Melatonin anterior pituitary of the female Wistar rat

FOLIAHISTOCHEMICAETCYTOBIOLOGICAVol. 48, No. 2, 2010pp. 278-283

Melatonin modulates the effects of diethylstilbestrol(DES) on the anteriorpituitary of the female Wistarrat

Weijiang Zhao1,2, Zhongfang Shi2, Fang Yuan2, Guilin Li2, Yilin Sun2,Yazhuo Zhang2, Zhongcheng Wang2

1Neuroscience Center, Shantou University Medical College, Shantou, Guangdong Province 515041, China2Beijing Neurosurgical Institute, Capital Medical University, Beijing 100050, China

Abstract:We studied the anti-tumorigenic effect of melatonin in diethylstilbestrol (DES)-treated anterior pituitaries in rats.Twenty-one female Wistar rats were randomly allocated into three groups: vehicle control rats, DES-treated rats, and DES-treated rats co-administrated with melatonin beginning at week 13. At the end of 16 weeks, rats were weighed and decapi-tated for morphological studies, including an H+E staining-based score evaluation in regard to cell proliferation, angiogen-esis, immunostaining for VEGF, MMP-9, and AQP-1, and electron microscopy. Compared with vehicle, long-term treatmentof DES significantly reduced rat body weight and increased H+E score, both of which were counteracted by melatonin.Administration of melatonin also reduced the expression of VEGF and MMP-9, although no changes were detected in AQP-1 expression. In rats cotreated with melatonin, the RER loosened and accumulated more secretion granules. We thus con-cluded that melatonin can modulate the effects of DES on the rat anterior pituitary by downregulating expression of VEGFand MMP-9 and suppressing the release of secretion granules, suggesting a therapeutic potential in estrogen-induced pitu-itary malfunctions.

Key words:melatonin, vascular endothelial growth factor, VEGF, aquaporin-1, AQP-1, MMP-9, ultrastructure

Introduction

It has been reported that estrogen exposure is one ofthe factors leading to the development of prolactino-ma, a tumor of the pituitary [1]. Experimental estrogenadministration can induce prolactinoma in mice andrats, which is characterized by cellular hyperprolifera-tion and angiogenesis, thus providing a means forinvestigating the mechanisms of pituitary tumorigene-sis and effective therapeutic methods against it [2-4].Melatonin, a neuroendocrine hormone derived from5-hydroxytryptamine (5-HT) and initially synthesizedin the pineal body, is widely distributed in a variety oforgans and tissues. Wu et al. [5] demonstrated strongexpression of melatonin receptors (MT) in several cere-bral nuclei and weak expression of the receptor MT1,through which melatonin might exert its physiologicalfunctions and pharmaceutical effects, in both the ante-rior pituitary and the posterior pituitary glands. In addi-tion, melatonin can protect neurons, enhance immune

Correspondence:F. Yuan and G. Li, Beijing Neurosurgical Institute, Capital Medical University, Beijing 100050, China;

e-mail: florayuan@, liguilin40@

©Polish Histochemical et Cytochemical Society

Folia Histochem Cytobiol. 2010:48(2): 278(278-283) 10.2478/v10042-010-0023-1

function, delay senescence, and regulate cell division[6,7]. The antiproliferative effects of melatonin werealso observed in multiple carcinoma cell lines of humanand mouse, as well as in diethylstilbestrol (DES)-induced prolactinoma [8]. Recent investigations showthat melatonin suppresses the expression of estrogenreceptor (ER), inhibits ER binding to the estrogenresponse element (ERE), reduces mutations in theestrogen enhancer, and induces apoptosis of prolactin-oma cells, leading to reductions in tumor volume [9-11]. However, the molecular mechanisms of melatonintreatment remain unclear.

Angiogenesis is a typical characteristic of pituitarytumors and is a pivotal event in tumor invasion[12,13]. The roles of VEGF, MMP-1, and AQP-1 havebeen established in angiogenesis, suggesting roles intumor behavior [14-16]. Lissoni et al. [17] evaluatedthe effect of melatonin on senior cancer patients, dis-covering that control of tumor growth by melatoninwas related to reduced serum VEGF concentrations,which suggested that melatonin functions as a naturalanti-angiogenesis agent to inhibit tumor growth. How-ever, we are not aware of any prior reports on the effectof DES on angiogenesis in pituitary tumors.

Melatonin modulates DES effects on the pituitary

melatonin on DES-induced expression of VEGF,In the present study, we investigated the effect ofMMP-9, and AQP-1 and its possible effect on theultrastructure of the anterior pituitary. Compared withrats without melatonin treatment, rats concurrentlyreceiving melatonin and DES demonstrated signifi-cantly reduced expression of VEGF and MMQ-9,accompanied by diminished ultrastructural deteriora-tion of the pituitary tissue. Our findings suggest bene-ficial effects of melatonin in estrogen-related pituitarymalfunction.

Materials and methods

Animals and materials.Animal manipulation was approved bythe Animal Use Committee of Beijing Neurosurgical Institute. Atotal of 21 female Wistar rats, 3 weeks old, and weighing 70-80 gwere used. All animals were housed with free access to tap waterand standard pellet food. They were kept at a controlled tempera-ture (24±1°C) and humidity (55±5%), and a 12-hour day-nightcycle (10 a.m.-10 p.m.) was maintained. Rats were randomlydivided into 3 groups of 7, with each group receiving a differenttreatment regimen: the vehicle control group, in which rats wereintraperitoneally administrated with sunflower seed oil (1 mL/kg,twice a week) for 16 weeks; the DES group, which received DES(5 mg/kg, twice a week) for 16 weeks; and the DES + melatoningroup, in which DES was administered for 16 weeks at the samedose as in the DES group, with melatonin (1 mg/day) co-adminis-tered at 5 p.m. each day from weeks 13 to 16. Rats in both vehicleand DES groups received the same dose of vehicle in place ofmelatonin, while the DES + melatonin group recei …… 此处隐藏：6130字，全部文档内容请下载后查看。喜欢就下载吧 ……