Trichothecenes are mycotoxins which produce Iethai toxicosis in humans and animals, yet no adequate therapeutic regimen has been developed. This study provides evidence that the selective platelet activating factor (PAF) antagonist, BN 52021 (5-15 mg/kg i.v.) can prolong the survival of conscious rats exposed to a highly Iethai T -2 toxicosis. These data also suggest that P AF is an important mediator of this unique toxicosis

Braquet, P.

Feuerstein, G.

Leader, P.

Sirén, Anna-Leena

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Toxicology Leiters, 38 (1987) 271-274 Elsevier TXL 01852 271 PROTECTIVE EFFECT OF A PAF-ACETHER ANTAGONIST, BN 52021, IN TRICHOTHECENE TOXICOSIS (T-2 toxin; mycotoxin; PAF-acether; BN 52021; rat) GIORA FEUERSTEIN, PAMELA LEADER, ANNA-LEENA SIREN and PIER BRAQUETa Neurobiology Research Division, Department oj Neurology, Uniformed Services University oj the Hea/th Sciences, Bethesda, MD (U.S.A.), and a/HB Laboratories, Institut Henri Beaujour, Le Plessis Robinson (France) (Received 5 March 1987) (Accepted 6 June 1987) SUMMARY Trichothecenes are mycotoxins which produce Iethai toxicosis in humans and animals, yet no adequate therapeutic regimen has been developed. This study provides evidence that the selective platelet activating factor (PAF) antagonist, BN 52021 (5-15 mg/kg i.v.) can prolong the survival of conscious rats exposed to a highly Iethai T -2 toxicosis. These data also suggest that P AF is an important mediator of this unique toxicosis. INTRODUCTION Trichothecenes are a chemically related group of biologically active fungal metabolites. T -2 toxin, a trichothecene mycotoxin, is a natural contaminant of foods and animal feeds that may cause severe illness in animals and humans [1] through deranged cardiorespiratory functions [2]. Although T -2 toxicosis is a disorder that has been associated with epidemic outbreaks in many countries, no specific therapy has been established for humans or animals. Recently, murine monoclonal antibody against T -2 toxin successfully protected and reversed severe T -2 toxicosis in the rat [2]. However, such therapeutic approach cannot be easily Address for correspondence: Giora Feuerstein, M.D., Department of Neurology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814-4799, U.S.A. Abbreviation: PAF, platelet activating factor. 0378-4274/87/$ 03.50 © 1987 Elsevier Science Publishers B. V. (Biomedical Division) 272 extrapolated to humans since no human anti-T -2 antibody is available to date. Recently, a potent and selective PAF-acether antagonist, BN 52021, (9Hl,7a-(epoxymethano)-1H,6aH-cyclopenta[c] furo [2,3-b] furo-[3' ,2' ,3,4) cyclopenta [1 ,2-d]furan-5,9, 12-(411)-trione, ß-tert-butylhexahydro-4,-7b,-ll hydroxy-8 methyl) was shown to provide substantial protection in several models of shock including en-dotoxemia [3,4}. Since lipopolysaccharide endotoxemia shows hemodynamic, cellular and endocrine similarities with T -2 toxicosis [5], we postulated tbat a P AF-acether antagonist might have a beneficial effect on survival from severe T-2 tox-icosis. METHODS Male Sprague-Dawley rats (250-300 g) were chronically implanted with a PE-50 catheter in the femoral vein as previously described [2). Three different protocols were used in which rats were subjected to i. v. injection of 0.65 mg/kg of T -2 toxin (Sigma, St. Louis, MO) in 200 ~tl of 1007o ethanol in 0.90Jo saline (sterile, pyrogen-free). This dose of T-2 toxin was selected from dose-response curves constructed in the conscious rat [2). Three different groups of rats were treated as follows: (1) BN 52021 (kindly provided by Dr. P. Braquet, IHB, France) 15 mg/kg, 3 h after T -2 administration; (2) BN 52021, 15 mg/kg, 30 min prior to and 8 h after T-2 ad-ministration; (3) BN 52021, 5 mg/kg, 30 min and 6 h after T-2 administration. BN 52021 was injected in 150-400 pl of 50'/o DMSO in 0.90'/o NaCI. Control rats received the vehicle injections of the T-2 and BN 52021 solvents. The vehicles used were shown to have absolutely no untoward effects in the rat. The rats were kept in single cages with food and water ad libitum for the complete duration of the experiment. Statistics Fisher's exact probability test was used to evaluate the difference in survival ratio between the control and BN 52021-treated groups. RESULTS In each group of rats treated with BN 52021, a substantial increase in survival rate was clearly demonstrated (Fig. 1 ). Most remarkably, a single dose of BN 52021 quadrupled the ultimate survival rate of the rats (Fig. 1, middle panel). DISCUSSION Although P AF -acether has not been demonstrated in T -2 toxicosis as yet, our data infer a role for PAF-acether also in the pathophysiology ofT -2 toxicosis. This conclusion is based on previous studies showing that BN 52021 is a potent and selec-tive P AF -acether antagonist [6]. Nevertheless, the substantial protective effect of 100 ..... 60 c E 50 ! '#- 40 30 20 10 0 -5 100 10 80 ~ 70 it: > Cl: IiD i i! H 40 30 20 10 0 100 90 80 ..... 70 c 2!: 60 > ! 50 .., ~ 40 30 20 10 I 0 t I 0 t I 35 t I • BN52021, 15 mg/kg, (12) o CONTJIOL ( 12) • p<.l5 • 5 10 15 20 25 38 35 ... 45 50 55 60 65 70 75 TWE (hours) * 10 15 20 %5 30 * • BN52021 (12) o CONTIOL (12) *'<.02 * • 8N 52021 (5 mg/kg) (8) o CONTROL (6) • p< 0 05 * 10 15 20 25 30 35 40 45 50 55 60 65 70 75 TIME (hours) 273 Fig. 1. Effect of BN 52021 on survival of rats exposed to T-2 toxin. Open circles·represent vehicle-treated rats; closed circles represent BN 52021-treated rats. Time of BN 52021 injection is denoted by il. T-2 toxin was injected always at 0 time. Numbers of rats in each group are given in parentheses for each panel. Asterisks denote statistical significance at P < 0.05 for the upper and lower panels and P < 0.02 for the middle panel. 274 BN 52021 in this highly Iethai mycotoxicosis might prove to be of beneficial effect in protecting livestock and hornans exposed to trichothecene mycotoxins. Since T -2 toxicosis is associated with widespread metabolic hematologic, respiratory and cardiovascular derangements it is difficult to assess at this point the exact contribution of P AF in these pathophysiological processes. Further studies will be needed to identify PAF in T-2 toxicosis and to identify its primary target organs and systems. ACKNOWLEDGEMENTS This work was supported in part by USAMRDC. The opinions or assertions con-tained herein are the private ones of the author(s) and are not to be construed as official or as necessarily reflecting the views of the Department of Defense or the Uniformed Services University of the Health Sciences. There is no objection to its presentation and/or publication. The experiments reported herein were conducted according to the principles set forth in the Guide for Care and Use of Labaratory Animals, Institute of Labaratory Animal Medicinet National Research Council, DHEW Publication No. (NIH) 80-23, 1980. We wish to thank Mrs. Laura Garza for preparing the manuscript. REFERENCES I A.W. Hayes, Mycotoxins: a review of biological effects and their role in human disease, Clin. Tox-icol., 17 (1980) 45-83. 2 G. Feuerstein, D.S. Ooldstein, P.O. Ramwell, R.L. Zerbe, W.E. Lux, A.I. Faden and M.A. Bayorh, Cardiorespiratory, sympathetic and biochemical responses to T -2 toxin in the conscious guinea pig and rat, J. Pharrnacol. Exp. Ther., 232 {1985) 786-794. 3 S. Adnot, J. Lefort, V. Lagent, P. Braquet and B.B. Vargaftig, Interference of BN 52021, a PAF acether antagonist, with endotoxin induced hypotension in the guinea pig, Lancet, (1986) (in press). 4 A. Etienne, F. Hecquet, C. Soulard, B. Spinnewyn, F. Clostre and P. Braquet, In vivo inhibition of plasma protein leakage and salmoneUa enteritidis-induced mortality in the rat by a specific P AF acether antagonist BN 52021, Agents Actions, 17 (1985) 368-371. 5 G. Feuerstein, J.A. Powell, A.T. Knower and K.W. Hunter, Jr., Monoclonal antibodies to T-2 toxin: in vitro neutralization of protein synthesis inhibition and protection of rats against Iethai toxemia, J. Clin. lnvest., 76 (1986) 2134-2138. 6 P. Braquet, B. Spimiewyn, M. Braquet, R.H. Bourgain, J.E. Taylor, A. Etienne and K. Drieu, BN 52021 and related compounds: a new series of highly specific PAF-acether receptor antagonists isolated from Gingko biloba L, Blood Vessels, 16 (1985) 558-572. 

Protective effect of PAF-acether antagonist, BN 52021, in trichothecen toxicosis

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Protective effect of PAF-acether antagonist, BN 52021, in trichothecen toxicosis

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