Nafamostat and sepimostat identified as novel neuroprotective agents via NR2B N-methyl-D-aspartate receptor antagonism using a rat retinal excitotoxicity model.
Animals
Benzamidines
Cell Death
/ drug effects
Cerebral Cortex
/ drug effects
Excitatory Amino Acid Antagonists
/ pharmacology
Guanidines
/ pharmacology
Imidazoles
/ pharmacology
Neurons
/ drug effects
Neuroprotective Agents
/ pharmacology
Rats
Rats, Sprague-Dawley
Receptors, N-Methyl-D-Aspartate
/ antagonists & inhibitors
Retinal Degeneration
/ prevention & control
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
31 12 2019
31 12 2019
Historique:
received:
09
09
2019
accepted:
16
12
2019
entrez:
2
1
2020
pubmed:
2
1
2020
medline:
11
11
2020
Statut:
epublish
Résumé
In addition to its role in the treatment of pancreatitis, the serine protease inhibitor nafamostat exhibits a retinal protective effect. However, the exact mechanisms underlying this effect are unknown. In this study, the neuroprotective effects of nafamostat and its orally active derivative sepimostat against excitotoxicity were further characterised in vitro and in vivo. In primary rat cortical neurons, nafamostat completely suppressed N-methyl-D-aspartate (NMDA)-induced cell death. Intravitreal injection of nafamostat and sepimostat protected the rat retina against NMDA-induced degeneration, whereas the structurally related compounds, gabexate and camostat, did not. The neuroprotective effects of nafamostat and the NR2B antagonist ifenprodil were remarkably suppressed by spermidine, a naturally occurring polyamine that modulates the NR2B subunit. Both nafamostat and sepimostat inhibited [
Identifiants
pubmed: 31892740
doi: 10.1038/s41598-019-56905-x
pii: 10.1038/s41598-019-56905-x
pmc: PMC6938488
doi:
Substances chimiques
Benzamidines
0
Excitatory Amino Acid Antagonists
0
Guanidines
0
Imidazoles
0
Neuroprotective Agents
0
Receptors, N-Methyl-D-Aspartate
0
sepimostate mesilate
103926-82-5
nafamostat
Y25LQ0H97D
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
20409Références
Arch Pharm Res. 2018 Feb;41(2):229-242
pubmed: 29196918
Exp Eye Res. 2008 Mar;86(3):492-9
pubmed: 18243176
J Neurosci. 2002 Jul 15;22(14):5955-65
pubmed: 12122058
Mol Pharmacol. 1993 Oct;44(4):851-9
pubmed: 7901753
Neural Regen Res. 2019 Mar;14(3):391-394
pubmed: 30539803
J Hepatobiliary Pancreat Sci. 2015 Jun;22(6):405-32
pubmed: 25973947
Eur J Pharmacol. 1990 Feb 6;176(2):249-50
pubmed: 2178949
Exp Neurol. 1997 Nov;148(1):157-66
pubmed: 9398458
Mol Neurobiol. 2017 Aug;54(6):4217-4231
pubmed: 27335029
Proc Natl Acad Sci U S A. 1988 Feb;85(4):1307-11
pubmed: 2448800
Nat Neurosci. 2002 Nov;5 Suppl:1039-42
pubmed: 12403981
Eur J Pharmacol. 1997 Jun 5;328(1):45-9
pubmed: 9203567
Biol Pharm Bull. 2012;35(12):2209-13
pubmed: 23207773
FASEB J. 2005 Aug;19(10):1280-9
pubmed: 16051695
Gan To Kagaku Ryoho. 1995 May;22(6):777-83
pubmed: 7755385
Sci Rep. 2014 Jul 02;4:5531
pubmed: 24985053
Surv Ophthalmol. 2015 Jul-Aug;60(4):310-26
pubmed: 25907525
Lancet. 2011 Apr 16;377(9774):1367-77
pubmed: 21453963
J Pharmacol Exp Ther. 2002 Sep;302(3):940-8
pubmed: 12183650
ChemMedChem. 2007 Oct;2(10):1498-510
pubmed: 17849398
Ann N Y Acad Sci. 1999;890:42-50
pubmed: 10668412
World J Gastroenterol. 2006 Jun 7;12(21):3314-23
pubmed: 16733846
Clin Biochem. 1985 Aug;18(4):224-9
pubmed: 2412725
J Neurosci. 1992 Mar;12(3):970-5
pubmed: 1532027
J Gen Physiol. 2018 Aug 6;150(8):1081-1105
pubmed: 30037851
CNS Neurosci Ther. 2018 May;24(5):429-438
pubmed: 29352519
Lancet. 2017 Nov 11;390(10108):2183-2193
pubmed: 28577860
J Med Chem. 1998 Mar 26;41(7):1172-84
pubmed: 9544217
J Pharmacol Exp Ther. 1988 Dec;247(3):1211-21
pubmed: 2849668
Prog Brain Res. 2015;220:127-53
pubmed: 26497788
Transplant Proc. 2016 Jul-Aug;48(6):2192-9
pubmed: 27569970
J Med Chem. 1995 Aug 4;38(16):3138-45
pubmed: 7636876
J Med Chem. 1998 Aug 27;41(18):3499-506
pubmed: 9719603
Graefes Arch Clin Exp Ophthalmol. 2000 Oct;238(10):846-52
pubmed: 11127572
Stroke. 1995 Mar;26(3):503-13
pubmed: 7886734
Auris Nasus Larynx. 2007 Dec;34(4):487-91
pubmed: 17337140
Prog Retin Eye Res. 2010 Nov;29(6):466-75
pubmed: 20452456
Klin Wochenschr. 1989 Feb 1;67(3):149-52
pubmed: 2467043
Hum Mol Genet. 2017 Aug 1;26(R1):R21-R27
pubmed: 28505344
Chem Pharm Bull (Tokyo). 1993 Jan;41(1):117-25
pubmed: 8448813
Invest Ophthalmol Vis Sci. 2005 Apr;46(4):1504-7
pubmed: 15790922
Vis Neurosci. 1992 Jun;8(6):567-73
pubmed: 1586655
Br J Ophthalmol. 2006 Mar;90(3):262-7
pubmed: 16488940
JAMA. 2014 May 14;311(18):1901-11
pubmed: 24825645
Eur J Pharmacol. 1994 Jan 1;266(1):67-77
pubmed: 7907988
Can J Ophthalmol. 2007 Jun;42(3):396-8
pubmed: 17508033
Curr Opin Struct Biol. 2015 Aug;33:68-75
pubmed: 26282925
Jpn J Pharmacol. 1984 Jul;35(3):203-27
pubmed: 6482087
Gan To Kagaku Ryoho. 1994 May;21(6):845-52
pubmed: 8185343
Biochem Pharmacol. 1973 Dec 1;22(23):3099-108
pubmed: 4202581
J Biol Chem. 1996 Apr 19;271(16):9603-11
pubmed: 8621635
Biochim Biophys Acta. 1977 Oct 13;484(2):417-22
pubmed: 143965
Neurosci Lett. 1992 Mar 30;137(2):193-7
pubmed: 1533903
Jpn J Pharmacol. 1990 Jan;52(1):23-34
pubmed: 1689782