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RESULTS I.In Vivo Studies I.a.General Observations : The general appearance of the animals in the control (CONT), adriamycin (ADR), adriamycin and probucol (ADR+PROB), and probucol (PROB) groups was observed regularly during the course of the study. Soon after the administration of adriamycin, the ADR group animals developed scruffy fur with a yellow coloration and showed signs of peripheral cyanosis. ADR group rats appeared sick and lethargic compared to CONT, PROB and ADR+PROB animals. On the other hand, CONT, PROB and ADR+PROB group animals did not show any changes in their general appearance. The administration of adriamycin also resulted in a decreased uptake of food and water in animals belonging to ADR group. The most prominent feature in ADR group animals was the development of dyspnea which was accompanied by the presence of grossly enlarged abdomen filled with transudate (ascites). This pathological condition became evident during the f,rrst week after the treatment with adriamycin and progressed during the post-treatment period. At the end of 3 weeks of post-treatment, ascites in ADR group was 63.6+10.1 ml (Table 2). The administration of probucol in the ADR+PROB group animals was found to prevent the development of ascites (Table 2). Animals belonging to CONT and PROB groups did not exhibit any signs of ascites (Table 2). The ADR group animals iost some weight soon after the beginning of adriamycin therapy (Fig. 6). This initial decrease in weight of adriamycin treated animals improved during the 3rd week post-treatment. However, during adriamycin post-treatment period (weeks 1-3), ADR treated animals 78
exhibited a significantly lower body weight when compared to their CONT, PROB and ADR+PROB group counterparts (Fig. 6). Table 2: Hemodynamics, asciteso heart weight and heart weight to body weight ratio in adriamycin-induced cardiomyopathy. PARAMETER CONT ADR ADR+PROB PROB LVSP (mmHg) 122.2+ 10.2 (6) 91.1+ 5.3* (6) tt0.2*2.6 (5) 119.16+3.0 (s) LVEDP (mmHg) 5.8 + 2.6 (6) 29 .6 * 3.2* (6) 6.9+0.3 #(5) s.6+0.2 (5) ASP (mmHg) 116.6 r 6.9 (6) 89.5 + 4.6* (6) 108.1+1.4 #(5) r 12.38+3.1 (5) ADP (mmHg) tt.8 + 7.2 (6) 69.4L3.9 (6) 71.8+0.9 (s) 69.76+1.1 (s) Ascites (ml) 0 (6) 63.6 + 10.1* (9) 3i2 #(s) 0 (s) Hw (g) 1.s3 + 0.05 (6) 1.18 r 0.03* (9) 1.33+0.09 #(s) 1.48+0.0s (5) HWBW( mg/g) 3.20 * 0.09 (6) 2.99+0.r1(9) 3.17+0.53 (s) 3.39+0.r6 (s) The number in parenthesis indicates the number of animals. Data are Mean + SEM. *) significantly different (p
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il\VOLVEMENT OF RETII\OIC ACID II{
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Title: AKNOWLEDGMENTS DEDICATION LI
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IV.b.3. The uptake to peripheral ti
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II.a. Total RAR and total RXR recep
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ACKNO\ryLEDGMENTS I must say that m
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DEDICATION To my toughest critic, m
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Figure: LIST OF FIGURES Page: 1. Ch
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30. A and B The expression of anti-
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treated (ADR), trolox treated (TROL
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INTRODUCTION Adriamycin, an anthrac
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apoptosis, which will ultimately pr
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LITERATURE REVIE\il I. Adriamycin i
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Binding and alkylation of DNA Inter
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myocardial inflammation which was s
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1990; Kusuoka et al. l99l; Olson et
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levels of antioxidant enzymes (Odom
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causing the increased leakage of el
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mechanisms which are involved in th
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to protect against adriamycin-induc
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The usage of Probucol.' Most promis
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II. Oxidative stress II.a. Introduc
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of a large array of cellular abnorm
Page 45 and 46: menstruation (Kokawa et al. 1996),
Page 47 and 48: DNA(Cohen 1997; Saikumar et al. 199
Page 49 and 50: pathogenesis of heart failure. A nu
Page 51 and 52: elonging to spontaneous hlpertensiv
Page 53 and 54: AlþTrsns Retlnolc Acld fAfRAl g€
Page 55 and 56: dehydrogenase (SDR), alcohol dehydr
Page 57 and 58: (Bavik et a|. 1991). Soon after its
Page 59 and 60: et al. 1994; Napoli 1996). The func
Page 61: is achieved through its binding to
Page 64 and 65: Retinoic acid signaling pathwaybegi
Page 66 and 67: (Bavik et al. 1997). One of the mos
Page 68 and 69: cells (Gaetano et ai. ZOot¡. The s
Page 70 and 71: neuroblastoma, genn cell tumors and
Page 72 and 73: presence of two distinctive pathway
Page 74 and 75: cytochrome C release from mitochond
Page 76 and 77: peroxidation (Sultana et a|.2004).
Page 78 and 79: adipose tissue and to a lesser exte
Page 80 and 81: such as; increased generation of re
Page 82 and 83: physiological and pathological proc
Page 84 and 85: Protective effects of PPAR y agonis
Page 86 and 87: IIYPOTHESIS This study tests the hy
Page 88 and 89: I.c.Collection of Tissues Hearts we
Page 90 and 91: thoracotomy was performed and heart
Page 92 and 93: Il.c.Western Blot Analvsis Western
Page 94 and 95: green were counted as dead cells. T
Page 101: Lc. Retinoic acid receptors Three w
Page 108: The RAR o and PPAR-õ receptors RNA
Page 113 and 114: significantly decreased when compar
Page 116: IL b.7. RAR alPha recePtor levels T
Page 120: ILb. 3. RAR sammø recEtor levels F
Page 124: ILb. 5. RXR baa recEúor levels The
Page 129: visible staining were accounted as
Page 137 and 138: DISSCUSION I. Adriamvcin CardiomvoP
Page 139 and 140: Treatment with adriamycin has been
Page 141 and 142: High RA 1 Adriamycin I oxidative st
Page 143 and 144: study as well as in others (Kumar e
Page 145 and 146: It is reported that PPAR y receptor
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expression. These effects of trolox
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REFERENCES Abdul Hamied,T.A., D.Par
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Bashor,M.M., D.O.Toft, and F.Chytll
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distribution of PPAR-alpha, -beta,
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colbert,M.C., D.G.Hall, T.R.Kimball
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Diep,Q.N., M'El Mabrouk, J.S.Cohn,
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Evans,R.M. 1988. "The steroid and t
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Ghione M. Development of Adriamycin
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Herman,E., R.Young, and S.Krop . Ig
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morphogenetic protein-2 inhibits se
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Khandoudi,N., P.Delerive, I.Berrebi
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Kusuoka,H., S.Futaki, Y.Koretsune,
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and myosin heavy chain gene express
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Mehta,J.L., B.Hu, J.Chen, and D.Li.
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Notario,B., M.Zamora, O.Vinas, and
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petkovich,M., N.J.Brand, A.Krust, a
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wi1liams,J.B. and J.L.Napoli. 1985.
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peroxisome proliferator-activated r
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