Dos Santos Filho Edvande Xavier, Ávila Paulo Henrique Marcelino, Bastos Carla Caroline Cunha, Batista Aline Carvalho, Naves Letícia Nasser, Marreto Ricardo Neves, Lima Eliana Martins, Mendonça Elismauro Frascisco, Valadares Marize Campos
Laboratory of Pharmacology and Cellular Toxicology, Pharmacy Faculty, Federal University of Goiás, Goiânia, Brazil.
Department of Stomatology, Dental Faculty, Federal University of Goiás, Goiânia, Brazil.
Toxicol Rep. 2015 Oct 23;3:55-62. doi: 10.1016/j.toxrep.2015.10.010. eCollection 2016.
Intestinal mucositis is a frequent limiting factor in anticancer therapy and there is currently no broadly effective treatment targeted to cure this side effect.
This study aimed to evaluate the effects of a mucoadhesive formulation containing curcuminoids (MFC) from L. on the pathogenesis of 5-fluorouracil (5-FU)-induced intestinal mucositis.
Three intraperitoneal 5-FU injections (200 mg/kg) were used to induce intestinal mucositis in adult Swiss male mice. Treatment was provided orally (MFC 3.75, 7.5 and 15 mg/kg), thirty minutes before 5-FU injections, daily until euthanasia. Duodenal samples were collected to perform morphometric and histopathological analysis, to investigate the expression of Ki-67, p53, Bax and Bcl-2 by immunohistochemistry, to evaluate neutrophil activity myeloperoxidase (MPO)-mediated and oxidative stress by malondialdehyde (MDA) determination. Mice body weight was assessed as well.
As expected, 5-FU induced a significant weight loss (∼17%, < 0.001), shortening in villi height (∼55.4%) and crypts depth (∼47%), and increased (∼64%) the histological severity score when compared to other groups (< 0.05). These pathological changes were markedly alleviated by the three MFC treatment doses (< 0.05), in special with the dose MFC 15 mg/kg. This dose also stimulated cell proliferation by ∼90% in the epithelial cells lining from villi and crypts (< 0.05), reduced MPO levels and MDA formation by 60% and 44%, respectively (< 0.05).
Our data suggest the therapeutic potential of the formulation for treating intestinal mucositis in mice. Supplementary studies are underway searching for the elucidation of mechanisms involved in the protective effects of MFC in order to make this formulation a clinical tool for mucositis treatment.
肠道黏膜炎是抗癌治疗中常见的限制因素，目前尚无广泛有效的针对性治疗方法来治愈这种副作用。
本研究旨在评估含姜黄素类化合物的黏膜黏附制剂（MFC）对5-氟尿嘧啶（5-FU）诱导的肠道黏膜炎发病机制的影响。
对成年瑞士雄性小鼠进行三次腹腔注射5-FU（200mg/kg）以诱导肠道黏膜炎。在每次5-FU注射前30分钟口服给予治疗（MFC剂量分别为3.75、7.5和15mg/kg），每天一次，直至安乐死。收集十二指肠样本进行形态计量学和组织病理学分析，通过免疫组织化学研究Ki-67、p53、Bax和Bcl-2的表达，通过测定髓过氧化物酶（MPO）评估中性粒细胞活性，通过测定丙二醛（MDA）评估氧化应激。同时评估小鼠体重。
正如预期的那样，与其他组相比，5-FU导致显著体重减轻（约17%，<0.001）、绒毛高度缩短（约55.4%）和隐窝深度缩短（约47%），组织学严重程度评分增加（约64%）（<0.05）。三种MFC治疗剂量均显著减轻了这些病理变化（<0.05），特别是MFC 15mg/kg剂量。该剂量还使绒毛和隐窝内衬上皮细胞的细胞增殖增加了约90%（<0.05），MPO水平和MDA形成分别降低了60%和44%（<0.05）。
我们的数据表明该制剂在治疗小鼠肠道黏膜炎方面具有治疗潜力。正在进行补充研究以阐明MFC保护作用的相关机制，以便使该制剂成为治疗黏膜炎的临床工具。
