D-甲硫胺酸改善順鉑誘導大鼠心臟毒性以及厭食之探討

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D-甲硫胺酸改善顺铂诱导大鼠心脏毒性以及厌食之探讨

Improvement of Cisplatin-induced Cardiotoxicity and Anorexia by D-methionine in Rats

黄冠婷 , 硕士　　导师：欧珠琴　　

繁体中文

D型甲硫胺酸；顺铂；厌食；心脏毒性； D- methionine ； cisplatin ； anorexia ； cardiotoxicity

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摘要 │ 参考文献 (112) │ 国际计量

摘要〈TOP〉

顺铂 (Cisplatin) 是一种含铂且常见的化学治疗药物，由於cisplatin会产生严重的副作用，如：耳毒性、肾毒性、神经毒性、心脏毒性、厌食/恶病质及肠胃道毒性等。D型甲硫胺酸 (D-methionine) 是L型甲硫胺酸的右旋异构物，目前已知藉由其抗氧化特性，降低cisplatin所引起的耳毒性与肾毒性，然而，D-methionine对於cisplatin引起的厌食与心脏毒性是否具有保护作用，尚未被探讨，本实验藉由大鼠模式探讨D-methionine是否可改善cispaltin所诱导的厌食与心脏毒性。我们将Wistar品系雄性大鼠随机分成四组，每组5-8只，其中，控制组 (Control) 与顺铂组 (Cisplatin) 在实验的前3天至第18天，管喂一般饮用水，且分别在实验的第1、8、15天进行腹腔注射0.9%NaCl与cisplatin，剂量皆为5 mg/kg；顺铂合并D型甲硫胺酸组 (Cisplatin+D-methionine) 与D型甲硫胺酸组 (D-methionine) 分别在注射第一剂cisplatin与0.9%NaCl的前三天，开始灌食D-methionine 300 mg/kg直到实验的第18天，并分别在实验的第1、8、15天进行腹腔注射cisplatin与0.9%NaCl，剂量皆为5 mg/kg，最後在实验的第19天进行牺牲。我们检测与食慾调节相关的因子 (例如:饥饿素、瘦体素、色胺酸羟化酶1、5-HT3 receptor、5-HT2C receptor、NPY、AgRP、POMC、CART) ，藉由生理纪录器测量心跳、收缩压、舒张压、平均动脉压、心电图，以及心脏毒性指标 (CK-MB、LDH) 与发炎反应 (IL-6、IL-1β、TNF-α) 、氧化压力 (MDA、GSH、GPx、SOD) ，作为心脏毒性指标检测。研究结果显示，在厌食方面，D-methionine可以显着改善cisplatin诱导的体重与摄食量降低，减少胃内容物残留量并增加胃排空，透过降低肠道中色胺酸羟化酶1 (TPH1) 的活性、5- HT3 receptor的阳性反应以及降低下视丘中5-HT2C receptor基因表现等改善胃肠功能失调进而减缓厌食的发生；此外，D-methionine透过增加血清中瘦体素的含量，而促进下视丘中POMC与CART的基因表现，与降低NPY与AgRP的基因表现，以维持能量的平衡状态。在心脏毒性方面，D-methionine可以轻微改善心脏功能异常，包括心跳、收缩压、舒张压以及平均动脉压，但是无法改善cisplatin所引起的心脏毒性 (LDH与CK-MB) 与发炎反应 (IL-6、IL-1β、TNF-α) ；我们也发现cisplatin并不会造成心律不整、胸主动脉受损、心脏组织损伤以及氧化压力。
  因此，口服D-methionine具有改善cisplatin所引起厌食的潜力，但无法减缓心脏毒性。

并列摘要〈TOP〉

Cisplatin, a platinum-containing compound is one of the most common chemotherapeutic drugs and leads to many serious side effects, such as ototoxicity, nephrotoxicity, neurotoxicity, cardiotoxicity, anorexia/cachexia and gastrointestinal toxicity. D-methionine, a dextral isomer of L-methionine is a sulfur-containing antioxidant. Owing to its antioxidant properties, D-methionine may attenuate ototoxicity and nephrotoxicity caused by cisplatin. However, effects of D-methionine on cisplatin-induced anorexia and cardiotoxicity have not been explored yet. In this study, we investigated whether D-methionine could attenuate cisplatin-induced anorexia and cardiotoxicity in rat model. Male Wistar rats were randomly divided into four groups of which from five to eight rats each. The control group and cisplatin group were administrated water from three days before to the 18th day of the experiment and injected with 0.9% NaCl and cisplatin (5 mg/kg) via intraperitoneal (i.p.) on the 1st, 8th and 15th day of the experiment respectively. Cisplatin plus D-methionine group and D-methionine alone group were pre-administrated daily with D-methionine (300 mg/kg) 3 day before cisplatin and 0.9% NaCl treatment until the study is completed. Also cisplatin and 0.9% NaCl were i.p. injected on the 1st, 8th and 15th day of the experiment, respectively. All animals were sacrificed on day 19 of the experiment. We detected the appetite regulated factors such as ghrelin, leptin, tryptophan hydroxylase 1, 5-HT3 receptor, 5-HT2C receptor, NPY, AgRP, POMC, CART, and used physiological recording machine to determine heart rate, systolic blood pressure, diastolic blood pressure, mean arterial pressure and electrocardiogram. The cardiotoxicity marker (CK-MB, LDH) ,inflammatory response (IL-6, IL-1β, TNF-α) and oxidative stress (MDA, GSH, GPx, SOD) were measured and deemed as cardiotoxicity index. As for anorexia, the results showed that D-methionine can significantly improve cisplatin-induced weight loss and food intake, decrease gastric contents, enhance gastric emptying in the stomach tissue. D-methionine could reduce the activity of tryptophan hydroxylase 1 (TPH1), increase the positive  response of 5-HT3 receptor in the intestine and decrease gene expression of 5-HT2C receptor in the hypothalamus in cisplatin-treated rats. In addition, to maintain energy balance in cisplatin-treated rats, D-methionine increased plasma levels of leptin in serum, which lead to enhance the gene expression of POMC, CART and decrease the gene expression of NPY and AgRP. By the results of cisplatin-induced cardiotoxicity, we found D-methionine can slightly improve the abnormal status of heart rate, systolic blood pressure, diastolic blood pressure, and mean arterial pressure, while it cannot ameliorate LDH and CK-MB activity and inflammatory response (IL-6 , IL-1β, TNF-α) after cisplatin injection. Besides, cisplatin did not cause arrhythmia, thoracic aorta damage, cardiac tissue damage and oxidative stress. These results indicate that oral D-methionine may have potential for improving cisplatin-induced anorexia but can not ameliorate cisplatin induced cardiotoxicity.

参考文献 ( 112 ) 〈TOP〉

Abdellatief SA, Galal AA, Farouk SM, Abdel-Daim MM (2017) Ameliorative effect of parsley oil on cisplatin-induced hepato-cardiotoxicity: A biochemical, histopathological, and immunohistochemical study. Biomed Pharmacother 86: 482-491
连结：
Abe M, Hirashima Y, Kasamatsu Y, Kado N, Komeda S, Kuji S, Tanaka A, Takahashi N, Takekuma M, Hihara H, Ichikawa Y, Itonaga Y, Hirakawa T, Nasu K, Miyagi K, Murakami J, Ito K (2016) Efficacy and safety of olanzapine combined with aprepitant, palonosetron, and dexamethasone for preventing nausea and vomiting induced by cisplatin-based chemotherapy in gynecological cancer: KCOG-G1301 phase II trial. Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer 24: 675-682
连结：
Adali F, Gonul Y, Kocak A, Yuksel Y, Ozkececi G, Ozdemir C, Tunay K, Bozkurt MF, Sen OG (2016) Effects of thymoquinone against cisplatin-induced cardiac injury in rats. Acta Cir Bras 31: 271-7
连结：
Adam CL, Archer ZA, Findlay PA, Thomas L, Marie M (2002) Hypothalamic gene expression in sheep for cocaine- and amphetamine-regulated transcript, pro-opiomelanocortin, neuropeptide Y, agouti-related peptide and leptin receptor and responses to negative energy balance. Neuroendocrinology 75: 250-6
连结：
Al-Majed AA, Sayed-Ahmed MM, Al-Yahya AA, Aleisa AM, Al-Rejaie SS, Al-Shabanah OA (2006) Propionyl-L-carnitine prevents the progression of cisplatin-induced cardiomyopathy in a carnitine-depleted rat model. Pharmacol Res 53: 278-86
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DOI可强化引用精确性、增强学术圈连结，并给予使用者跨平台的良好使用经验，目前在全世界已有超过五千万个对象申请DOI。如想对DOI的使用与概念有进一步了解，请参考（）。