臺灣博碩士論文加值系統

迷迭香酸是咖啡酸和 3,4-dihydroxyphenyllactic acid 經酯化鍵結的植物二次代謝產物,普遍存在紫草科和唇形花科,最主要來源是迷迭香。已知迷迭香酸有抗病毒、抗細菌、抗發炎以及抗氧化等功能。Cisplatin(順鉑)是臨床上用於治療腫瘤的化學治療用藥之一，但其具有腎毒性副作用，而且與氧化壓力有關。本研究的目的在於運用動物模式來評估迷迭香酸對順鉑引起的急性腎功能損害的潛在保護作用。
連續7天每日管餵給予小鼠迷迭香酸，在實驗第5天時以腹腔注射的方式給予順鉑以誘發腎損傷。評估腎損傷的指標包括血清中的肌酸酐和血尿氮素的濃度，尿液中水合作用的指標探討；同時透過組織病理學觀察評估順鉑引起腎損害的程度。研究結果顯示迷迭香酸可以顯著的降低注射順鉑小鼠血清中的肌酸酐和血尿氮素的濃度，以及降低腎臟組織中的脂質過氧化指標TBARS的濃度。
在實驗結果50mg/kg迷迭香酸(RA)對於順鉑對於誘發腎損傷的效果差不多，在加重迷迭香酸(RA) 濃度至100mg/kg對於誘發腎損傷的效果，迷迭香酸(RA)雖然有些許改善。在尿液及血液的檢測中及病理切片可以看出，不論是100mg/kg有效的差異變化，並可以佐證迷迭香酸有效的減緩順鉑對於誘發腎損傷。綜合以上結果顯示，迷迭香酸對於順鉑引起的急性腎功能損害具有潛在保護作用，其主要的作用機轉可能是經由增加抗氧化防禦系統及減少脂質過氧化的發生。

Rosmarinic acid is an ester of caffeic acid and 3,4-dihydroxyphenyllactc acid. It is commonly found in species of the Boraginaceae and the subfamily Nepetoideae of the Lamiaceae, mainly, Rosmarinus officinalis L. Rosmarinic acid has a number of biological activities, including antiviral, antibacterial, anti-inflammatory and antioxidant effects. Cisplatin is a potent chemotherapeutic drug for cancer therapy, but it has serious side effect in clinical treatment, particularly nephrotoxicity.
The purpose of this study was to evaluate the potential nephroprotective effects of rosmarinic acid against cisplatin-induced renal damage in male ICR mice. The mice were orally treated with rosmarinic acid daily for 7 days accompanied by administration of one dose of cisplatin on 5 day. The results demonstrated that administration of rosmarinic acid in mice significantly decreased elevated serum levels of creatinine and blood urea nitrogen (BUN) were induced by cisplatin. Histopathology also showed that rosmarinic acid protects against cisplatin-induced damage in the kidneys. These results suggest that rosmarinic acid exhibits potent nephroprotective effects on cisplatin-induced kidney damage in mice, likely due to both the increase in antioxidant-defense system activity and the inhibition of lipid peroxidation.

中文摘要（Abstract） ii
Abstract iii
目 錄 iv
第一章 前言緒論 1
第二章 文獻回顧 2
第一節 癌症 2
第二節 順鉑 3
第三節 腎毒性 3
第四節 迷迭香酸 5
研究目的 6
第三章 材料方法 7
第一節 實驗架構 7
第二節 材料方法 8
第三節病理組織切片分析 10
第四章 實驗結果 12
第一節、迷迭香酸減緩抗癌藥物順鉑誘發大鼠腎毒性，血液檢測分析 12
第二節、迷迭香酸減緩抗癌藥物順鉑誘發大鼠腎毒性，尿液分析評估 15
第三節、迷迭香酸減緩抗癌藥物順鉑誘發大鼠腎毒性，病理組織評估 17
第五章 結論 17
第六章 參考文獻 18

圖表目錄 i
圖一、順鉑結構式 i
圖二、迷迭香酸結構式 i
圖三、順鉑的藥物化學機制 ii
圖四、順鉑化學合成 ii
圖五、順鉑造成急性腎損傷機轉You-Hsien Lin等人 (2011) iii
圖六、迷迭香酸對順鉑誘發大鼠腎毒性之體內血液鈣離子之影響 iv
圖七、迷迭香酸對順鉑誘發大鼠腎毒性之體內血液滲透壓之影響 iv
圖八、迷迭香酸對順鉑誘發大鼠腎毒性之體內血液鈉離子之影響 v
圖九、迷迭香酸對順鉑誘發大鼠腎毒性之體內血液尿素氮之影響 v
圖十、迷迭香酸對順鉑誘發大鼠腎毒性之體內血液鉀離子之影響 vi
圖十一、迷迭香酸對順鉑誘發大鼠腎毒性之體內血液肌酸酐之影響 vi
圖十二、迷迭香酸對順鉑誘發大鼠腎毒性之體內血液磷之影響 vii
圖十三、迷迭香酸對順鉑誘發大鼠腎毒性之體內血液鐵離子之影響 vii
圖十四、迷迭香酸對順鉑誘發大鼠腎毒性之體內血液鎂離子之影響 viii
圖十五、迷迭香酸對順鉑誘發大鼠腎毒性之體內尿液肌酸酐之影響。 viii
圖十六、迷迭香酸對順鉑誘發大鼠腎毒性之體內尿液滲透壓之影響。 ix
圖十七、迷迭香酸對順鉑誘發大鼠腎毒性之體內尿液尿素氮之影響 ix
圖十八、迷迭香酸對順鉑誘發大鼠腎毒性之體內尿液鉀離子之影響 x
表一、實驗分組 xi
表二、病理評估標準 xi
表三、迷迭香酸對順鉑誘發大鼠腎毒性之組織病理評估 13
圖十九、迷迭香酸對順鉑誘發大鼠腎毒性之空白組腎組織病理學檢查 xiv
圖二十、迷迭香酸對順鉑誘發大鼠腎毒性之順鉑組腎組織病理學檢查 xv
圖廿一、低劑量迷迭香酸組之腎組織病理學檢查。 xvi
圖廿二、高劑量迷迭香酸組之腎組織病理學檢查 xvii

Delanghe J; De Slypere JP, De Buyzere M, Robbrecht J, Wieme R, Vermeulen A. Normal reference values for creatine, creatinine, and carnitine are lower in vegetarians (PDF). Clin. Chem. Aug 1989, 35 (8): 1802–3 [2009-03-01]. PMID 2758659.

Dursun B, He Z, Somerset H, et al. Caspases and calpain are independent mediators of cisplatin-induced endothelial cell necrosis. Am J Physiol Renal Physiol 2006; 291: F578-87.

Faubel S, Ljubanovic D, Reznikov L, et al. Caspase-1-deficient mice are protected against cisplatin-inducedapoptosis and acute tubular necrosis. Kidney Int 2004; 66:
2202-13.

Furtado, M. A., de Almeida, L. C., Furtado, R. A., Cunha, W. R. and Tavares, D. C. 2008. Antimutagenicity of rosmarinic acid in Swiss mice evaluated by the micronucleus assay. Mutat. Res., 657, 150-154.

Huang SS, Zheng RL,Biphasic regulation of angiogenesis by reactive oxygen species.2006 Mar;61(3):223-9.

Kelland L. The resurgence of platinum-based cancer chemotherapy. Nat.Rev.Cancer. 2007;7:573–584.
 
Last page of Deepak A. Rao; Le, Tao; Bhushan, Vikas. First Aid for the USMLE Step 1 2008 (First Aid for the Usmle Step 1). McGraw-Hill Medical. 2007. ISBN 0-07-149868-0.

Lebwohl & Canetta, Clinical development of platinum complexes in cancer therapy: an historical perspective and an update.34.1522-34。

Li S, Basnakian A, Bhatt R, et al. PPAR-alpha ligandameliorates acute renal failure by reducing cisplatin-inducedincreased expression of renal endonuclease G. Am J Physiol
Renal Physiol 2004; 287: F990-8.

Lieberthal W, Triaca V, Levine J. Mechanisms of deathinduced by cisplatin in proximal tubular epithelial cells:apoptosis vs. necrosis. Am J Physiol 1996; 270: F700-8.

Mazumder, A., Neamati, N., Sunder, S., Schulz, J., Pertz, H., Eich, E. and Pommier, Y. 1997. Curcumin analogs with altered potencies against HIV-1 integrase as probes for biochemical mechanism of drug actin. J. Med. Chem. 40, 3057-3063.

Megyesi J, Safirstein R, Price PM. Induction of p21WAF1/CIP1/SDI1 in kidney tubule cells affects the course ofcisplatin-induced acute renal failure. J Clin Invest 1998; 101:777-82.
 
Moreno, S., Scheyer, T., Romano, C. S. and Vojnov, A. A.2006. Antioxidation and antimicrobial of rosemary extracts linked to their polyphenol composition. Free. Radic. Res. 40(2), 223-231.

Pabla N, Dong Z. Cisplatin nephrotoxicity: mechanisms and renoprotective strategies. Kidney Int 2008; 73: 994-1007.

Parnham MJ, Kesselring K. Rosmarinic acid. Drugs of the Future. 1985;10(9):756–757.

Ramesh G, Reeves WB. p38 MAP kinase inhibition ameliorates cisplatin nephrotoxicity in mice. Am J Physiol Renal Physiol 2005; 289: F166-74.

Strasser A, O'Connor L, Dixit VM. Apoptosis signaling. 421 Annu Rev Biochem 2000; 69: 217-45

Tsuruya K, Ninomiya T, Tokumoto M, et al. Directinvolvement of the receptor-mediated apoptotic pathways incisplatin-induced renal tubular cell death. Kidney Int 2003;63: 72-82.
 
Uzunoglu, S., Karagol, H., Ozpuyan, F., Cosar, R., Cicin, I., Yurutcaloglu, V., Denizli, B., Tanriverdi, O., Sut, N., Kocak, Z., 2010. Protective effect of L-carnitine versus amifostine against cisplatininduced nephrotoxicity in rats. Med. Oncol. DOI: 10.1007/s12032-010- 9746-2.

Wei Q, Dong G, Franklin J, et al. The pathological role of Bax in cisplatin nephrotoxicity. Kidney Int 2007; 72: 53-62.

You-Hsien Lin , Sheng-Fung Lin , Hui-Hua Hsiao , Yi-Chang Liu , Wen-Chi Yang2, Daw-Yang Hwang , Chi-Chih Hung , Sang- Jyh Hwang , Jinn-Yuh Guh , and Hung-Chun .Chen Recent Update on Cisplatin induced Acute Kidney Injury
2011:22:416-422