Prothrombin/thrombin and the thrombin receptors PAR-1 and PAR-4 in the brain: Localization, expression and participation in neurodegenerative diseases

Summary

Emerging evidence demonstrates that thrombin exerts physiological and pathological functions in the central nervous system. Both prothrombin and its active form thrombin have been detected locally in the brain. The cellular functions of thrombin are mainly regulated by G protein-coupled protease-activated receptors (PARs). Thrombin can signal via PAR-1, PAR-3 and PAR-4. Some neurological diseases (e.g. Alzheimer’s disease or Parkinson’s disease) are characterized by increased levels of both active thrombin and PAR-1. This indicates that thrombin and its receptor may be closely involved in the development of neurodegenerative processes. The role of thrombin in brain injury can be either protective or deleterious, depending on the concentration of thrombin. Thrombin at high concentrations exacerbates brain damage. In contrast, low concentrations of thrombin rescue neural cells from death after brain insults. Also thrombin preconditioning has neuroprotective effects. Therefore, thrombin and thrombin receptors represent novel therapeutic targets for treating neurodegenerative diseases.

Keywords

Thrombin - PAR - central nervous system - neurodegeneration - neuroprotection

• References

• 1 Mann KG. Biochemistry and physiology of blood coagulation. Thromb Haemost 1999; 82: 165-174.
• 2 Stubbs MT, Bode W. The clot thickens: clues provided by thrombin structure. Trends Biochem Sci 1995; 20: 23-28.
• 3 Stubbs MT, Bode W. A player of many parts: the spotlight falls on thrombin’s structure. Thromb Res 1993; 69: 1-58.
• 4 Dumas JJ, Kumar R, Seehra J. et al. Crystal structure of the GpIbalpha-thrombin complex essential for platelet aggregation. Science 2003; 301: 222-226.
• 5 Strukova SM. Role of platelets and serine proteinases in coupling of blood coagulation and inflammation. Biochemistry (Mosc) 2004; 69: 1067-1081.
• 6 Ossovskaya VS, Bunnett NW. Protease-activated receptors: contribution to physiology and disease. Physiol Rev 2004; 84: 579-621.
• 7 Vergnolle N. Review article: proteinase-activated receptors - novel signals for gastrointestinal pathophysiology. Aliment Pharmacol Ther 2000; 14: 257-266.
• 8 Steinhoff M, Buddenkotte J, Shpacovitch V. et al. Proteinase-activated receptors: transducers of proteinase-mediated signaling in inflammation and immune response. Endocr Rev 2005; 26: 1-43.
• 9 Martorell L, Martinez-Gonzalez J, Rodriguez C. et al. Thrombin and protease-activated receptors (PARs) in atherothrombosis. Thromb Haemost 2008; 99: 305-315.
• 10 Macfarlane SR, Seatter MJ, Kanke T. et al. Proteinase-activated receptors. Pharmacol Rev 2001; 53: 245-282.
• 11 Vu TK, Hung DT, Wheaton VI. et al. Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation. Cell 1991; 64: 1057-1068.
• 12 Kahn ML, Zheng YW, Huang W. et al. A dual thrombin receptor system for platelet activation. Nature 1998; 394: 690-694.
• 13 Vretenbrant K, Ramstrom S, Bjerke M. et al. Platelet activation via PAR4 is involved in the initiation of thrombin generation and in clot elasticity development. Thromb Haemost 2007; 97: 417-424.
• 14 Luo W, Wang Y, Reiser G. Protease-activated receptors in the brain: receptor expression, activation, and functions in neurodegeneration and neuroprotection. Brain Res Brain Res Rev 2007; 56: 331-345.
• 15 Rohatgi T, Sedehizade F, Reymann KG. et al. Protease-activated receptors in neuronal development, neurodegeneration, and neuroprotection: thrombin as signaling molecule in the brain. Neuroscientist 2004; 10: 501-512.
• 16 Sokolova E, Reiser G. A novel therapeutic target in various lung diseases: Airway proteases and protease-activated receptors. Pharmacol Ther 2007; 115: 70-83.
• 17 Wang H, Reiser G. Thrombin signaling in the brain: the role of protease-activated receptors. Biol Chem 2003; 384: 193-202.
• 18 Weinstein JR, Gold SJ, Cunningham DD. et al. Cellular localization of thrombin receptor mRNA in rat brain: expression by mesencephalic dopaminergic neurons and codistribution with prothrombin mRNA. J Neurosci 1995; 15: 2906-2919.
• 19 Arai T, Miklossy J, Klegeris A. et al. Thrombin and prothrombin are expressed by neurons and glial cells and accumulate in neurofibrillary tangles in Alzheimer disease brain. J Neuropathol Exp Neurol 2006; 65: 19-25.
• 20 Boven LA, Vergnolle N, Henry SD. et al. Up-regulation of proteinase-activated receptor 1 expression in astrocytes during HIV encephalitis. J Immunol 2003; 170: 2638-2646.
• 21 Ishida Y, Nagai A, Kobayashi S. et al. Upregulation of protease-activated receptor-1 in astrocytes in Parkinson disease: astrocyte-mediated neuroprotection through increased levels of glutathione peroxidase. J Neuropathol Exp Neurol 2006; 65: 66-77.
• 22 Dihanich M, Kaser M, Reinhard E. et al. Prothrombin mRNA is expressed by cells of the nervous system. Neuron 1991; 06: 575-581.
• 23 Shikamoto Y, Morita T. Expression of factor X in both the rat brain and cells of the central nervous system. FEBS Lett 1999; 463: 387-389.
• 24 Deschepper CF, Bigornia V, Berens ME. et al. Production of thrombin and antithrombin III by brain and astroglial cell cultures. Brain Res Mol Brain Res 1991; 11: 355-358.
• 25 Niclou SP, Suidan HS, Pavlik A. et al. Changes in the expression of protease-activated receptor 1 and protease nexin-1 mRNA during rat nervous system development and after nerve lesion. Eur J Neurosci 1998; 10: 1590-1607.
• 26 Choi BH, Suzuki M, Kim T. et al. Protease nexin-1. Localization in the human brain suggests a protective role against extravasated serine proteases. Am J Pathol 1990; 137: 741-747.
• 27 Olianas MC, Dedoni S, Onali P. Proteinase-activated receptors 1 and 2 in rat olfactory system: layer-specific regulation of multiple signaling pathways in the main olfactory bulb and induction of neurite retraction in olfactory sensory neurons. Neuroscience 2007; 146: 1289-1301.
• 28 Striggow F, Riek-Burchardt M, Kiesel A. et al. Four different types of protease-activated receptors are widely expressed in the brain and are up-regulated in hippocampus by severe ischemia. Eur J Neurosci 2001; 14: 595-608.
• 29 Herrera AJ, de Pablos RM, Carreno-Muller E. et al. The intrastriatal injection of thrombin in rat induced a retrograde apoptotic degeneration of nigral dopaminergic neurons through synaptic elimination. J Neurochem 2008; 105: 750-762.
• 30 Junge CE, Lee CJ, Hubbard KB. et al. Protease-activated receptor-1 in human brain: localization and functional expression in astrocytes. Exp Neurol 2004; 188: 94-103.
• 31 Sinnreich M, Meins M, Niclou SP. et al. Prothrombin overexpressed in post-natal neurones requires blood factors for activation in the mouse brain. J Neurochem 2004; 88: 1380-1388.
• 32 Grammas P, Samany PG, Thirumangalakudi L. Thrombin and inflammatory proteins are elevated in Alzheimer’s disease microvessels: implications for disease pathogenesis. J Alzheimers Dis 2006; 09: 51-58.
• 33 Riek-Burchardt M, Striggow F, Henrich-Noack P. et al. Increase of prothrombin-mRNA after global cerebral ischemia in rats, with constant expression of protease nexin-1 and protease-activated receptors. Neurosci Lett 2002; 329: 181-184.
• 34 Möller T, Hanisch UK, Ransom BR. Thrombin-induced activation of cultured rodent microglia. J Neurochem 2000; 75: 1539-1547.
• 35 Suo Z, Wu M, Ameenuddin S. et al. Participation of protease-activated receptor-1 in thrombin-induced microglial activation. J Neurochem 2002; 80: 655-666.
• 36 Wang H, Ubl JJ, Reiser G. Four subtypes of protease-activated receptors, co-expressed in rat astrocytes, evoke different physiological signaling. Glia 2002; 37: 53-63.
• 37 Wang H, Ubl JJ, Stricker R. et al. Thrombin (PA R1)-induced proliferation in astrocytes via MAPK involves multiple signaling pathways. Am J Physiol Cell Physiol 2002; 283: C1351-1364.
• 38 Nicole O, Goldshmidt A, Hamill CE. et al. Activation of protease-activated receptor-1 triggers astrogliosis after brain injury. J Neurosci 2005; 25: 4319-4329.
• 39 Carreno-Muller E, Herrera AJ, de Pablos RM. et al. Thrombin induces in vivo degeneration of nigral dopaminergic neurones along with the activation of microglia. J Neurochem 2003; 84: 1201-1214.
• 40 Choi SH, Joe EH, Kim SU. et al. Thrombin-induced microglial activation produces degeneration of nigral dopaminergic neurons in vivo. J Neurosci 2003; 23: 5877-5886.
• 41 Choi SH, Lee DY, Chung ES. et al. Inhibition of thrombin-induced microglial activation and NADPH oxidase by minocycline protects dopaminergic neurons in the substantia nigra in vivo. J Neurochem 2005; 95: 1755-1765.
• 42 Fujimoto S, Katsuki H, Ohnishi M. et al. Thrombin induces striatal neurotoxicity depending on mitogen-activated protein kinase pathways in vivo. Neuroscience 2007; 144: 694-701.
• 43 Kim KY, Kim MY, Choi HS. et al. Thrombin induces IL-10 production in microglia as a negative feedback regulator of TNF-alpha release. Neuroreport 2002; 13: 849-852.
• 44 Lee DY, Park KW, Jin BK. Thrombin induces neurodegeneration and microglial activation in the cortex in vivo and in vitro: proteolytic and non-proteolytic actions. Biochem Biophys Res Commun 2006; 346: 727-738.
• 45 Lee DY, Oh YJ, Jin BK. Thrombin-activated microglia contribute to death of dopaminergic neurons in rat mesencephalic cultures: dual roles of mitogen-activated protein kinase signaling pathways. Glia 2005; 51: 98-110.
• 46 Ryu J, Pyo H, Jou I. et al. Thrombin induces NO release from cultured rat microglia via protein kinase C, mitogen-activated protein kinase, and NF-kappa B. J Biol Chem 2000; 275: 29955-29959.
• 47 Hanisch UK, van Rossum D, Xie Y. et al. The microglia-activating potential of thrombin: the protease is not involved in the induction of proinflammatory cytokines and chemokines. J Biol Chem 2004; 279: 51880-51887.
• 48 Hernandez M, Bayon Y, Sanchez Crespo M. et al. Thrombin produces phosphorylation of cytosolic phospholipase A2 by a mitogen-activated protein kinase kinase-independent mechanism in the human as-trocytoma cell line 1321N1. Biochem J 1997; 328: 263-269.
• 49 Strokin M, Sergeeva M, Reiser G. Docosahexaenoic acid and arachidonic acid release in rat brain astrocytes is mediated by two separate isoforms of phospholipase A₂ and is differently regulated by cyclic AMP and Ca²⁺ . Br J Pharmacol 2003; 139: 1014-1022.
• 50 Wang Y, Luo W, Reiser G. Activation of protease-activated receptors in astrocytes evokes a novel neuroprotective pathway through release of chemokines of the growth-regulated oncogene/cytokine-induced neutrophil chemoattractant family. Eur J Neurosci 2007; 26: 3159-3168.
• 51 Meli R, Raso GM, Cicala C. et al. Thrombin and PA R-1 activating peptide increase iNOS expression in cytokine-stimulated C6 glioma cells. J Neurochem 2001; 79: 556-563.
• 52 de Castro Ribeiro M, Badaut J, Price M. et al. Thrombin in ischemic neuronal death. Exp Neurol 2006; 198: 199-203.
• 53 Rohatgi T, Henrich-Noack P, Sedehizade F. et al. Transient focal ischemia in rat brain differentially regulates mRNA expression of protease-activated receptors 1 to 4. J Neurosci Res 2004; 75: 273-279.
• 54 Henrich-Noack P, Riek-Burchardt M, Baldauf K. et al. Focal ischemia induces expression of protease-activated receptor1 (PAR1) and PAR3 on microglia and enhances PAR4 labeling in the penumbra. Brain Res 2006; 1070: 232-241.
• 55 Vaughan PJ, Cunningham DD. Regulation of protease nexin-1 synthesis and secretion in cultured brain cells by injury-related factors. J Biol Chem 1993; 268: 3720-3727.
• 56 Cunningham DD, Pulliam L, Vaughan PJ. Protease nexin-1 and thrombin: injury-related processes in the brain. Thromb Haemost 1993; 70: 168-171.
• 57 Hoffmann MC, Nitsch C, Scotti AL. et al. The prolonged presence of glia-derived nexin, an endogenous protease inhibitor, in the hippocampus after ischemia-induced delayed neuronal death. Neuroscience 1992; 49: 397-408.
• 58 Striggow F, Riek M, Breder J. et al. The protease thrombin is an endogenous mediator of hippocampal neuroprotection against ischemia at low concentrations but causes degeneration at high concentrations. Proc Natl Acad Sci USA 2000; 97: 2264-2269.
• 59 Vaughan PJ, Pike CJ, Cotman CW. et al. Thrombin receptor activation protects neurons and astrocytes from cell death produced by environmental insults. J Neurosci 1995; 15: 5389-5401.
• 60 Masada T, Xi G, Hua Y. et al. The effects of thrombin preconditioning on focal cerebral ischemia in rats. Brain Res 2000; 867: 173-179.
• 61 Xi G, Keep RF, Hua Y. et al. Attenuation of thrombin-induced brain edema by cerebral thrombin preconditioning. Stroke 1999; 30: 1247-1255.
• 62 Henrich-Noack P, Striggow F, Reiser G. et al. Preconditioning with thrombin can be protective or worsen damage after endothelin-1-induced focal ischemia in rats. J Neurosci Res 2006; 83: 469-475.
• 63 Granziera C, Thevenet J, Price M. et al. Thrombin-induced ischemic tolerance is prevented by inhibiting c-jun N-terminal kinase. Brain Res 2007; 1148: 217-225.
• 64 Jiang Y, Wu J, Hua Y. et al. Thrombin-receptor activation and thrombin-induced brain tolerance. J Cereb Blood Flow Metab 2002; 22: 404-410.
• 65 Xi G, Reiser G, Keep RF. The role of thrombin and thrombin receptors in ischemic, hemorrhagic and traumatic brain injury: deleterious or protective?. J Neurochem 2003; 84: 3-9.
• 66 Fujimoto S, Katsuki H, Kume T. et al. Thrombin-induced delayed injury involves multiple and distinct signaling pathways in the cerebral cortex and the striatum in organotypic slice cultures. Neurobiol Dis 2006; 22: 130-142.
• 67 Junge CE, Sugawara T, Mannaioni G. et al. The contribution of protease-activated receptor 1 to neuronal damage caused by transient focal cerebral ischemia. Proc Natl Acad Sci USA 2003; 100: 13019-13024.
• 68 Olson EE, Lyuboslavsky P, Traynelis SF. et al. PA R-1 deficiency protects against neuronal damage and neurologic deficits after unilateral cerebral hypoxia/ischemia. J Cereb Blood Flow Metab 2004; 24: 964-971.
• 69 Cuomo O, Pignataro G, Gala R. et al. Antithrombin reduces ischemic volume, ameliorates neurologic deficits, and prolongs animal survival in both transient and permanent focal ischemia. Stroke 2007; 38: 3272-3279.
• 70 Lee CJ, Mannaioni G, Yuan H. et al. Astrocytic control of synaptic NMDA receptors. J Physiol 2007; 581: 1057-1081.
• 71 Ramos-Mandujano G, Vazquez-Juarez E, Hern-andez-Benitez R. et al. Thrombin potently enhances swelling-sensitive glutamate efflux from cultured astrocytes. Glia 2007; 55: 917-925.
• 72 Olanow CW, Tatton WG. Etiology and pathogenesis of Parkinson’s disease. Annu Rev Neurosci 1999; 22: 123-144.
• 73 Hirsch EC, Hunot S, Damier P. et al. Glial cells and inflammation in Parkinson’s disease: a role in neurode-generation?. Ann Neurol 1998; 44: S115-120.
• 74 McGeer PL, Itagaki S, Boyes BE. et al. Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains. Neurology 1988; 38: 1285-1291.
• 75 Choi SH, Lee DY, Ryu JK. et al. Thrombin induces nigral dopaminergic neurodegeneration in vivo by altering expression of death-related proteins. Neurobiol Dis 2003; 14: 181-193.
• 76 Huang CF, Li G, Ma R. et al. Thrombin-induced microglial activation contributes to the degeneration of nigral dopaminergic neurons in vivo. Neurosci Bull 2008; 24: 66-72.
• 77 Cannon JR, Keep RF, Schallert T. et al. Protease-activated receptor-1 mediates protection elicited by thrombin preconditioning in a rat 6-hydroxydopamine model of Parkinson’s disease. Brain Res 2006; 1116: 177-186.
• 78 Cannon JR, Hua Y, Richardson RJ. et al. The effect of thrombin on a 6-hydroxydopamine model of Parkinson’s disease depends on timing. Behav Brain Res 2007; 183: 161-168.
• 79 Pompili E, Nori SL, Geloso MC. et al. Trimethyltininduced differential expression of PA R subtypes in reactive astrocytes of the rat hippocampus. Brain Res Mol Brain Res 2004; 122: 93-98.
• 80 Vaughan PJ, Su J, Cotman CW. et al. Protease nexin-1, a potent thrombin inhibitor, is reduced around cerebral blood vessels in Alzheimer’s disease. Brain Res 1994; 668: 160-170.
• 81 Arai T, Guo JP, McGeer PL. Proteolysis of non-phosphorylated and phosphorylated tau by thrombin. J Biol Chem 2005; 280: 5145-5153.
• 82 Suo Z, Wu M, Citron BA. et al. Rapid tau aggregation and delayed hippocampal neuronal death induced by persistent thrombin signaling. J Biol Chem 2003; 278: 37681-37689.
• 83 Chong YH, Jung JM, Choi W. et al. Bacterial expression, purification of full length and carboxyl terminal fragment of Alzheimer amyloid precursor protein and their proteolytic processing by thrombin. Life Sci 1994; 54: 1259-1268.
• 84 Davis-Salinas J, Saporito-Irwin SM, Donovan FM. et al. Thrombin receptor activation induces secretion and nonamyloidogenic processing of amyloid beta-protein precursor. J Biol Chem 1994; 269: 22623-22627.
• 85 Brewer GJ. Thrombin causes cell spreading and redistribution of beta-amyloid immunoreactivity in cultured hippocampal neurons. J Neurochem 1996; 67: 119-130.
• 86 Smith-Swintosky VL, Zimmer S, Fenton 2nd JW. et al. Opposing actions of thrombin and protease nexin-1 on amyloid beta-peptide toxicity and on accumulation of peroxides and calcium in hippocampal neurons. J Neurochem 1995; 65: 1415-1418.
• 87 Pike CJ, Vaughan PJ, Cunningham DD. et al. Thrombin attenuates neuronal cell death andmodulates astrocyte reactivity induced by beta-amyloid in vitro. J Neurochem 1996; 66: 1374-1382.
• 88 Ostrowska E, Reiser G. The protease-activated re-ceptor-3 (PAR-3) can signal autonomously to induce interleukin-8 release. Cell Mol Life Sci 2008; 65: 970-981.