title: Contribution of protease-activated receptor 1 in status epilepticus-induced epileptogenesis.
abstract: Clinical observations and studies on different animal models of acquired epilepsy consistently demonstrate that blood-brain barrier (BBB) leakage can be an important risk factor for developing recurrent seizures. However, the involved signaling pathways remain largely unclear. Given the important role of thrombin and its major receptor in the brain, protease-activated receptor 1 (PAR1), in the pathophysiology of neurological injury, we hypothesized that PAR1 may contribute to status epilepticus (SE)-induced epileptogenesis and that its inhibition shortly after SE will have neuroprotective and antiepileptogenic effects. Adult rats subjected to lithium-pilocarpine SE were administrated with SCH79797 (a PAR1 selective antagonist) after SE termination. Thrombin and PAR1 levels and neuronal cell survival were evaluated 48h following SE. The effect of PAR1 inhibition on animal survival, interictal spikes (IIS) and electrographic seizures during the first two weeks after SE and behavioral seizures during the chronic period was evaluated. SE resulted in a high mortality rate and incidence of IIS and seizures in the surviving animals. There was a marked increase in thrombin, decrease in PAR1 immunoreactivity and hippocampal cell loss in the SE-treated rats. Inhibition of PAR1 following SE resulted in a decrease in mortality and morbidity, increase in neuronal cell survival in the hippocampus and suppression of IIS, electrographic and behavioral seizures following SE. These data suggest that the PAR1 signaling pathway contributes to epileptogenesis following SE. Because breakdown of the BBB occurs frequently in brain injuries, PAR1 inhibition may have beneficial effects in a variety of acquired injuries leading to epilepsy.
authors.affiliation: Department of Cellular Membranology, Bogomoletz Institute of Physiology, Kiev, Ukraine; Department of Neurological Sciences, University of Vermont College of Medicine, Burlington, VT, USA.
authors.forename: D
authors.initials: D
authors.lastname: Isaev
authors.affiliation: Department of Cytology, Bogomoletz Institute of Physiology, Kiev, Ukraine.
authors.forename: I
authors.initials: I
authors.lastname: Lushnikova
authors.affiliation: Department of Cellular Membranology, Bogomoletz Institute of Physiology, Kiev, Ukraine.
authors.forename: O
authors.initials: O
authors.lastname: Lunko
authors.affiliation: Department of Cellular Membranology, Bogomoletz Institute of Physiology, Kiev, Ukraine.
authors.forename: O
authors.initials: O
authors.lastname: Zapukhliak
authors.affiliation: Department of Cellular Membranology, Bogomoletz Institute of Physiology, Kiev, Ukraine.
authors.forename: O
authors.initials: O
authors.lastname: Maximyuk
authors.affiliation: Department of Cellular Membranology, Bogomoletz Institute of Physiology, Kiev, Ukraine.
authors.forename: A
authors.initials: A
authors.lastname: Romanov
authors.affiliation: Department of Cytology, Bogomoletz Institute of Physiology, Kiev, Ukraine.
authors.forename: G G
authors.initials: GG
authors.lastname: Skibo
authors.affiliation: Department of Neurological Sciences, University of Vermont College of Medicine, Burlington, VT, USA.
authors.forename: C
authors.initials: C
authors.lastname: Tian
authors.affiliation: Department of Neurological Sciences, University of Vermont College of Medicine, Burlington, VT, USA.
authors.forename: G L
authors.initials: GL
authors.lastname: Holmes
authors.affiliation: Department of Cellular Membranology, Bogomoletz Institute of Physiology, Kiev, Ukraine; Department of Neurological Sciences, University of Vermont College of Medicine, Burlington, VT, USA. Electronic address: olena.isaeva@gmail.com.
authors.forename: E
authors.initials: E
authors.lastname: Isaeva
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D011758:Pyrroles / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044463:Receptor, PAR-1 / Q000378:metabolism*; D013226:Status Epilepticus / Q000378:metabolism* / Q000473:pathology; D013917:Thrombin / Q000378:metabolism*; D010975:Platelet Aggregation Inhibitors
chemical_list: C415424:N3-cyclopropyl-7-((4-(1-methylethyl)phenyl)methyl)-7H-pyrrolo(3, 2-f)quinazoline-1,3-diamine; D011758:Pyrroles; D011799:Quinazolines; D044463:Receptor, PAR-1; D013917:Thrombin; D010975:Platelet Aggregation Inhibitors
keywords: Epileptogenesis; Hippocampus; Pilocarpine; Protease-activated receptor; Status epilepticus; Thrombin
references.citation: Exp Neurol. 2004 Jan;185(1):182-90
references.pmid: 14697329
references.citation: Neurotox Res. 2013 Apr;23(3):238-48
references.pmid: 22810835
references.citation: J Mol Neurosci. 2010 Sep;42(1):53-8
references.pmid: 20140537
references.citation: J Neurosci. 2005 Apr 20;25(16):4082-90
references.pmid: 15843610
references.citation: Exp Neurol. 2006 Apr;198(2):361-9
references.pmid: 16448651
references.citation: Ann Neurol. 2004 Oct;56(4):468-77
references.pmid: 15389899
references.citation: J Cell Biochem. 2009 Dec 1;108(5):1143-52
references.pmid: 19739103
references.citation: Basic Res Cardiol. 2007 Jul;102(4):350-8
references.pmid: 17468933
references.citation: Neuroscience. 2007 Jan 19;144(2):694-701
references.pmid: 17084034
references.citation: Brain. 2007 Feb;130(Pt 2):521-34
references.pmid: 17124188
references.citation: Epilepsia. 2010 Mar;51(3):371-83
references.pmid: 19845739
references.citation: Pharmacol Rev. 2001 Jun;53(2):245-82
references.pmid: 11356985
references.citation: Proc Natl Acad Sci U S A. 2000 Feb 29;97(5):2264-9
references.pmid: 10681455
references.citation: Proc Natl Acad Sci U S A. 2003 Oct 28;100(22):13019-24
references.pmid: 14559973
references.citation: Epilepsia. 2011 Oct;52 Suppl 8:19-20
references.pmid: 21967353
references.citation: J Cereb Blood Flow Metab. 2002 Apr;22(4):404-10
references.pmid: 11919511
references.citation: J Neurosurg. 1997 Jul;87(1):73-8
references.pmid: 9202268
references.citation: Neuropathol Appl Neurobiol. 2009 Apr;35(2):132-46
references.pmid: 19077110
references.citation: Epilepsia. 2012 Aug;53(8):1411-20
references.pmid: 22780884
references.citation: Neurobiol Dis. 2013 Feb;50:171-8
references.pmid: 23103417
references.citation: Eur J Neurol. 2015 Feb;22(2):402-5
references.pmid: 24684345
references.citation: Trends Pharmacol Sci. 2001 Mar;22(3):146-52
references.pmid: 11239578
references.citation: Biomark Med. 2011 Oct;5(5):607-14
references.pmid: 22003909
references.citation: J Exp Med. 1996 Mar 1;183(3):821-7
references.pmid: 8642286
references.citation: J Neurosci. 1997 Jul 15;17(14):5316-26
references.pmid: 9204916
references.citation: Neuron. 1991 Apr;6(4):575-81
references.pmid: 2015093
references.citation: Brain Res Rev. 2007 Dec;56(2):331-45
references.pmid: 17915333
references.citation: Neurobiol Dis. 2003 Nov;14(2):181-93
references.pmid: 14572441
references.citation: Autoimmun Rev. 2006 Oct;5(8):528-31
references.pmid: 17027887
references.citation: J Cereb Blood Flow Metab. 2004 Sep;24(9):964-71
references.pmid: 15356417
references.citation: Proc Natl Acad Sci U S A. 2013 Feb 26;110(9):3591-6
references.pmid: 23401547
references.citation: Acta Neuropathol. 1997 Aug;94(2):158-63
references.pmid: 9255391
references.citation: Epilepsia. 2013 Aug;54 Suppl 4:35-43
references.pmid: 23909852
references.citation: Acta Neuropathol. 1984;65(1):25-34
references.pmid: 6516799
references.citation: Neurobiol Dis. 2007 Feb;25(2):367-77
references.pmid: 17188501
references.citation: Electroencephalogr Clin Neurophysiol. 1972 Mar;32(3):281-94
references.pmid: 4110397
references.citation: Epilepsia. 2006 Nov;47(11):1761-74
references.pmid: 17116015
references.citation: Mol Psychiatry. 2013 Oct;18(10):1136-45
references.pmid: 23032873
references.citation: J Neurosci Res. 2005 Aug 15;81(4):581-8
references.pmid: 15948190
references.citation: Neuropharmacology. 1987 Dec;26(12):1733-7
references.pmid: 3437939
references.citation: Brain Res. 2004 Jul 23;1015(1-2):169-74
references.pmid: 15223381
references.citation: Neurosci Lett. 2011 Jun 27;497(3):247-50
references.pmid: 21458535
references.citation: J Neurosci Res. 2004 Jan 15;75(2):273-9
references.pmid: 14705148
references.citation: Neurobiol Dis. 2013 Feb;50:13-20
references.pmid: 23000356
references.citation: Exp Neurol. 2012 Dec;238(2):156-67
references.pmid: 22960187
references.citation: J Neurooncol. 2013 Jan;111(2):133-43
references.pmid: 23184143
references.citation: Exp Neurol. 2009 May;217(1):136-46
references.pmid: 19416668
references.citation: Neurosci Lett. 2011 Jun 27;497(3):223-30
references.pmid: 21362451
references.citation: Neurobiol Dis. 2014 Jul;67:97-106
references.pmid: 24686305
references.citation: Transl Stroke Res. 2011 Mar;2(1):67-71
references.pmid: 24323586
references.citation: Mol Brain. 2011;4:32
references.pmid: 21827709
references.citation: J Neurochem. 2002 Jul;82(1):192-201
references.pmid: 12091480
references.citation: J Neurochem. 2003 Jan;84(1):3-9
references.pmid: 12485396
references.citation: Biochem Biophys Res Commun. 1994 Jul 29;202(2):1163-8
references.pmid: 7519421
references.citation: J Neurobiol. 1998 Jul;36(1):64-80
references.pmid: 9658339
references.citation: Ann Neurol. 2012 Jun;71(6):805-14
references.pmid: 22718546
references.citation: Eur J Neurosci. 2001 Aug;14(4):595-608
references.pmid: 11556885
references.citation: Epilepsia. 2011 Mar;52(3):e12-5
references.pmid: 21366554
references.citation: J Neurochem. 1998 Sep;71(3):1034-50
references.pmid: 9721728
references.citation: J Neurosci. 2012 May 30;32(22):7622-31
references.pmid: 22649241
references.citation: Epilepsy Res. 2001 Aug;46(2):111-9
references.pmid: 11463512
references.citation: Ann Neurol. 1978 Oct;4(4):329-36
references.pmid: 103489
references.citation: PLoS One. 2011;6(3):e18200
references.pmid: 21464890
references.citation: Stroke. 2012 Sep;43(9):2476-82
references.pmid: 22811450
references.citation: Exp Neurol. 2006 Mar;198(1):199-203
references.pmid: 16427045
references.citation: Ann Neurol. 2012 Aug;72(2):192-8
references.pmid: 22926852
references.citation: Thromb Res. 2000 Sep 1;99(5):417-27
references.pmid: 10973669
references.citation: Transl Stroke Res. 2011 Dec;2(4):492-516
references.pmid: 22299022
references.citation: Neuroscientist. 2004 Dec;10(6):501-12
references.pmid: 15534036
references.citation: J Biol Chem. 2006 Apr 28;281(17):11792-804
references.pmid: 16467309
references.citation: Neurosci Lett. 2002 Aug 30;329(2):181-4
references.pmid: 12165407
references.citation: Neuroscience. 2010 Mar 10;166(1):312-32
references.pmid: 20004712
references.citation: Seizure. 2009 Jul;18(6):405-11
references.pmid: 19324574
references.citation: J Neurochem. 1993 Jan;60(1):330-6
references.pmid: 8417154
references.citation: Neurosci Lett. 2009 Mar 13;452(2):172-5
references.pmid: 19383433