Salsolinol, an endogenous neurotoxin, enhances platelet aggregation and thrombus formation

Ok-Nam Bae; Young-Dae Kim; Kyung-Min Lim; Ji-Yoon Noh; Seung-Min Chung; Keunyoung Kim; Suyoung Hong; Sue Shin; Jong-HyunYo on; Jin-Ho Chung

doi:10.1160/TH07-08-0529

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2008; 100(01): 52-59
DOI: 10.1160/TH07-08-0529

Platelets and Blood Cells

Schattauer GmbH

Salsolinol, an endogenous neurotoxin, enhances platelet aggregation and thrombus formation

Ok-Nam Bae^*

¹College of Pharmacy, Seoul National University, Seoul, Korea

,

Young-Dae Kim^*

¹College of Pharmacy, Seoul National University, Seoul, Korea

,

Kyung-Min Lim

¹College of Pharmacy, Seoul National University, Seoul, Korea

²AMOREPACIFIC CO/R&D Center, Gyeonggi-do, Korea

,

Ji-Yoon Noh

¹College of Pharmacy, Seoul National University, Seoul, Korea

,

Seung-Min Chung

¹College of Pharmacy, Seoul National University, Seoul, Korea

,

Keunyoung Kim

¹College of Pharmacy, Seoul National University, Seoul, Korea

,

Suyoung Hong

¹College of Pharmacy, Seoul National University, Seoul, Korea

,

Sue Shin

³Department of Laboratory Medicine, Boramae Hospital, Boramae, Korea

,

Jong-HyunYo on

³Department of Laboratory Medicine, Boramae Hospital, Boramae, Korea

,

Jin-Ho Chung

¹College of Pharmacy, Seoul National University, Seoul, Korea

› Institutsangaben

Abstract

Summary

Salsolinol, an endogenous neurotoxin, is known to be involved in the neuropathy of Parkinson’s disease and chronic alcoholism. In these diseases, increased thrombotic events are also commonly reported, yet the mechanism underlying remains poorly understood. Here we report that salsolinol can enhance agonist-induced platelet aggregation and granular secretion, which is essential in the thrombus formation. In rat and human platelets, agonist-induced platelet aggregation was significantly increased by salsolinol in a concentration-dependent manner. Agonist-induced granular secretions of serotonin and concomitant P-selectin expression were also augmented by salsolinol. α2-adrenergic blockers attenuated the salsolinol-enhanced aggregation and the inhibition of cyclic AMP generation was found, suggesting the involvement of α2-adrenergic receptor-mediated pathways in these events. In accord with the in-vitro results, in an arterial and venous thrombosis model in vivo in the rat, salsolinol shortened vessel occlusion time and increased thrombus formation, respectively. In conclusion, we demonstrated that sal-solinol can enhance agonist-induced aggregation and granular secretion in platelets through α2-adrenergic receptor activation, which resulted in the increased thrombus formation in vivo.These results suggest that salsolinol-enhanced platelet aggregation could be a possible contributing factor to the thrombotic events observed in Parkinson’s disease and alcoholism.

Keywords

Platelets - salsolinol - Parkinson’s disease - alcoholism - thrombosis

Volltext

Referenzen

References
1 Nagatsu T. Isoquinoline neurotoxins in the brain and Parkinson's disease. Neurosci Res 1997; 29: 99-111.
2 Naoi M, Maruyama W, Nagy GM. Dopamine-derived salsolinol derivatives as endogenous monoamine oxidase inhibitors: occurrence, metabolism and function in human brains. Neurotoxicology 2004; 25: 193-204.
3 Mravec B. Salsolinol, a derivate of dopamine, is a possible modulator of catecholaminergic transmission: a review of recent developments. Physiol Res 2006; 55: 353-364.
4 Maruyama W, Sobue G, Matsubara K. et al. A dopaminergic neurotoxin, 1(R), 2(N)-dimethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, N-methyl(R) salsolinol, and its oxidation product, 1,2(N)-dimethyl-6,7-dihydroxyisoquinolinium ion, accumulate in the nigro-striatal system of the human brain. Neurosci Lett 1997; 223: 61-64.
5 Moser A, Kompf D. Presence of methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinolines, derivatives of the neurotoxin isoquinoline, in parkinsonian lumbar CSF. Life Sci 1992; 50: 1885-1891.
6 Collins MA, Nijm WP, Borge GF. et al. Dopamine-related tetrahydroisoquinolines: significant urinary excretion by alcoholics after alcohol consumption. Science 1979; 206: 1184-1186.
7 Faraj BA, Camp VM, Davis DC. et al. Elevation of plasma salsolinol sulfate in chronic alcoholics as compared to nonalcoholics. Alcohol Clin Exp Res 1989; 13: 155-163.
8 Rommelspacher H, Sllstrom Baum S, Dufeu P. et al. Determination of (R)- and (S)-salsolinol sulfate and dopamine sulfate levels in plasma of nonalcoholics and alcoholics. Alcohol 1995; 12: 309-315.
9 Bollimuntha S, Ebadi M, Singh BB. TRPC1 protects human SH-SY5Y cells against salsolinol-induced cytotoxicity by inhibiting apoptosis. Brain Res 2006; 1099: 141-149.
10 Kim HJ, Soh Y, Jang JH. et al. Differential cell death induced by salsolinol with and without copper: possible role of reactive oxygen species. Mol Pharmacol 2001; 60: 440-449.
11 Maruyama W, Naoi M. Cell death in Parkinson's disease. J Neurol 2002; 249 (Suppl. 00) II6-10.
12 Wanpen S, Kooncumchoo P, Shavali S. et al. Salsolinol, an endogenous neurotoxin, activates JNK and NF-kappaB signaling pathways in human neuroblasto-ma cells. Neurochem Res 2007; 32: 443-450.
13 Puddey IB, Rakic V, Dimmitt SB. et al. Influence of pattern of drinking on cardiovascular disease and cardiovascular risk factors--a review. Addiction 1999; 94: 649-663.
14 Struck LK, Rodnitzky RL, Dobson JK. Stroke and its modification in Parkinson's disease. Stroke 1990; 21: 1395-1399.
15 Hung SC, Tai CT. Parkinson's disease with recurrent pulmonary embolism. Zhonghua Yi Xue Za Zhi (Taipei) 2000; 63: 487-491.
16 Mosewich RK, Rajput AH, Shuaib A. et al. Pulmonary embolism: an under-recognized yet frequent cause of death in parkinsonism. Mov Disord 1994; 09: 350-352.
17 Dyer AR, Stamler J, Paul O. et al. Alcohol consumption, cardiovascular risk factors, and mortality in two Chicago epidemiologic studies. Circulation 1977; 56: 1067-1074.
18 Lee K. Alcoholism and cerebrovascular thrombosis in the young. Acta Neurol Scand 1979; 59: 270-274.
19 Given MB, Longenecker GL. Effects of acetaldehyde condensation products on human platelet aggregation. Alcohol Drug Res 1987; 07: 383-392.
20 Melzig MF, Zipper J. Effects of salsolinol on cultivated endothelial cells. Neurochem Res 1993; 18: 689-693.
21 Gawaz M. Role of platelets in coronary thrombosis and reperfusion of ischemic myocardium. Cardiovasc Res 2004; 61: 498-511.
22 Ruggeri ZM. Platelets in atherothrombosis. Nat Med 2002; 08: 1227-1234.
23 Andrews RK, Berndt MC. Platelet physiology and thrombosis. Thromb Res 2004; 114: 447-453.
24 Jurk K, Kehrel BE. Platelets: physiology and biochemistry. Semin Thromb Hemost 2005; 31: 381-392.
25 Blann AD, Nadar S, Lip GY. Pharmacological modulation of platelet function in hypertension. Hypertension 2003; 42: 1-7.
26 Colwell JA, Nesto RW. The platelet in diabetes: focus on prevention of ischemic events. Diabetes Care 2003; 26: 2181-2188.
27 Durand P, Blache D. Enhanced platelet thromboxane synthesis and reduced macrophage-dependent fibrinolytic activity related to oxidative stress in oral contraceptive-treated female rats. Atherosclerosis 1996; 121: 205-216.
28 Lee MY, Bae ON, Chung SM. et al. Enhancement of platelet aggregation and thrombus formation by arsenic in drinking water: a contributing factor to cardiovascular disease. Toxicol Appl Pharmacol 2002; 179: 83-88.
29 Chou KJ, Jan CR, Lee PT. et al. Platelet hyperreactivity in hemodialysis patients with frequently occluded vascular access. Thromb Haemost 2004; 92: 621-626.
30 Haseruck N, Erl W, Pandey D. et al. The plaque lipid lysophosphatidic acid stimulates platelet activation and platelet-monocyte aggregate formation in whole blood: involvement of P2Y1 and P2Y12 receptors. Blood 2004; 103: 2585-2592.
31 Kang KT, Jung BI, Bae ON. et al. Antithrombotic activity of LB30057, a newly synthesized direct thrombin inhibitor. Thromb Haemost 2003; 89: 104-111.
32 Given MB, Longenecker GL. Te trahydroisoquino-lines and beta-carbolines: specific binding to human platelet alpha 2-receptors in vitro. Res Commun Chem Pathol Pharmacol 1983; 41: 349-352.
33 van Willigen G, Donath J, Lapetina EG. et al. Identification of alpha-subunits of trimeric GTP-bind-ing proteins in human platelets by RT-PCR. Biochem Biophys Res Commun 1995; 214: 254-262.
34 Jerjes-Sanchez C. Venous and arterial thrombosis: a continuous spectrum of the same disease?. Eur Heart J 2005; 26: 3-4.
35 Fateh-Moghadam S, Htun P, Tomandl B. et al. Hyperresponsiveness of platelets in ischemic stroke. Thromb Haemost 2007; 97: 974-978.
36 Davignon J, Ganz P. Role of endothelial dysfunction in atherosclerosis. Circulation 2004; 109: III27-32.
37 Thomas T, Thomas G, McLendon C. et al. beta-Amyloid-mediated vasoactivity and vascular endothelial damage. Nature 1996; 380: 168-171.
38 Keularts IM, van Gorp RM, Feijge MA. et al. alpha(2A)-adrenergic receptor stimulation potentiates calcium release in platelets by modulating cAMP levels. J Biol Chem 2000; 275: 1763-1772.
39 Lanza F, Cazenave JP. Studies of alpha 2-adrenergic receptors of intact and functional washed human platelets by binding of 3H-dihydroergocryptine and 3H-yohimbine--correlation of 3H-yohimbine binding with the potentiation by adrenaline of ADP-induced aggregation. Thromb Haemost 1985; 54: 402-408.
40 Hsiao G, Shen MY, Fang CL. et al. Morphine-potentiated platelet aggregation in in vitro and platelet plug formation in in vivo experiments. J Biomed Sci 2003; 10: 292-301.
41 Sheu JR, Yeh GC, Fang CL. et al. Morphine-potentiated agonist-induced platelet aggregation through alpha2-adrenoceptors in human platelets. J Cardiovasc Pharmacol 2002; 40: 743-750.
42 Manns JM, Brenna KJ, Colman RW. et al. Differential regulation of human platelet responses by cGMP inhibited and stimulated cAMP phosphodiesterases. Thromb Haemost 2002; 87: 873-879.
43 Vandendries ER, Furie BC, Furie B. Role of P-selectin and PSGL-1 in coagulation and thrombosis. Thromb Haemost 2004; 92: 459-466.
44 Fanburg BL, Lee SL. A new role for an old molecule: serotonin as a mitogen. Am J Physiol 1997; 272: L795-806.
45 Frishman WH, Grewall P. Serotonin and the heart. Ann Med 2000; 32: 195-209.
46 Heikkila R, Cohen G, Dembiec D. Tetrahydroisoquinoline alkaloids: uptake by rat brain homogenates and inhibition of catecholamine uptake. J Pharmacol Exp Ther 1971; 179: 250-258.
47 Baum SS, Rommelspacher H. Determination of total dopamine, R- and S-salsolinol in human plasma by cyclodextrin bonded-phase liquid chromatography with electrochemical detection. J Chromatogr B Biomed Appl 1994; 660: 235-241.
48 Haber H, Winkler A, Putscher I. et al. Plasma and urine salsolinol in humans: effect of acute ethanol intake on the enantiomeric composition of salsolinol. Alcohol Clin Exp Res 1996; 20: 87-92.