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The use of an adapted model allows contributing to the “Reduction” of mice used in experimental protocols: the case of the apoE–deficient (apo E-/-) mice in a model of atherosclerosis control

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BCLAS Symposium 1&2 /12/ 2009 Blankenberge- Belgium

The use of an adapted model allows contributing to the “Reduction” of mice used in experimental protocols: the case of the apoE– deficient (apo E-/-) mice in a model of atherosclerosis control.

C. Cherdon 1*, S. Rolin 2*, L. de Leval 3*, P. Drion4* , J.O. Defraigne 1*, Ooms A1*, J.M. Dogné 2*

1

Dept. of Cardiovascular Research, University of Liege, 1 Av de l'Hôpital, B-4000 Liege, Belgium, phone: +32 4 3664583, email : ccherdon@ulg.ac.be, 2 Dept. of Pharmacy, University of Namur, Belgium, 3 Dept. of Pathology, University of Liege, Belgium. 4Animal

Facility of the ULG-GIGA-R, University of Liege, Belgium *: all authors participated equally to the work.

Atherosclerosis is a chronic vascular disease whose development is influenced by several mediators 1. Among them, the prostanoids large family lipids generated from the metabolism of arachidonic acid by the action of COX includes various types of PGs and thromboxane. Thromboxane A2 and PGI2 are present in

abnormally elevated concentration in atherosclerosis 2-3. To exert its effects TXA2

and its precursor PGH2 act at a specific receptor termed TP receptor 4. As a result,

TXA2 synthase inhibitors and TP antagonists have been developed to reduce and to

prevent TXA2 production and actions, respectively.

The present study was undertaken in order to investigate whether BM-573, an original sulfonylurea derivate synthesized in our lab 5, and aspirin would be effective in preventing the progression of atherosclerosis in an apo E deficient mouse model.

Mice are highly resistant to atherosclerosis. The only exception in mice is the C57BL/ 6 strain fed with a very high content of cholesterol diet However the vascular lesion in these mice differ from the human in the histological nature and location 6. So, in this study, apo E deficient mice model was chosen to test the efficacy of BM-573 and aspirin in atherogenesis because of its propensity to spontaneously and quickly develop sever atherosclerotic lesion very similar to those present in human, when fed with chow diet. The effect of 10 weeks of treatment with BM573 (2-2,5mg/kg/d) and aspirin (20-25mg/kg/d) on early aortic atherosclerotic lesions of apo E deficient mice was assessed. These mice presented spontaneous increase of total plasma cholesterol and triglycerides. In this experiment, while BM-573 and aspirin did not affect body weight, only BM-573 significantly decreases early atherogenesis lesions confirmed by macroscopic, microscopic and biochemical analysis. These results confirm that selective antagonism of TP receptor is more effective in reducing atherosclerotic lesion in

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apo E deficient mice than COX-1 inhibition. Consequently, BM-573 could be a potential drug for prevention of atherosclerosis and this hypothesis will be tested in further investigation. This works emphases on the fact that severe selection of the mice strain chosen for the experiment allows producing reliable results with an adapted reduction in number of animals used.

1. Ross R. et al. N Engl J Med, 1976. 295(8): p. 420-5. 2. Belton O. et al., Circulation, 2000. 102(8): p. 840-5.

3. FitzGerald G.A. et al., N Engl J Med, 1984. 310(17): p. 1065-8.

4. Coleman et al., Comprehensive Medicinal Chemistry, 1990. 3: p. 644-706. 5. Dogne J.M. et al., Curr Med Chem, 2000. 7(6): p. 609-28.

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