+ mobilization and tyrosine phosphorylation in platelets from diabetics. We conclude that extract from U. dioica shows antiaggregant actions and might be used for the treatment and/or prevention of cardiovascular complications associated with type 2 diabetes mellitus.

KEY WORDS
platelets; type 2 diabetes mellitus; Urtica dioica; calcium mobilization; antioxidant; tyrosine phosphorylation


REFERENCES
Belton OA, Duffy A, Toomey S, Fitzgerald DJ: Cyclooxygenase isoforms and platelet vessel wall interactions in the apolipoprotein E knockout mouse model of atherosclerosis. Circulation 108:3017-3023, 2003.

Ben-Amor N, Redondo PC, Bartegi A, Pariente JA, Salido GM, Rosado JA: A role for 5,6- epoxyeicosatrienoic acid in calcium entry by de novo conformational coupling in human platelets. J Physiol 570:309-323, 2006.

Blankenship KA, Dawson CB, Aronoff GR, Dean WL: Tyrosine phosphorylation of human platelet plasma membrane Ca2+-ATPase in hypertension. Hypertension 35:103-107, 2000.

Blann AD, Nadar S, Lip GY: Pharmacological modulation of platelet function in hypertension. Hypertension 42:1-7, 2003.

Bnouham M, Merhfour FZ, Ziyyat A, Mekhfi H, Aziz M, Legssyer A: Antihyperglycemic activity of the aqueous extract of Urtica dioica. Fitoterapia 74:677-681, 2003.

Dixon LJ, Hughes SM, Rooney K, Madden A, Devine A, Leahey W, Henry W, Johnston GD, McVeigh GE: Increased superoxide production in hypertensive patients with diabetes mellitus: role of nitric oxide synthase. Am J Hypertens 18:839-843, 2005.

Dogne JM, Leval XD, Benoit P, Delarge J, Masereel B, David JL: Recent advances in antiplatelet agents. Curr Med Chem 9:577-589, 2002.

El Haouari M, Bnouham M, Bendahou M, Aziz M, Ziyyat A, Legssyer A, Mekhfi H: Inhibition of rat platelet aggregation by Urtica dioica leaves extracts. Phytother Res 20:568-572, 2006.

Garnier G, Bezanger-Beauquesne L, Debraux G: Ressources medicinales de la flore francaise, Vol 2, Vigot Freres, Paris 1961, pp. 962-964.

Grynkiewicz G, Poenie M, Tsien RY: A new generation of Ca2+ indicators with greatly improved fluorescence properties. J Biol Chem 260:3440-3450, 1985.

Jardin I, Redondo PC, Salido GM, Pariente JA, Rosado JA: Endogenously generated reactive oxygen species reduce PMCA activity in platelets from patients with non-insulin dependent diabetes mellitus. Platelets 17:283-288, 2006.

Legssyer A, Ziyyat A, Mekhfi H, Bnouham M, Tahri A, Serhrouchni M, Hoerter J, Fischmeister R: Cardiovascular effects of Urtica dioica L. in isolated rat heart and aorta. Phytother Res 16:503-507, 2002.

Lopez JJ, Redondo PC, Salido GM, Pariente JA, Rosado JA: Two distinct Ca2+ compartments show differential sensitivity to thrombin, ADP and vasopressin in human platelets. Cell Signal 18:373-381, 2006.

Mandal S, Sarode R, Dash S, Dash RJ: Hyperaggregation of platelets detected by whole blood platelet aggregometry in newly diagnosed noninsulin-dependent diabetes mellitus. Am J Clin Pathol 100:103-107, 1993.

Minuz P, Fumagalli L, Gaino S, Tommasoli RM, Degan M, Cavallini C, Lecchi A, Cattaneo M, Lechi Santonastaso C, Berton G: Rapid stimulation of tyrosine phosphorylation signals downstream of G-protein-coupled receptors for thromboxane A2 in human platelets. Biochem J 15:127-134, 2006.

Pignatelli P, Pulcinelli FM, Lenti L, Gazzaniga PP, Violi F: Hydrogen peroxide is involved in collagen-induced platelet activation. Blood 91:484-490, 1998.

Redondo PC, Jardin I, Hernandez-Cruz JM, Pariente JA, Salido GM, Rosado JA: Hydrogen peroxide and peroxynitrite enhance Ca2+ mobilization and aggregation in platelets from type 2 diabetic patients. Biochem Biophys Res Commun 334:779-786, 2005.

Rosado JA, Graves D, Sage SO: Tyrosine kinases activate store-mediated Ca2+ entry in human p latelets through the reorganization of the actin cytoskeleton. Biochem J 351:429-437, 2000.

Rosado JA, Lopez JJ, Harper AG, Harper MT, Redondo PC, Pariente JA, Sage, SO, Salido GM: Two pathways for store-mediated calcium entry differentially dependent on the actin cytoskeleton in human platelets. J Biol Chem 279:29231-29235, 2004a.

Rosado JA, Porras T, Conde M, Sage SO: Cyclic nucleotides modulate store-mediated calcium entry through the activation of protein-tyrosine phosphatases and altered actin polymerization in human platelets. J Biol Chem 276:15666-15675, 2001.

Rosado JA, Redondo PC, Salido GM, Gomez- Arteta E, Sage SO, Pariente JA: Hydrogen peroxide generation induces pp60src activation in human platelets: evidence for the involvement of this pathway in store-mediated calcium entry. J Biol Chem 279:1665-1675, 2004b.

Rosado JA, Saavedra FR, Redondo PC, Hernandez- Cruz JM, Salido GM, Pariente JA: Reduced plasma membrane Ca2+-ATPase function in platelets from patients with non-insulindependent diabetes mellitus. Haematologica 89:1142-1144, 2004c.

Rosado JA, Sage SO: The actin cytoskeleton in store-mediated calcium entry. J Physiol 526:221-229, 2000.

Ruf JC: Alcohol, wine and platelet function. Biol Res 37:209-215, 2004.

Saavedra FR, Redondo PC, Hernandez-Cruz JM, Salido GM, Pariente JA, Rosado JA: Storeoperated Ca2+ entry and tyrosine kinase pp60src hyperactivity are modulated by hyperglycemia in platelets from patients with non-insulin-dependent diabetes mellitus. Arch Biochem Biophys 432:261-268, 2004.

Seno T, Inoue N, Gao D, Okuda M, Sumi Y, Matsui K, Yamada S, Hirata K, Kawashima S, Tawa R, Imajoh-Ohmi S, Sakurai H, Yokoyama M: Involvement of NADH/NADPH oxidase in human platelet ROS production. Thromb Res 103:399-409, 2001.

Tahri A, Yamani S, Legssyer A, Aziz M, Mekhfi H, Bnouham M, Ziyyat A: Acute diuretic, natriuretic and hypotensive effects of a continuous perfusion of aqueous extract of Urtica dioica. J Ethnopharmacol 73:95-100, 2000.

Willoughby S, Holmes A, Loscalzo J: Platelets and cardiovascular disease. Eur J Cardiovasc Nurs 1:273-288 , 2002.

Ziyyat A, Legssyer A, Mekhfi H, Dassouli A, Serhrouchni M, Benjelloun W: Phytotherapy of hypertension and diabetes in oriental Morocco. J Ethnopharmacol 58:45-54, 1997.
CITED

Sujatha S, Jemima Shalin J. Complementary therapeutic potential: A focus on polyherbal products for hyperglycemia. Asian J Sci Res. 5: 1-13, 2012.

Mehri A, Hasani-Ranjbar S, Larijani B, Abdollahi MA. systematic review of efficacy and safety of urtica dioica in the treatment of diabetes. Int J Pharm. 7: 161-170, 2011.

El Haouari M, Rosado JA. Modulation of Platelet Function and Signaling by Flavonoids. Mini-Rev Med Chem. 11: 131-142, 2011.

El Haouari M, Rosado JA. Platelet signalling abnormalities in patients with type 2 diabetes mellitus: A review. Blood Cells Mol Dis. 41: 119-123, 2008.

Lopez JJ, Jardin I, Salido GM, Rosado JA. Cinnamtannin B-1 as an antioxidant and platelet aggregation inhibitor. Life Sci. 82: 977-982, 2008.

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