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| N-[3-(aminomethyl)benzyl]acetamidine |
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| CHEBI:90721 |
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| N-[3-(aminomethyl)benzyl]acetamidine |
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| An aralkylamine that is Nbenzylacetamidine substituted at position 3 on the benzene ring by an aminomethyl group. An inhibitor of nitric oxide synthase. |
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This entity has been manually annotated by the ChEBI Team.
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| eMolecules:1934669, ZINC000003870614 |
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more structures >>
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call loadScript javascripts\jsmol\core\package.js call loadScript javascripts\jsmol\core\core.z.js -- required by ClazzNode call loadScript javascripts\jsmol\J\awtjs2d\WebOutputChannel.js Jmol JavaScript applet jmolApplet0_object__5761715441574897__ initializing getValue debug = null getValue logLevel = null getValue allowjavascript = null AppletRegistry.checkIn(jmolApplet0_object__5761715441574897__) call loadScript javascripts\jsmol\core\corestate.z.js viewerOptions: { "name":"jmolApplet0_object","applet":true,"documentBase":"https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI%3ACHEBI%3A90721","platform":"J.awtjs2d.Platform","fullName":"jmolApplet0_object__5761715441574897__","display":"jmolApplet0_canvas2d","signedApplet":"true","appletReadyCallback":"Jmol._readyCallback","statusListener":"[J.appletjs.Jmol.MyStatusListener object]","codeBase":"https://www.ebi.ac.uk/chebi/javascripts/jsmol/","syncId":"5761715441574897","bgcolor":"#000" } (C) 2012 Jmol Development Jmol Version: 13.2.7 $Date: 2013-10-01 11:35:15 -0500 (Tue, 01 Oct 2013) $ java.vendor: j2s java.version: 0.0 os.name: j2s Access: ALL memory: 0.0/0.0 processors available: 1 useCommandThread: false appletId:jmolApplet0_object (signed) starting HoverWatcher_1 getValue emulate = null defaults = "Jmol" getValue boxbgcolor = null getValue bgcolor = #000 backgroundColor = "#000" getValue ANIMFRAMECallback = null getValue APPLETREADYCallback = Jmol._readyCallback APPLETREADYCallback = "Jmol._readyCallback" getValue ATOMMOVEDCallback = null getValue CLICKCallback = null getValue ECHOCallback = null getValue ERRORCallback = null getValue EVALCallback = null getValue HOVERCallback = null getValue LOADSTRUCTCallback = null getValue MEASURECallback = null getValue MESSAGECallback = null getValue MINIMIZATIONCallback = null getValue PICKCallback = null getValue RESIZECallback = null getValue SCRIPTCallback = null getValue SYNCCallback = null getValue STRUCTUREMODIFIEDCallback = null getValue doTranslate = null language=en_US getValue popupMenu = null getValue script = null Jmol applet jmolApplet0_object__5761715441574897__ ready call loadScript javascripts\jsmol\core\corescript.z.js call loadScript javascripts\jsmol\J\script\FileLoadThread.js starting QueueThread0_2 script 1 started starting HoverWatcher_3 starting HoverWatcher_4 The Resolver thinks Mol 14W - Ideal conformer Mrv1927 09232115313D starting HoverWatcher_5 Time for openFile(14W - Ideal conformer Mrv1927 09232115313D 28 28 0 0 0 0 999 V2000 3.7060 2.6270 1.9770 C 0 0 0 0 0 0 0 0 0 0 0 0 4.1900 3.0450 3.2160 C 0 0 0 0 0 0 0 0 0 0 0 0 4.0080 4.3660 3.6260 C 0 0 0 0 0 0 0 0 0 0 0 0 3.3420 5.2680 2.7960 C 0 0 0 0 0 0 0 0 0 0 0 0 2.8580 4.8500 1.5570 C 0 0 0 0 0 0 0 0 0 0 0 0 3.0430 3.5320 1.1560 C 0 0 0 0 0 0 0 0 0 0 0 0 2.5220 3.0820 -0.1780 C 0 0 1 0 0 0 0 0 0 0 0 0 3.4990 3.2560 -1.2260 N 0 0 0 0 0 0 0 0 0 0 0 0 3.2730 2.9630 -2.5540 C 0 0 0 0 0 0 0 0 0 0 0 0 4.4170 3.2140 -3.5120 C 0 0 0 0 0 0 0 0 0 0 0 0 2.1580 2.5040 -3.0390 N 0 0 0 0 0 0 0 0 0 0 0 0 4.9020 2.0810 4.1030 C 0 0 1 0 0 0 0 0 0 0 0 0 6.3230 2.0620 3.8630 N 0 0 0 0 0 0 0 0 0 0 0 0 3.8480 1.5970 1.6570 H 0 0 0 0 0 0 0 0 0 0 0 0 4.3830 4.7010 4.5890 H 0 0 0 0 0 0 0 0 0 0 0 0 3.2010 6.2970 3.1160 H 0 0 0 0 0 0 0 0 0 0 0 0 2.3410 5.5600 0.9170 H 0 0 0 0 0 0 0 0 0 0 0 0 2.2460 2.0220 -0.1470 H 0 0 0 0 0 0 0 0 0 0 0 0 1.6250 3.6440 -0.4590 H 0 0 0 0 0 0 0 0 0 0 0 0 4.4040 3.6220 -0.9430 H 0 0 0 0 0 0 0 0 0 0 0 0 4.1550 4.0470 -4.1710 H 0 0 0 0 0 0 0 0 0 0 0 0 5.3370 3.4600 -2.9750 H 0 0 0 0 0 0 0 0 0 0 0 0 4.5900 2.3210 -4.1190 H 0 0 0 0 0 0 0 0 0 0 0 0 1.4670 2.3780 -2.2920 H 0 0 0 0 0 0 0 0 0 0 0 0 4.7500 2.3310 5.1630 H 0 0 0 0 0 0 0 0 0 0 0 0 4.5320 1.0560 3.9630 H 0 0 0 0 0 0 0 0 0 0 0 0 6.6870 2.5320 3.0520 H 0 0 0 0 0 0 0 0 0 0 0 0 6.8970 1.4200 4.3830 H 0 0 0 0 0 0 0 0 0 0 0 0 1 2 2 0 0 0 0 1 6 1 0 0 0 0 1 14 1 0 0 0 0 2 3 1 0 0 0 0 2 12 1 0 0 0 0 3 4 2 0 0 0 0 3 15 1 0 0 0 0 4 5 1 0 0 0 0 4 16 1 0 0 0 0 5 6 2 0 0 0 0 5 17 1 0 0 0 0 6 7 1 0 0 0 0 7 8 1 0 0 0 0 7 18 1 0 0 0 0 7 19 1 0 0 0 0 8 9 1 0 0 0 0 8 20 1 0 0 0 0 9 10 1 0 0 0 0 9 11 2 0 0 0 0 10 21 1 0 0 0 0 10 22 1 0 0 0 0 10 23 1 0 0 0 0 11 24 1 0 0 0 0 12 13 1 0 0 0 0 12 25 1 0 0 0 0 12 26 1 0 0 0 0 13 27 1 0 0 0 0 13 28 1 0 0 0 0 M END): 14 ms reading 28 atoms ModelSet: haveSymmetry:false haveUnitcells:false haveFractionalCoord:false 1 model in this collection. Use getProperty "modelInfo" or getProperty "auxiliaryInfo" to inspect them. Default Van der Waals type for model set to Babel 28 atoms created ModelSet: not autobonding; use forceAutobond=true to force automatic bond creation Script completed Jmol script terminated
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| InChI=1S/C10H15N3/c1-8(12)13-7-10-4-2-3-9(5-10)6-11/h2-5H,6-7,11H2,1H3,(H2,12,13) |
| RODUKNYOEVZQPR-UHFFFAOYSA-N |
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Bronsted base
A molecular entity capable of accepting a hydron from a donor (Bronsted acid).
(via organic amino compound )
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EC 1.14.13.39 (nitric oxide synthase) inhibitor
An EC 1.14.13.* (oxidoreductase acting on paired donors, incorporating 1 atom of oxygen, with NADH or NADPH as one donor) inhibitor that interferes with the action of nitric oxide synthase (EC 1.14.13.39).
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geroprotector
Any compound that supports healthy aging, slows the biological aging process, or extends lifespan.
angiogenesis inhibitor
An agent and endogenous substances that antagonize or inhibit the development of new blood vessels.
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View more via ChEBI Ontology
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N-{[3-(aminomethyl)phenyl]methyl}ethanimidamide
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1400 W
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ChEBI
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1400W
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ChEBI
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W 1400
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ChemIDplus
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W1400
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ChEBI
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180001-34-7
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CAS Registry Number
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ChemIDplus
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8054187
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Reaxys Registry Number
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Reaxys
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Schnichels S, Joachim SC (2021)
The inducible nitric oxide synthase-inhibitor 1400W as a potential treatment for retinal diseases.
Neural regeneration research 16, 1221-1222 [PubMed:33269785] | Putra M, Sharma S, Gage M, Gasser G, Hinojo-Perez A, Olson A, Gregory-Flores A, Puttachary S, Wang C, Anantharam V, Thippeswamy T (2020)
Inducible nitric oxide synthase inhibitor, 1400W, mitigates DFP-induced long-term neurotoxicity in the rat model.
Neurobiology of disease 133, 104443 [PubMed:30940499]
[show Abstract]
Chemical nerve agents (CNA) are increasingly becoming a threat to both civilians and military personnel. CNA-induced acute effects on the nervous system have been known for some time and the long-term consequences are beginning to emerge. In this study, we used diisopropylfluorophosphate (DFP), a seizurogenic CNA to investigate the long-term impact of its acute exposure on the brain and its mitigation by an inducible nitric oxide synthase (iNOS) inhibitor, 1400W as a neuroprotectant in the rat model. Several experimental studies have demonstrated that DFP-induced seizures and/or status epilepticus (SE) causes permanent brain injury, even after the countermeasure medication (atropine, oxime, and diazepam). In the present study, DFP-induced SE caused a significant increase in iNOS and 3-nitrotyrosine (3-NT) at 24 h, 48 h, 7d, and persisted for a long-term (12 weeks post-exposure), which led to the hypothesis that iNOS is a potential therapeutic target in DFP-induced brain injury. To test the hypothesis, we administered 1400W (20 mg/kg, i.m.) or the vehicle twice daily for the first three days of post-exposure. 1400W significantly reduced DFP-induced iNOS and 3-NT upregulation in the hippocampus and piriform cortex, and the serum nitrite levels at 24 h post-exposure. 1400W also prevented DFP-induced mortality in <24 h. The brain immunohistochemistry (IHC) at 7d post-exposure revealed a significant reduction in gliosis and neurodegeneration (NeuN+ FJB positive cells) in the 1400W-treated group. 1400W, in contrast to the vehicle, caused a significant reduction in the epileptiform spiking and spontaneous recurrent seizures (SRS) during 12 weeks of continuous video-EEG study. IHC of brain sections from the same animals revealed a significant reduction in reactive gliosis (both microgliosis and astrogliosis) and neurodegeneration across various brain regions in the 1400W-treated group when compared to the vehicle-treated group. A multiplex assay from hippocampal lysates at 6 weeks post-exposure showed a significant increase in several key pro-inflammatory cytokines/chemokines such as IL-1α, TNFα, IL-1β, IL-2, IL-6, IL-12, IL-17a, MCP-1, LIX, and Eotaxin, and a growth factor, VEGF in the vehicle-treated animals. 1400W significantly suppressed IL-1α, TNFα, IL-2, IL-12, and MCP-1 levels. It also suppressed DFP-induced serum nitrite levels at 6 weeks post-exposure. In the Morris water maze, the vehicle-treated animals spent significantly less time in the target quadrant in a probe trial at 9d post-exposure compared to their time spent in the same quadrant 11 days previously (i.e., 2 days prior to DFP exposure). Such a difference was not observed in the 1400W and control groups. However, learning and short-term memory were unaffected when tested at 10-16d and 28-34d post-exposure. Accelerated rotarod, horizontal bar test, and the forced swim test revealed no significant changes between groups. Overall, the findings from this study suggest that 1400W may be considered as a potential therapeutic agent as a follow-on therapy for CNA exposure, after controlling the acute symptoms, to prevent mortality and some of the long-term neurotoxicity parameters such as epileptiform spiking, SRS, neurodegeneration, reactive gliosis in some brain regions, and certain key proinflammatory cytokines and chemokine. | Shepherd E, Greiner SP, Bowdridge SA (2020)
Characterization of ovine monocyte activity when cultured with Haemonchus contortus larvae in vitro.
Parasite immunology 42, e12773 [PubMed:32603502]
[show Abstract]
AimsThe objective of this study was to identify and characterize cell populations within ovine peripheral blood mononuclear cells (PBMCs) associated with Haemonchus contortus (Hc) larval morbidity and impairment in vitro.Methods and resultsMonocytes and lymphocytes were separated from PBMC from parasite-resistant St. Croix (STC) sheep and parasite-susceptible Suffolk (SUF) sheep. Cells were cultured with Hc third stage larvae (L3) for 9 h. Larval morbidity was assessed using ATP concentration. Activation status was determined through gene expression analysis and enzyme inhibition. Enzymes arginase-1 (Arg1) and inducible nitric oxide synthase (iNOS) were inhibited using BEC (S-(2-boronoethyl)-I-cysteine) and 1400W (N-(3-(aminomethyl)benzyl)acetamidine), respectively. Larval ATP was lower when cultured with STC-derived monocytes (0.015 μmol/L ATP) compared to SUF-derived monocytes (0.067 μmol/L ATP) (P < .001), or lymphocytes from either breed (STC: 0.085 μmol/L, SUF: 0.112 μmol/L ATP) (P < .001). SUF-derived monocytes displayed higher expression of M1 genes, whereas STC-derived monocytes displayed M2 genes continuously. Inhibition of Arg1 decreased monocyte function in both breeds, whereas iNOS inhibition restored SUF-derived monocyte function.ConclusionsTogether, these data indicate STC-derived monocytes favour M2 phenotype when exposed to L3, where SUF-derived monocyte function resembled M1 phenotype and described potential for improving Suffolk sheep through modulating inflammatory responses. | Palumbo P, Lombardi F, Augello FR, Giusti I, Luzzi S, Dolo V, Cifone MG, Cinque B (2019)
NOS2 inhibitor 1400W Induces Autophagic Flux and Influences Extracellular Vesicle Profile in Human Glioblastoma U87MG Cell Line.
International journal of molecular sciences 20, E3010 [PubMed:31226744]
[show Abstract]
The relevance of nitric oxide synthase 2 (NOS2) as a prognostic factor in Glioblastoma Multiforme (GBM) malignancy is emerging. We analyzed the effect of NOS2 inhibitor 1400W on the autophagic flux and extracellular vesicle (EV) secretion in U87MG glioma cells. The effects of glioma stem cells (GSC)-derived EVs on adherent U87MG were evaluated. Cell proliferation and migration were examined while using Cell Counting Kit-8 assay (CCK-8) and scratch wound healing assay. Cell cycle profile and apoptosis were analyzed by flow cytometry. Autophagy-associated acidic vesicular organelles were detected and quantified by acridine orange staining. The number and size of EVs were assessed by nanoparticle tracking analysis. EV ultrastructure was verified by transmission electron microscopy (TEM). WB was used to analyze protein expression and acid sphingomyelinase was determined through ceramide levels. 1400W induced autophagy and EV secretion in both adherent U87MG and GSCs. EVs secreted by 1400W-treated GSC, but not those from untreated cells, were able to inhibit adherent U87MG cell growth and migration while also inducing a relevant level of autophagy. The hypothesis of NOS2 expression as GBM profile marker or interesting therapeutic target is supported by our findings. Autophagy and EV release following treatment with the NOS2 inhibitor could represent useful elements to better understand the complex biomolecular frame of GBM. | Tse K, Hammond D, Simpson D, Beynon RJ, Beamer E, Tymianski M, Salter MW, Sills GJ, Thippeswamy T (2019)
The impact of postsynaptic density 95 blocking peptide (Tat-NR2B9c) and an iNOS inhibitor (1400W) on proteomic profile of the hippocampus in C57BL/6J mouse model of kainate-induced epileptogenesis.
Journal of neuroscience research 97, 1378-1392 [PubMed:31090233]
[show Abstract]
Antiepileptogenic agents that prevent the development of epilepsy following a brain insult remain the holy grail of epilepsy therapeutics. We have employed a label-free proteomic approach that allows quantification of large numbers of brain-expressed proteins in a single analysis in the mouse (male C57BL/6J) kainate (KA) model of epileptogenesis. In addition, we have incorporated two putative antiepileptogenic drugs, postsynaptic density protein-95 blocking peptide (PSD95BP or Tat-NR2B9c) and a highly selective inducible nitric oxide synthase inhibitor, 1400W, to give an insight into how such agents might ameliorate epileptogenesis. The test drugs were administered after the induction of status epilepticus (SE) and the animals were euthanized at 7 days, their hippocampi removed, and subjected to LC-MS/MS analysis. A total of 2,579 proteins were identified; their normalized abundance was compared between treatment groups using ANOVA, with correction for multiple testing by false discovery rate. Significantly altered proteins were subjected to gene ontology and KEGG pathway enrichment analyses. KA-induced SE was most robustly associated with an alteration in the abundance of proteins involved in neuroinflammation, including heat shock protein beta-1 (HSP27), glial fibrillary acidic protein, and CD44 antigen. Treatment with PSD95BP or 1400W moderated the abundance of several of these proteins plus that of secretogranin and Src substrate cortactin. Pathway analysis identified the glutamatergic synapse as a key target for both drugs. Our observations require validation in a larger-scale investigation, with candidate proteins explored in more detail. Nevertheless, this study has identified several mechanisms by which epilepsy might develop and several targets for novel drug development. OPEN PRACTICES: This article has been awarded Open Data. All materials and data are publicly accessible as supporting information. Learn more about the Open Practices badges from the Center for Open Science: https://osf.io/tvyxz/wiki. | Gao Y, Zhou S, Xu Y, Sheng S, Qian SY, Huo X (2019)
Nitric oxide synthase inhibitors 1400W and L-NIO inhibit angiogenesis pathway of colorectal cancer.
Nitric oxide : biology and chemistry 83, 33-39 [PubMed:30590117]
[show Abstract]
BackgroundIt has been widely accepted that angiogenesis plays fundamental roles in colorectal cancer development, and therapeutic targeting of this pathway has achieved promising outcome. Recent reports have highlighted the involvement of nitric oxide synthases (NOS) in the development of angiogenesis in cancer; however, the mechanism and therapeutic value of NOS inhibitors in colon cancer are largely unknown.ObjectiveIn this study, we investigated the effects and mechanism of the NOS inhibitors 1400W and L-NIO on the angiogenesis pathway in colorectal cancer cells.MethodsTwo colorectal cancer cell lines, HT 29 and HCT 116, were used for in vitro study. The expression of iNOS and eNOS in cells was knocked down via shRNA transfection. MTS assays and wound healing assays were performed to assess cell proliferation and migration after shRNA transfection or treatment with 1400W, L-NIO, and 5-fluorouracil. Human angiogenesis PCR arrays and proteome profiler human angiogenesis arrays were used to detect changes in key genes/proteins involved in modulating angiogenesis after 1400W and L-NIO treatment.ResultsKnockdown of iNOS and eNOS significantly inhibited colorectal cancer cell growth. Treatment with NOS inhibitors inhibited colorectal cancer cell growth and migration, and was associated with suppression of the expression of key genes/proteins involved in the angiogenesis pathway. In addition, the combined use of NOS inhibitors with 5-fluorouracil showed enhanced inhibition of cell proliferation and migration.ConclusionNOS inhibitors could suppress colorectal cancer cell growth and migration, likely via suppressing the angiogenesis pathway. | Sumayao R, Newsholme P, McMorrow T (2018)
Inducible nitric oxide synthase inhibitor 1400W increases Na+ ,K+ -ATPase levels and activity and ameliorates mitochondrial dysfunction in Ctns null kidney proximal tubular epithelial cells.
Clinical and experimental pharmacology & physiology 45, 1149-1160 [PubMed:29924417]
[show Abstract]
Nitric oxide (NO) has been shown to play an important role in renal physiology and pathophysiology partly through its influence on various transport systems in the kidney proximal tubule. The role of NO in kidney dysfunction associated with lysosomal storage disorder, cystinosis, is largely unknown. In the present study, the effects of inducible nitric oxide synthase (iNOS)-specific inhibitor, 1400W, on Na+ ,K+ -ATPase activity and expression, mitochondrial integrity and function, nutrient metabolism, and apoptosis were investigated in Ctns null proximal tubular epithelial cells (PTECs). Ctns null PTECs exhibited an increase in iNOS expression, augmented NO and nitrite/nitrate production, and reduced Na+ ,K+ -ATPase expression and activity. In addition, these cells displayed depolarized mitochondria, reduced adenosine triphosphate content, altered nutrient metabolism, and elevated apoptosis. Treatment of Ctns null PTECs with 1400W abolished these effects which culminated in the mitigation of apoptosis in these cells. These findings indicate that uncontrolled NO production may constitute the upstream event that leads to the molecular and biochemical alterations observed in Ctns null PTECs and may explain, at least in part, the generalized proximal tubular dysfunction associated with cystinosis. Further studies are needed to realize the potential benefits of anti-nitrosative therapies in improving renal function and/or attenuating renal injury in cystinosis. | Staunton CA, Barrett-Jolley R, Djouhri L, Thippeswamy T (2018)
Inducible nitric oxide synthase inhibition by 1400W limits pain hypersensitivity in a neuropathic pain rat model.
Experimental physiology 103, 535-544 [PubMed:29441689]
[show Abstract]
New findingsWhat is the central question of this study? Can modulation of inducible NO synthase reduce pain behaviour and pro-inflammatory cytokine signalling in a rat model of neuropathic pain? What is the main finding and its importance? Nitric oxide synthase-based therapies could be effective for the treatment of peripheral neuropathic pain.AbstractPeripheral neuropathic pain (PNP), resulting from injury to or dysfunction of a peripheral nerve, is a major health problem that affects 7-8% of the population. It is inadequately controlled by current drugs and is characterized by pain hypersensitivity, which is believed to be attributable to sensitization of peripheral and CNS neurons by various inflammatory mediators. Here we examined, in a rat model of PNP: (i) whether reducing levels of nitric oxide (NO) with 1400W, a highly selective inhibitor of inducible NO synthase (iNOS), would prevent or attenuate pain hypersensitivity; and (ii) the effects of 1400W on plasma concentrations of several cytokines that are secreted after iNOS upregulation during chronic pain states. The L5 spinal nerve axotomy (SNA) model of PNP was used, and 1400W (20 mg kg-1 ) was administered i.p. at 8 h intervals for 3 days starting at 18 h post-SNA. Changes in plasma concentrations of 12 cytokines in SNA rats treated with 1400W were examined using multiplex enzyme-linked immunosorbent assay. The SNA rats developed behavioural signs of mechanical and heat hypersensitivity. Compared with the vehicle/control, 1400W significantly: (i) limited development of mechanical hypersensitivity at 66 h post-SNA and of heat hypersensitivity at 42 h and at several time points tested thereafter; and (ii) increased the plasma concentrations of interleukin (IL)-1α, IL-1β and IL-10 in the SNA rats. The findings suggest that 1400W might exert its analgesic effects by reducing iNOS and altering the balance between the pro-inflammatory (IL-1β and IL-1α) and anti-inflammatory (IL-10) cytokines and that therapies targeting NO or its enzymes might be effective for the treatment of PNP. | Shi Q, Liu X, Wang N, Zheng X, Ran J, Liu Z, Fu J, Zheng J (2017)
1400W ameliorates acute hypobaric hypoxia/reoxygenation-induced cognitive deficits by suppressing the induction of inducible nitric oxide synthase in rat cerebral cortex microglia.
Behavioural brain research 319, 188-199 [PubMed:27888018]
[show Abstract]
Nitric oxide (NO) is involved in neuronal modifications, and overproduction of NO contributes to memory deficits after acute hypobaric hypoxia-reoxygenation. This study investigated the ability of the iNOS inhibitor 1400W to counteract spatial memory deficits following acute hypobaric hypoxia-reoxygenation, and to affect expression of NOS, NO, 3-NT and MDA production, and apoptosis in rat cerebral cortex. We also used primary rat microglia to investigate the effect of 1400W on expression of NOS, NO, 3-NT and MDA production, and apoptosis. Acute hypobaric hypoxia-reoxygenation impaired spatial memory, and was accompanied by activated microglia, increased iNOS expression, NO, 3-NT and MDA production, and neuronal cell apoptosis in rat cerebral cortex one day post-reoxygenation. 1400W treatment inhibited iNOS expression without affecting nNOS or eNOS. 1400W also reduced NO, 3-NT and MDA production, and prevented neuronal cell apoptosis in cerebral cortex, in addition to reversing spatial memory impairment after acute hypobaric hypoxia-reoxygenation. Hypoxia-reoxygenation activated primary microglia, and increased iNOS and nNOS expression, NO, 3-NT, and MDA production, and apoptosis. Treatment with 1400W inhibited iNOS expression without affecting nNOS, reduced NO, 3-NT and MDA production, and prevented apoptosis in primary microglia. Based on the above findings, we concluded that the highly selective iNOS inhibitor 1400W inhibited iNOS induction in microglial cells, and reduced generation of NO, thereby mitigating oxidative stress and neuronal cell apoptosis in the rat cerebral cortex, and improving the spatial memory dysfunction caused by acute hypobaric hypoxia-reoxygenation. | Guo C, Atochina-Vasserman E, Abramova H, George B, Manoj V, Scott P, Gow A (2016)
Role of NOS2 in pulmonary injury and repair in response to bleomycin.
Free radical biology & medicine 91, 293-301 [PubMed:26526764]
[show Abstract]
Nitric oxide (NO) is derived from multiple isoforms of the Nitric Oxide Synthases (NOSs) within the lung for a variety of functions; however, NOS2-derived nitrogen oxides seem to play an important role in inflammatory regulation. In this study, we investigate the role of NOS2 in pulmonary inflammation/fibrosis in response to intratracheal bleomycin instillation (ITB) and to determine if these effects are related to macrophage phenotype. Systemic NOS2 inhibition was achieved by administration of 1400W, a specific and potent NOS2 inhibitor, via osmotic pump starting six days prior to ITB. 1400W administration attenuated lung inflammation, decreased chemotactic activity of the broncheoalveolar lavage (BAL), and reduced BAL cell count and nitrogen oxide production. S-nitrosylated SP-D (SNO-SP-D), which has a pro-inflammatory function, was formed in response to ITB; but this formation, as well as structural disruption of SP-D, was inhibited by 1400W. mRNA levels of IL-1β, CCL2 and Ptgs2 were decreased by 1400W treatment. In contrast, expression of genes associated with alternate macrophage activation and fibrosis Fizz1, TGF-β and Ym-1 was not changed by 1400W. Similar to the effects of 1400W, NOS2-/- mice displayed an attenuated inflammatory response to ITB (day 3 and day 8 post-instillation). The DNA-binding activity of NF-κB was attenuated in NOS2-/- mice; in addition, expression of alternate activation genes (Fizz1, Ym-1, Gal3, Arg1) was increased. This shift towards an increase in alternate activation was confirmed by western blot for Fizz-1 and Gal-3 that show persistent up-regulation 15 days after ITB. In contrast arginase, which is increased in expression at 8 days post ITB in NOS2-/-, resolves by day 15. These data suggest that NOS2, while critical to the development of the acute inflammatory response to injury, is also necessary to control the late phase response to ITB. | Puttachary S, Sharma S, Verma S, Yang Y, Putra M, Thippeswamy A, Luo D, Thippeswamy T (2016)
1400W, a highly selective inducible nitric oxide synthase inhibitor is a potential disease modifier in the rat kainate model of temporal lobe epilepsy.
Neurobiology of disease 93, 184-200 [PubMed:27208748]
[show Abstract]
Status epilepticus (SE) initiates epileptogenesis to transform normal brain to epileptic state which is characterized by spontaneous recurrent seizures (SRS). Prior to SRS, progressive changes occur in the brain soon after SE, for example, loss of blood-brain barrier (BBB) integrity, neuronal hyper-excitability (epileptiform spiking), neuroinflammation [reactive gliosis, high levels of reactive oxygen/nitrogen species (ROS/RNS)], neurodegeneration and synaptic re-organization. Our hypothesis was that modification of early epileptogenic events will alter the course of disease development and its progression. We tested the hypothesis in the rat kainate model of chronic epilepsy using a novel disease modifying drug, 1400W, a highly selective inhibitor of inducible nitric oxide synthase (iNOS/NOS-II). In an in vitro mouse brain slice model, using a multi-electrode array system, co-application of 1400W with kainate significantly suppressed kainate-induced epileptiform spiking. In the rats, in vivo, 4h after the induction of SE with kainate, 1400W (20mg/kg, i.p.) was administered twice daily for three days to target early events of epileptogenesis. The rats were subjected to continuous (24/7) video-EEG monitoring, remotely, for six months from epidurally implanted cortical electrodes. The 1400W treatment significantly reduced the epileptiform spike rate during the first 12-74h post-SE, which resulted in >90% reduction in SRS in long-term during the six month period when compared to the vehicle-treated control group (257±113 versus 19±10 episodes). Immunohistochemistry (IHC) of brain sections at seven days and six months revealed a significant reduction in; reactive astrogliosis and microgliosis (M1 type), extravascular serum albumin (a marker for BBB leakage) and neurodegeneration in the hippocampus, amygdala and entorhinal cortex in the 1400W-treated rats when compared to the vehicle control. In the seven day group, hippocampal Western blots revealed downregulation of inwardly-rectifying potassium (Kir 4.1) channels and glutamate transporter-1 (GLT-1) levels in the vehicle group, and 1400W treatment partially reversed Kir 4.1 levels, however, GLT-1 levels were unaffected. In the six month group, a significant reduction in mossy fiber staining intensity in the inner molecular layer of the dentate gyrus was observed in the 1400W-treated group. Overall these findings demonstrate that 1400W, by reducing the epileptiform spike rate during the first three days of post-insult, potentially modifies epileptogenesis and the severity of chronic epilepsy in the rat kainate model of TLE. | Oversø Hansen P, Kringelholt S, Simonsen U, Bek T (2015)
Hypoxia-induced relaxation of porcine retinal arterioles in vitro depends on inducible NO synthase and EP4 receptor stimulation in the perivascular retina.
Acta ophthalmologica 93, 457-463 [PubMed:25619924]
[show Abstract]
PurposeHypoxia-induced relaxation of porcine retinal arterioles has been shown to be reduced during inhibition of prostaglandin synthesis and nitric oxide synthase (NOS). The purpose of this study was to identity the specific prostaglandin receptor(s) and source(s) of NO mediating this effect.MethodsPorcine retinal arterioles with preserved perivascular retinal tissue were mounted in a myograph and were exposed to hypoxia in the presence of one of the following: the general NO synthase inhibitor L-NAME, the selective iNOS inhibitor 1400W, the selective nNOS inhibitor 7-nitroindazole, the general cyclooxygenase (COX) inhibitor ibuprofen or an antagonist to the FP- (AL 8810), DP- (BWA868C), EP1 - (SC-19220), EP2 - (PF-044189) or EP4 receptors (GW627368X). The experiments were repeated after removal of the perivascular retinal tissue.ResultsHypoxia induced relaxation of retinal arterioles with preserved perivascular retinal tissue. This relaxation was significantly reduced in the presence of L-NAME, 1400W, ibuprofen and the EP4 receptor antagonist GW627368X. The simultaneous addition of L-NAME or 1400W in combination with ibuprofen, but not GW627368X, reduced hypoxia-induced vasorelaxation additively as compared to the effect of the compounds individually.ConclusionHypoxia-induced vasorelaxation of porcine retinal arterioles is mediated by inducible NOS and stimulation of EP4 receptors acting through separate pathways, but mechanisms unrelated to the studied prostaglandin receptors and NOS products are also involved. | Gautam M, Kumar R, Prasoon P, Ray SB (2015)
Antinociceptive effect of 1400 W, an inhibitor of inducible nitric oxide synthase, following hind paw incision in rats.
Nitric oxide : biology and chemistry 50, 98-104 [PubMed:26362773]
[show Abstract]
Acute tissue damage is accompanied by synthesis of nitric oxide (NO) in the inflamed tissue as well as in the spinal cord. NO release at the spinal level is likely involved in the neuroplastic changes contributing to pain. Also, previous studies indicate that this could be due to the inducible isoform of the nitric oxide synthase (iNOS) enzyme. Though, the role of NO has been investigated in several animal models of nociception, the precise contribution of NO to nociception arising from hind paw incision is unknown, which is a rodent model of postoperative pain. In the present work, we have estimated the formation of NO in Sprague-Dawley rats, both at the site of incision and the corresponding spinal cord levels by Griess assay. Subsequently, naive rats were implanted with chronic indwelling intrathecal (i.t.) catheters. Fixed quantity (30 μg) of 1400 W, an iNOS inhibitor, was either administered locally into the wound at the time of incision or into the i.t. space, 15 min before hind paw incision. In a different set, i.t. 1400 W was administered, 20 h after incision. Control group received i.t. saline. Nociception was evaluated by guarding score, mechanical allodynia and thermal hyperalgesia. NO level was significantly increased between 4 h - day 1 locally and at 4 h at the spinal level after incision. Local inhibition of iNOS produced transient decrease of guarding (4-12 h) whereas pronounced decrease of guarding and allodynia was evident after spinal inhibition of iNOS. Also, spinal NO level decreased after i.t. drug administration. Post-incision drug treatment resulted in greater antinociceptive effect at day 1 though not on day 2. These results indicate involvement of NO in postincisional nociception in rats. | Mertas A, Duliban H, Szliszka E, Machorowska-Pieniążek A, Król W (2014)
N-[3-(aminomethyl)benzyl]acetamidine (1400 W) as a potential immunomodulatory agent.
Oxidative medicine and cellular longevity 2014, 491214 [PubMed:24995119]
[show Abstract]
This study was designed to investigate the relationship between NO, IL-12, and TNF-α production by J774A.1 macrophages activated with LPS and IFN-γ in the presence of N-[3-(aminomethyl)benzyl]acetamidine (1400 W). 1400 W is a novel, highly selective inhibitor of inducible nitric oxide synthase (iNOS). We compared the obtained data with the effect of N(G)-monomethyl-L-arginine (L-NMMA) (a nonselective NOS inhibitor) and L-N(G)-(1-iminoethyl)lysine (L-NIL) (a relatively selective inhibitor of iNOS activity) on cells in this model. To investigate the involvement of an exogenous NO on IL-12 and TNF-α production we used NO donor-S-nitrosocaptopril (S-NO-Cap). The most potent inhibitor of NO generation was 1400 W. This compound also markedly increased IL-12 p40 secretion and decreased TNF-α release. L-NIL suppressed both NO and TNF-α production, but it did not change IL-12 p40 synthesis. The effect of L-NMMA on NO generation was weaker than other inhibitors. Moreover, it decreased TNF-α secretion slightly but not significantly. IL-12 p40 production by stimulated cells was inhibited by S-NO-Cap in a dose dependent manner, but no effect on TNF-α release was observed. The potency and selectivity of 1400 W as an inhibitor of iNOS and cytokine release modifier are encouraging for therapeutic use. | Hosgood SA, Yates PJ, Nicholson ML (2014)
1400W reduces ischemia reperfusion injury in an ex-vivo porcine model of the donation after circulatory death kidney donor.
World journal of transplantation 4, 299-305 [PubMed:25540738]
[show Abstract]
AimTo investigate the effects of 1400W-a selective inducible nitric oxide synthase (iNOS) inhibitor in a model of donation after circulatory death (DCD) kidneys.MethodsPorcine kidneys were retrieved after 25 min warm ischemia. They were then stored on ice for 18 h before being reperfused ex vivo with oxygenated autologous blood on an isolated organ perfusion system. The selective iNOS inhibitor 1400W (10 mg/kg) was administered before reperfusion (n = 6) vs control group (n = 7). Creatinine (1000 μmol/L) was added to the system, renal and tubular cell function and the level of ischemia reperfusion injury were assessed over 3 h of reperfusion using plasma, urine and tissue samples.ResultsKidneys treated with 1400W had a higher level of creatinine clearance (CrCl) [area under the curve (AUC) CrCl: 2.37 ± 0.97 mL/min per 100 g vs 0.96 ± 0.32 mL/min per 100 g, P = 0.004] and urine output [Total: 320 ± 96 mL vs 156 ± 82 mL, P = 0.008]. There was no significant difference in levels of fractional excretion of sodium (AUC, Fr ex Na+: Control, 186.3% ± 81.7%.h vs 1400W, 153.4% ± 12.1%.h, P = 0.429). Levels of total protein creatinine ratio were significantly lower in the 1400W group after 1 h of reperfusion (1h Pr/Cr: 1400W 9068 ± 6910 mg/L/mmol/L vs Control 21586 ± 5464 mg/L/mmol/L, P = 0.026). Levels of 8-isoprostane were significantly lower in the 1400W group [8-iso/creatinine ratio: Control 239 ± 136 pg/L/mmol/L vs 1400W 139 ± 47 pg/L/mmol/L, P = 0.041].ConclusionThis study demonstrated that 1400W reduced ischaemia reperfusion injury in this porcine kidney model of DCD donor. Kidneys had improved renal function and reduced oxidative stress. | Danilov A, Shaposhnikov M, Plyusnina E, Kogan V, Fedichev P, Moskalev A (2013)
Selective anticancer agents suppress aging in Drosophila.
Oncotarget 4, 1507-1526 [PubMed:24096697]
[show Abstract]
Mutations of the PI3K, TOR, iNOS, and NF-κB genes increase lifespan of model organisms and reduce the risk of some aging-associated diseases. We studied the effects of inhibitors of PI3K (wortmannin), TOR (rapamycin), iNOS (1400W), NF-κB (pyrrolidin dithiocarbamate and QNZ), and the combined effects of inhibitors: PI3K (wortmannin) and TOR (rapamycin), NF-κB (pyrrolidin dithiocarbamates) and PI3K (wortmannin), NF-κB (pyrrolidine dithiocarbamates) and TOR (rapamycin) on Drosophila melanogaster lifespan and quality of life (locomotor activity and fertility). Our data demonstrate that pharmacological inhibition of PI3K, TOR, NF-κB, and iNOS increases lifespan of Drosophila without decreasing quality of life. The greatest lifespan expanding effect was achieved by a combination of rapamycin (5 μM) and wortmannin (5 μM) (by 23.4%). The bioinformatic analysis (KEGG, REACTOME.PATH, DOLite, and GO.BP) showed the greatest aging-suppressor activity of rapamycin, consistent with experimental data. | Rus A, Castro L, Del Moral ML, Peinado A (2010)
Inducible NOS inhibitor 1400W reduces hypoxia/re-oxygenation injury in rat lung.
Redox report : communications in free radical research 15, 169-178 [PubMed:20663293]
[show Abstract]
Nitric oxide (NO(*)) from inducible NO(*) synthase (iNOS) has been reported to either protect against, or contribute to, hypoxia/re-oxygenation lung injury. The present work aimed to clarify this double role in the hypoxic lung. With this objective, a follow-up study was made in Wistar rats submitted to hypoxia/re-oxygenation (hypoxia for 30 min; re-oxygenation of 0 h, 48 h, and 5 days), with or without prior treatment with the selective iNOS inhibitor 1400W (10 mg/kg). NO(*) levels (NOx), lipid peroxidation, apoptosis, and protein nitration were analysed. This is the first time-course study which investigates the effects of 1400W during hypoxia/re-oxygenation in the rat lung. The results showed that the administration of 1400W lowered NOx levels in all the experimental groups. In addition, lipid peroxidation, the percentage of apoptotic cells, and nitrated protein expression fell in the late post-hypoxia period (48 h and 5 days). Our results reveal that the inhibition of iNOS in the hypoxic lung reduced the damage observed before the treatment with 1400W, suggesting that iNOS-derived NO(*) may exert a negative effect on this organ during hypoxia/re-oxygenation. These findings are notable, since they indicate that any therapeutic strategy aimed at controlling excess generation of NO(*) from iNOS may be useful in alleviating NO(*)-mediated adverse effects in hypoxic lungs. | Fedorov R, Hartmann E, Ghosh DK, Schlichting I (2003)
Structural basis for the specificity of the nitric-oxide synthase inhibitors W1400 and Nomega-propyl-L-Arg for the inducible and neuronal isoforms.
The Journal of biological chemistry 278, 45818-45825 [PubMed:12954642]
[show Abstract]
The high level of amino acid conservation and structural similarity in the immediate vicinity of the substrate binding sites of the oxygenase domains of the nitric-oxide synthase (NOS) isoforms (eNOSoxy, iNOSoxy, and nNOSoxy) make the interpretation of the structural basis of inhibitor isoform specificity a challenge and provide few clues for the design of new selective compounds. Crystal structures of iNOSoxy and nNOSoxy complexed with the inhibitors W1400 and Nomega-propyl-l-arginine provide a rationale for their isoform specificity. It involves differences outside the immediate active site as well as a conformational flexibility in the active site that allows the adoption of distinct conformations in response to interactions with the inhibitors. This flexibility is determined by isoform-specific residues outside the active site. | Li H, Raman CS, Martásek P, Masters BS, Poulos TL (2001)
Crystallographic studies on endothelial nitric oxide synthase complexed with nitric oxide and mechanism-based inhibitors.
Biochemistry 40, 5399-5406 [PubMed:11331003]
[show Abstract]
The crystal structure of the endothelial nitric oxide synthase (NOS) heme domain complexed with NO reveals close hydrogen bonding interactions between NO and the terminal guanidino nitrogen of the substrate, L-arginine. Dioxygen is expected to bind in a similar mode which will facilitate proton abstraction from L-Arg to dioxygen, a required step for O-O bond cleavage. Structures of mechanism-based NOS inhibitors, N(5)-(1-iminoethyl)-L-ornithine and N-(3-(aminomethyl)benzyl)acetamidine, provide clues on how this class of compounds operate as suicide substrate inhibitors leading to heme oxidation. | Muijsers RB, van Ark I, Folkerts G, Koster AS, van Oosterhout AJ, Postma DS, Nijkamp FP (2001)
Apocynin and 1400 W prevents airway hyperresponsiveness during allergic reactions in mice.
British journal of pharmacology 134, 434-440 [PubMed:11564663]
[show Abstract]
1. The contribution of reactive nitrogen species to the development of airway hyperresponsiveness in a mouse model of allergic inflammation was investigated by the use of selective inhibitors of nitric oxide and superoxide formation. 2. Sensitized mice, repeatedly challenged with ovalbumin showed a significant (P<0.001, n=9) increase in airway responsiveness measured using whole body plethysmography. This hyperresponsiveness was accompanied by an influx of eosinophils into the airway lumen and increased levels of ovalbumin-specific serum IgE. 3. Treatment of mice with the iNOS inhibitor 1400 W or the NADPH-oxidase inhibitor apocynin did not significantly alter cellular influx into the airway lumen nor serum ovalbumin specific IgE. In contrast, apocynin as well as 1400 W inhibited ovalbumin-induced airway hyperresponsiveness (P<0.001 and P<0.05 respectively, n=9). Furthermore, the airways of allergen challenged animals showed clear 3-nitrotyrosine staining, which was mainly located in eosinophils. Remarkably, treatment with apocynin or 1400 W did not alter 3-nitrotyrosine staining. 4. These data suggest that the development of airway hyperresponsiveness during the airway inflammation upon ovalbumin challenge is dependent on the release of both superoxide and nitric oxide and is therefore likely to be dependent on reactive nitrogen species. This mechanism, however, is not reflected by 3-nitrotyrosine formation in the airways. | Menchén LA, Colón AL, Moro MA, Leza JC, Lizasoain I, Menchén P, Alvarez E, Lorenzo P (2001)
N-(3-(aminomethyl)benzyl)acetamidine, an inducible nitric oxide synthase inhibitor, decreases colonic inflammation induced by trinitrobenzene sulphonic acid in rats.
Life sciences 69, 479-491 [PubMed:11459438]
[show Abstract]
Gastrointestinal inflammation has been associated with an increased generation of nitric oxide (NO) and the expression of the inducible NO synthase (iNOS). Using an experimental model of colitis induced by trinitrobenzene sulphonic acid (TNBS), we sought to determine whether the administration of N-(3-(Aminomethyl)benzyl)acetamidine (1400W), a specific inhibitor of iNOS, has a beneficial action on the colonic injury. 1400W (0.4 and 2 mg/kg/day) was administered intraperitoneally from day 5 to 10 after intrarectal instillation of TNBS. TNBS led to colonic ulceration and inflammation, an increase of colonic myeloperoxidase activity and the expression of the calcium-independent NOS from days 1 to 15. 1400W reduced the macroscopic damage and the histological changes induced by TNBS as well as the calcium-independent NOS activity and myeloperoxidase activity determined over 30 min after sacrifice. These findings indicate that the expression of iNOS accounts for most of the damage caused by TNBS and that the administration of 1400W after the onset of colitis has a beneficial action on the colonic injury. | Kankuri E, Vaali K, Knowles RG, Lähde M, Korpela R, Vapaatalo H, Moilanen E (2001)
Suppression of acute experimental colitis by a highly selective inducible nitric-oxide synthase inhibitor, N-[3-(aminomethyl)benzyl]acetamidine.
The Journal of pharmacology and experimental therapeutics 298, 1128-1132 [PubMed:11504810]
[show Abstract]
High concentrations of nitric oxide (NO) produced by the inducible nitric-oxide synthase (iNOS) are associated with ulcerative inflammation and disease activity in colitis. Therefore, inhibition of iNOS serves as a novel experimental approach to treat gut inflammation. The aim of the present study was to investigate the effects of a novel highly selective iNOS inhibitor, N-[3-(aminomethyl)benzyl]acetamidine (1400W), as compared with a nonselective NOS inhibitor, N(G)-nitro-L-arginine-methyl-ester (L-NAME), in 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced acute colitis in the rat. Increased expression of iNOS protein and mRNA was found in acute TNBS-induced colitis along with neutrophil infiltration, inflammatory edema, and tissue damage. In a 24-h model of acute colitis, subcutaneous injections of 1400W (5 or 10 mg/kg t.i.d.) produced a 56 and 95% reduction in inflammatory edema formation, a 68 and 63% reduction in neutrophil infiltration (measured as myeloperoxidase activity), and a 19 and 26% decrease in the size of mucosal lesions as compared with vehicle treatment. Administration of L-NAME (35 mg/kg) failed to produce any significant beneficial effects as compared with vehicle treatment in this experimental model of acute colitis. Treatment with 1400W, a highly selective inhibitor of iNOS, reduced formation of edema, neutrophil infiltration, and macroscopic inflammatory damage in experimentally induced acute colitis in the rat. In contrast, nonselective nitric-oxide synthase inhibition with L-NAME provided no benefit. These results support the idea that selective iNOS inhibitors have a promise in the treatment of colitis. | Cárdenas A, De Alba J, Moro MA, Leza JC, Lorenzo P, Lizasoain I (1998)
Protective effect of N-(3-(aminomethyl)benzyl) acetamidine, an inducible nitric oxide synthase inhibitor, in brain slices exposed to oxygen-glucose deprivation.
European journal of pharmacology 354, 161-165 [PubMed:9754916]
[show Abstract]
It has been suggested that large amounts of nitric oxide (NO) produced by inducible NO synthase are involved in the mechanisms of neurotoxicity after cerebral ischaemia. We have recently demonstrated that inducible NO synthase was expressed within hours after rat forebrain slices were exposed to oxygen-glucose deprivation. Therefore, we sought to determine whether NO produced by inducible NO synthase contributes to tissue damage in this model, by using a new, highly selective, inhibitor of inducible NO synthase, N-(3-(aminomethyl)benzyl)acetamidine (1400W). We found that incubation with 1400W from the start of the oxygen-glucose deprivation period until the end of the experiment decreases tissue damage determined as lactate dehydrogenase (LDH) efflux 4 h after the oxygen-glucose deprivation period, the time at which inducible NO synthase expression is maximal in this model. This effect may be a result of direct inhibition of inducible NO synthase activity, raising the possibility of a clinical use of selective inhibitors of this NO synthase isoform in the management of cerebral ischaemia. |
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