Effect of Caffeic Acid Phenethyl Ester on the Regression of Endometrial Explants in an Experimental Rat Model

Abstract

The objective of this study is to determine the effects of antioxidant and anti-inflammatory caffeic acid phenethyl ester (CAPE) on experimental endometriosis, peritoneal superoxide dismutase (SOD) and catalase (CAT) activities, and malondialdehyde (MDA) levels in the rat endometriosis model. Thirty rats with experimentally induced endometriosis were randomly divided into 2 groups and treated for 4 weeks with intraperitoneal CAPE (CAPE-treated group; 10 µmol/kg/d, n = 13) or vehicle (control group; n = 13). The volume and weight changes of the implants were calculated. Immunohistochemical and histologic examinations of endometriotic explants by semiquantitative analysis and measurements of peritoneal SOD, CAT, and MDA levels were made. Following 4 weeks of treatment with CAPE, there were significant differences in posttreatment spherical volumes (37.4 ± 14.7 mm³ vs 147.5 ± 41.2 mm³) and explant weights (49.1 ± 28.5 mg vs 158.9 ± 50.3 mg) between the CAPE-treated groups and controls. The mean evaluation nomogram levels in glandular epithelium for COX-2 positivity by scoring system were 2.1 ± 0.3 in the CAPE-treated group and 3.9 ± 0.3 in the control group. In the CAPE-treated group, peritoneal levels of MDA and activities of SOD and CAT significantly decreased when compared with the control group (P < .01). Histologic analysis of the explants demonstrated mostly atrophy and regression in the treatment group, and semiquantitative analysis showed significantly lower scores in rats treated with CAPE compared with the control group. CAPE appeared to cause regression of experimental endometriosis.

Keywords

Endometriosis cyclooxygenase type 2 inhibitors caffeic acid phenethyl ester oxidative stress.

Get full access to this article

View all access options for this article.

References

Alpay Z. , Saed GM , Diamond MP Female infertility and free radicals: potential role in adhesions and endometriosis . J Soc Gynecol Investig. 2006;13:390-398.

Sampson J. Peritoneal endometriosis is due to the menstrual dissemination of endometrial tissue into the peritoneal cavity. Am J Obstet Gynecol. 1927;4:433-469.

Gupta S. , Agarwal A. , Agarwal R. , Loret de Mola JR. Impact of ovarian endometrioma on assisted reproduction outcomes. Reprod Biomed Online. 2006;13:349-360.

Van Langendonckt A. , Casanas-Roux F. , Donnez J. Iron overload in the peritoneal cavity of women with pelvic endometriosis. Fertil Steril. 2002;78:712-718.

Ota H. , Igarashi S. , Hatazawa J. , Tanaka T. Immunohistochemical assessment of superoxide dismutase expression in the endometrium in endometriosis and adenomyosis. Fertil Steril. 1999; 72: 129-134.

Ota H. , Igarashi S. , Kato N. , Tanaka T. Aberrant expression of glutathione peroxidase in eutopic and ectopic endometrium in endometriosis and adenomyosis. Fertil Steril. 2000;74: 313-318.

Ota H. , Igarashi S. , Tanaka T. Xanthine oxidase in eutopic and ectopic endometrium in endometriosis and adenomyosis . Fertil Steril. 2001;75:785-790.

Ilhan A. , Koltuksuz U. , Ozen S. , Uz E. , Ciralik H. , Akyol O. The effects of caffeic acid phenethyl ester (CAPE) on spinal cord ischemia/reperfusion injury in rabbits. Eur J Cardiothorac Surg. 1999;16:458-463.

Khayyal MT , el-Ghazaly MA , el-Khatip AS Mechanisms involved in the antiinflammatory effect of propolis extract. Drugs Exp Clin Res. 1993;19:197-203.

10.

Michaluart P. , Masferrer JL , Carothers AM , et al. Inhibitory effects of caffeic acid phenethyl ester on the activity and expression of cyclooxygenase-2 in human oral epithelial cells and in a rat model of inflammation. Cancer Res. 1999;59: 2347-2352.

11.

Sud'ina GF , Mirzoeva OK , Pushkareva MA , Korshunova GA , Sumbatyan NV , Varfolomeev SD Caffeic acid phenethyl ester as a lipoxygenase inhibitor with antioxidant properties. FEBS Lett. 1993;329:21-24.

12.

Chan WS , Wen PC , Chiang HC Structure-activity relationship of caffeic acid analogues on xanthine oxidase inhibition. Anticancer Res. 1995;15:703-707.

13.

Schefferlie JG , van Bladeren PJ. In vitro and in vivo reversible and irreversible inhibition of rat glutathione S-transferase isoenzymes by caffeic acid and its 2-S-glutathionyl conjugate. Food Chem Toxicol. 1993;31:475-482.

14.

Chen YJ , Shiao MS , Wang SY The antioxidant caffeic acid phenethyl ester induces apoptosis associated with selective scavenging of hydrogen peroxide in human leukemic HL-60 cells . Anticancer Drugs. 2001;12:143-149.

15.

Fesen MR , Pommier Y. , Leteurtre E. , Hiroguchi S. , Yung J. , Kohn KW Inhibition of HIV-1 integrase by flavones, caffeic acid phenethyl ester (CAPE) and related compounds. Biochem Pharmacol. 1994;48:595-608.

16.

Park EH , Kahng JH Suppressive effects of propolis in rat adjuvant arthritis. Arch Pharm Res. 1999;22:554-558.

17.

Vernon MW , Wilson EA Studies on the surgical induction of endometriosis in the rat. Fertil Steril. 1985;44:684-694.

18.

Uygur D. , Aytan H. , Zergeroglu S. , Batioglu S. Leflunomide— an immunomodulator—induces regression of endometrial explants in a rat model of endometriosis. J Soc Gynecol Investig . 2006;13:378-383.

19.

Ozguner F. , Oktem F. , Armagan A. , et al. Comparative analysis of the protective effects of melatonin and caffeic acid phenethyl ester (CAPE) on mobile phone-induced renal impairment in rat. Mol Cell Biochem. 2005;276:31-37.

20.

21.

SunY. , Oberley LW , Li Y. A simple method for clinical assay of superoxide dismutase. Clin Chem. 1998;34;497-500.

22.

Durak I. , Yurtarslani Z. , Canbolat O. , Akyol O. A methodological approach to superoxide dismutase (SOD) activity assay based on inhibition of nitroblue tetrazolium (NBT) reduction. Clin Chim Acta. 1993;214:103-104.

23.

Aebi Y. Catalase in vitro. Methods Enzymol. 1984;105:121-126.

24.

Keenan JA , Williams-Boyce PK , Massey PJ , Chen TT , Caudleb MR , Bukovsky A. Regression of endometrial explants in a rat model of endometriosis treated with the immune modulators loxoribine and levamisole. Fertil Steril. 1999;72:135-134.

25.

Ota H. , Igarashi S. , Sasaki M. , Tanaka T. Distribution of cyclooxygenase-2 in eutopic and ectopic endometrium in endometriosis and adenomyosis. Hum Reprod. 2001;16:561-566.

26.

Sharpe-Timms KL Using rats as a research model for the study of endometriosis. Ann N Y Acad Sci. 2002;955:318-327.

27.

Uchiide I. , Ihara T. , Sugamata M. Pathological evaluation of the rat endometriosis model. Fertil Steril. 2002;78:782-786.

28.

Zeller JM , Henig I. , Radwanska E. , Dmowski WP

Enhancement of human monocyte and peritoneal macrophage chemiluminescence activities in women with endometriosis. Am J Reprod Immun

Microbiol. 1987;3:78-82.

29.

Bedaiwy MA , Falcone T. , Sharnii RK , Goldberg JM , Attaran M. , Nelson DR Prediction of endometriosis with serum and peritoneal fluid markers: a prospective controlled trial. Hum Reprod. 2002;17:426-431.

30.

Wang Y. , Sharma RK , Falcone T. , Goldberg J. , Agarwal A. Importance of reactive oxygen species in the peritoneal fluid of women with endometriosis or idiopathic infertility. Fertil Steril. 1997;68:826-830.

31.

Polak G. , Rola R. , Gogacz M. , Koziol-Montewka M. , Kotarski J. Malonyldialdehyde and total antioxidant status in the peritoneal fluid of infertile women [in Polish]. Ginekol Pol. 1999; 70:135-140.

32.

Shanti A. , Santanam N. , Morales AJ , Parthasarathy S. , Murphy AA Autoantibodies to markers of oxidative stress are elevated in women with endometriosis . Fertil Steril. 1999;71:1115-1118.

33.

Santanam NK , Kavlaradze N. , Dominguez C. Antioxidant supplementation reduces total chemokines and inflammatory cytokines in women with endometriosis. Fertil Steril. 2003;8: 32-33.

34.

Steinleitner A. , Lambert H. , Roy S. Immunomodulation with pentoxifylline abrogates macrophage-mediated infertility in an in vivo model: a paradigm for a novel approach to the treatment of endometriosis-associated subfertility. Fertil Steril. 1991;55:26-31.

35.

Steinleitner A. , Lambert H. , Suarez M. , Serpa N. , Robin B. , Cantor B. Periovulatory calcium channel blockade enhances reproductive performance in an animal model for endometriosis-associated subfertility . Am J Obstet Gynecol. 1991;164:949-952.

36.

Spitz IM Progesterone antagonists and progesterone receptor modulators: an overview . Steroids. 2003;68:981-993.

37.

Portz DM , Elkins TE , While R. , Warren J. , Adadevoh S. , Randolph J. Oxygen free radicals and pelvic adhesion formation: I. Blocking oxygen free radical toxicity to prevent adhesion formation in an endometriosis model. Int J Fertil. 1991; 16:39-42.

38.

Szczepanska M. , Kozlik J. , Skrzypczak J. , Mikolajczyk M. Oxidative stress may be a piece in the endometriosis puzzle. Fertil Steril. 2003;79:1288-1293.

39.

Polak G. , Koziol-Montewka M. , Gogacz M. , Tarkowski R. , Kotarski J. Total antioxidant status of peritoneal fluid in infertile women. Eur J Obstet Gynecol Reprod Biol. 2001;94:261-263.

40.

Arici A. , Oral E. , Attar E. , Tazuke SI , Olive DL Monocyte chemotactic protein-1 concentration in peritoneal fluid of women with endometriosis and its modulation of expression in mesothelial cells. Fertil Steril. 1997;67:1065-1072.

41.

Barrier BF , Bates GW , Leland MM , Leach DA , Robinson RD , Propst AM Efficacy of anti-tumor necrosis factor therapy in the treatment of spontaneous endometriosis in baboons. Fertil Steril. 2004 ;81(suppl 1):775-779.

42.

Chen MF , Keng PC , Lin PY , Yang CT , Liao SK , Chen WC

Caffeic acid phenethyl ester decreases acute pneumonitis after irradiation in vitro and in vivo. BMC

Cancer. 2005;5:158-165.

43.

Vermon MN , Beard JS , Graves K. , Wilson EA Classification of endometriotic implants by morphologic appearance and capacity to synthesize prostaglandin F. Fertil Steril. 1986;46:801-806.

44.

Fagotti A. , Ferrandina G. , Fanfani F. , Legge F. , Lauriola L. , Gessi M. Analysis of cyclooxygenase-2 (COX-2) expression in different sites of endometriosis and correlation with clinicopathological parameters. Hum Reprod. 2004;19:393-397.

45.

Ebert AD , Bartley J. , David M.

Aromatase inhibitors and cyclooxygenase-2 (COX-2) inhibitors in endometriosis: new questions-old answers?

Eur J Obstet Gynecol Reprod Biol. 2005;122:144-150.

46.

Bulun SE , Zeitoun KM , Takayama K. , Sasano H. Molecular basis for treating endometriosis with aromatase inhibitors. Hum Reprod Update. 2000;6:413-418.