Protective effect of an inhibitor of nitric oxide synthase on sulphur mustard toxicity in vitro

Sawyer, Thomas W.; Lundy, Paul M.; Weiss, M.

doi:10.1016/s0041-008x(96)80019-6

Cited by 34 publications

(18 citation statements)

References 30 publications

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“…HD toxicity may represent a third pathway that does not involve activation of NOS. However, in spite of the fact that NOS is not activated, it has been shown that NOS inhibitor (Sawyer et al, 1996), thiocitrulline (Sawyer et al, 1998), arginine analogs (Sawyer et al, 2000) or in combination with other drugs (Rappeneau et al, 2000), protect cells against HD toxicity in an unknown mechanism. In our experiments the NOS inhibitor L-NMMA did not protect the RAW264.7 cell line from any HD cytotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Lipopolysaccharide induced protection against sulfur mustard cytotoxicity in RAW264.7 cells through generation of TNF-.ALPHA.

et al. 2010

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-Sulfur mustard (HD), a very potent alkylating agent and lipopolysacchride (LPS), are both well characterized inflammatory factors. We have found that concomitant exposure of murine macrophage cells (RAW264.7) to LPS and HD induced protection against HD induced cytotoxicity. Both HD and LPS induce release of inflammatory markers in RAW264.7 cells. However, there are marked differences in the repertoire of inflammatory factors released by the two toxins: While exposure to HD, induced a dose-dependant death of these cells, no significant change in survival rate was observed following LPS (1-100 ng/ml) exposure. Additionally, LPS elicited a robust nitric oxide (NO) and TNF-α secretion whereas HD was practically ineffective. Both toxins increased PGE 2 secretion in a concentration dependent manner. Treatment of HD-exposed RAW264.7 cells with anti-inflammatory drugs such as dexamethazone (5 μM), voltaren (diclofenac) (8 μM) or doxycycline (5 μM), decreased the release of cytokines but had no effect on cell viability. Simultaneous application of LPS (100 ng/ml) and HD (20-100 μM) resulted in an amelioration of HD cytotoxicity. Adding the NO generator S-nitrosoglutathione (GSNO) or inhibiting NO production using L-N G -monomethyl Arginine, had no effect on cell viability. Moreover, addition of PGE 2 (20 ng/ml) failed to induce any changes in cell viability under basal or HD-induced toxicity. In contrast, TNF-α (20 ng/ml) provided remarkable protection against HD-induced cell death. These findings strongly suggest that LPS exerts its protective action against HD toxicity through the generation of TNF-α and may provide better understanding of the mechanism of cytoprotection.Key words: Sulfur mustard, RAW 264.7, LPS, TNF-α, NO, Cytotoxicity Correspondence: Nahum Allon (E-mail: nahuma@iibr,gov.il) Original ArticleThe Journal of Toxicological Sciences (J. Toxicol. Sci.) Vol.35, No.3, 345-355, 2010 Vol. 35 No. 3 345 Similarly, cutaneous application of HD is also associated with an acute inflammatory response accompanied by blister formation and epithelial necrosis (Dannenberg et al., 1985;Casillas et al., 2000;Dachir et al., 2002). Notably, early studies using isolated skin explants treated with HD have shown a rapid production of cytokines and prostaglandins (Rikimaru et al., 1991).In vitro studies, where the effects of adjacent tissue are absent, have indicated that HD exposure can directly induce cytokine secretion from macrophages as shown in various cells in culture including in human monocytes (Rikimaru et al., 1991;Arroyo et al., 1995). A number of cell lines such as macrophages (Amir et al., 1998, monocytes (Arroyo et al., 1995), lymphocytes and keratinocytes (Arroyo et al., 2000), show acute reaction to HD, similar to that reported in in-vivo studies, and thus, can serve as a model. These studies showed that HD can induce the release of TNFα and other inflammatory mediators by direct action on epithelial cells, suggesting that an inflammatory response can be initiated directly by HD in a single cell (Dan...

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Section: Discussionmentioning

confidence: 99%

Lipopolysaccharide induced protection against sulfur mustard cytotoxicity in RAW264.7 cells through generation of TNF-.ALPHA.

et al. 2010

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“…1). Pretreatment with DRDE-30 did not protect completely the SM induced liver lesions, and pretreat- chemical decontamination Smith et al, 1995); antihistaminics (Yourick et al, 1995); bioflavonoids (Vijayaraghavan et al, 1991;Om Kumar et al, 2001); anti-inflammatory agents (Yourick et al, 1995;Zhang et al, 1995;Casillas et al, 2000;Amir et al, 2000); Xanthine oxidase inhibitors (Papirmeister et al, 1991); NAD + level stabilisers (Mol, et al, 1989;Yourick et al, 1991;Meier and Johnson, 1992;Yourick et al, 1995); intracellular scavengers of SM (Zhang et al, 1995); PARP inhibitors (Meier et al, 2000); nitric oxide synthase inhibitors (Sawyer, 1998a;1998b) and arginine analogues (Sawyer et al, 1996). Some PARP inhibitors and povidone iodine ointment (Wormser et al, 2000) were found to be effective as post-treatment also.…”

Section: Effect Of Analogues On Histological Lesions Induced By Sm Inmentioning

confidence: 99%

“…Although many compounds have shown good prophylactic as well as therapeutic protection in vitro (Sawyer, 1998a;1998b;Sawyer et al, 1996;Sawyer and Risk, 2000), their in vivo efficacy is questionable. To date there is no definitive therapy to counteract the toxic effects of SM on the body.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of analogues of DRDE-07 as prophylactic agents against the lethality and toxicity of sulfur mustard administered through percutaneous route

et al. 2006

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Sulfur mustard (SM), chemically bis (2-chloroethyl) sulfide is a bifunctional alkylating agent that causes serious blisters on contact with human skin. Although several antidotes have been reported for the systemic toxicity of SM in experimental animals none of them are approved so far and decontamination of SM immediately by physical or chemical means is recommended as the best protection. Two compounds amifostine [S-2(3-aminopropylamino) ethyl phosphorothioate] and DRDE-07 [S-2(2-aminoethylamino) ethyl phenyl sulfide] gave very good protection as an oral prophylactic agent against SM the in mouse model, but in the rat model the protection was only moderate. In the search for more effective and less toxic compounds, a number of analogues of DRDE-07 were synthesised and their protective efficacy was evaluated in mouse and rat models. The LD50 of S-aryl substitution was between 1 and 2 g kg(-1) and S-alkyl substitution was more than 2 g kg(-1). In the mouse model, DRDE-07, DRDE-10, DRDE-21, DRDE-30 and DRDE-35 gave about 20 fold protection, and DRDE-23 and DRDE-38 gave less protection of 4.8 and 9.0 fold respectively, against percutaneously administered SM. In the rat model, DRDE-07, DRDE-09, DRDE-10 and DRDE-21 gave about two fold protection. Percutaneously administered SM (19.33 mg kg(-1)) significantly depleted the hepatic GSH content in mice. Pretreatment with DRDE-21 significantly elevated the levels. A 4.4 fold increase in % DNA fragmentation was observed 7 days after SM administration (19.33 mg kg(-1)) in mice. Pretreatment with DRDE-07, DRDE-09, DRDE-10, DRDE-21, DRDE-30 and DRDE-35 significantly protected the mice from SM induced DNA damage. The histopathological lesions in liver and spleen induced by percutaneously administered SM was reduced by pretreatment with DRDE-07, DRDE-09, DRDE-10 and DRDE-21. These analogues may prove as prototypes for the designing of more effective prophylactic drug for SM.

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“…(a) Prevention of SM from entering the system (personal decontamination at the site of contact), Several antidotes have been reported for reducing the systemic toxicity of SM in experimental animals [9][10][11][12][13][14][15] . Most of the antidotes are in various stages of development and so far none recommended.…”

Section: Introductionmentioning

confidence: 99%

Protective Effect of Quercetin Against Sulphur Mustard-inducedOxidative Stress in Mice

Gautam¹,

Vijayaraghavan²,

Pant³

et al. 2007

DSJ

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Sulphur mustard (SM) is a chemical warfare agent that causes serious blisters upon contact with human skin. SM alkylates DNA and several other macromolecules, and also induces oxidative stress. Quercetin, a bioflavonoid has wide pharmacological actions. The protective efficacy of quercetin (100 mg/kg, i.p. and 200 mg/kg, i.p.) was studied by administering three doses in mice against SM. The first dose was administered at 30 min prior, simultaneous, 2 h post or 24 h post, and two more doses on the next two days. SM was administered (in PEG 300) percutaneously at varying doses for survival and protection studies. SM was also administered at a dose of 2 LD 50 (19.3 mg/kg) with and without quercetin treatment and various biochemical markers were estimated 7 days after SM administration. Histological examinations of vital organs were also carried out. The animals administered with SM died at various days depending upon the dose. The body weight decreased significantly. Quercetin protected the mice significantly, in a dosedependent manner. The protection was better when the first dose of quercetin administered was 30 min prior or simultaneously. A significant decrease in reduced as well as oxidised glutathione and an increase in malondialdehyde, WBC count, RBC count, and haemoglobin were observed with 2 LD 50 SM. Quercetin at 100 mg/kg and 200 mg/kg doses significantly protected the biochemical markers when the first dose of quercetin administered was 30 min prior or as simultaneous treatment. The histological lesions induced by sulphur mustard on liver, spleen, and skin were also significantly protected by quercetin when the first dose was administered 30 min prior or as simultaneous treatment. The present study shows that percutaneous administration of SM induces oxidative stress and quercetin can protect it as a prophylactic agent.Keywords: Sulphur mustard, quercetin, oxidative stress, glutathione, malondialdehyde, DNA damage, prophylactic agent, chemical warfare agent . INTRODUCTIONThe organophosphorus nerve agents and the blistering agents continue to be threats not only as chemical warfare agents, but also from the terrorist organisations. Though the Chemical Weapons Convention is signed and ratified by several countries and the stockpiled chemical warfare agents are being destroyed, still the threat persists from the Defence Science Journal, Vol. 57, No. 5, September 2007, pp. 707-720 2007, DESIDOC 707 use of chemical weapons. The mechanism of action of the nerve agents is clearly understood and effective and accepted treatment protocols are known 1 . In spite of research over several decades, no satisfactory prophylactic or treatment regimen has evolved for sulphur mustard (SM), a well known blistering agent. So the search for a better antidote is being pursued the world over.

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Protective effect of an inhibitor of nitric oxide synthase on sulphur mustard toxicity in vitro

Cited by 34 publications

References 30 publications

Lipopolysaccharide induced protection against sulfur mustard cytotoxicity in RAW264.7 cells through generation of TNF-.ALPHA.

Lipopolysaccharide induced protection against sulfur mustard cytotoxicity in RAW264.7 cells through generation of TNF-.ALPHA.

Evaluation of analogues of DRDE-07 as prophylactic agents against the lethality and toxicity of sulfur mustard administered through percutaneous route

Protective Effect of Quercetin Against Sulphur Mustard-inducedOxidative Stress in Mice

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