Singh Smrita, Moksha Laxmi, Sharma Namrata, Titiyal Jeevan Singh, Biswas Nirhar Ranjan, Velpandian Thirumurthy
Department of Ocular Pharmacology and Pharmacy, Dr. R. P. Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India.
Department of Cornea and Refractory Surgery, Dr. R. P. Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India.
J Pharmacol Toxicol Methods. 2014 Jul-Aug;70(1):29-34. doi: 10.1016/j.vascn.2014.03.004. Epub 2014 Mar 13.
The present study was conducted to develop animal models to mimic postmenopausal/androgen deficiency dry eye and to evaluate the expression of sex steroid receptors (NR3A1, NR3A2 and NR3C4) in the ocular tissues of the developed models.
The study was conducted in healthy Wistar rats of either sex weighing 180-250g. Bilateral ovariectomy was performed in female rats and oral finasteride (dose of 1.16mg/kg/day) challenge was given to both male and female rats. Along with time tear film stability was assessed by using cotton thread method and tear breakup time (TBUT). Dew point calculation was done using August-Roche-Magnus approximation during the tear assessments to correlate environmental factors affecting the tear function tests. At the end, animals were sacrificed and ocular tissues (lacrimal gland and cornea) were subjected for the quantification of the expression of NR3A1 (ER-α), NR3A2 (ER-β) and androgen (NR3C4) receptors.
The impact of ovariectomy caused a significant tear film deficiency from the 20th day onwards in all female rats. The ten day finasteride administration also showed a significant tear film deficiency in both male and female rats. However, subjecting 60days post ovariectomy rats to finasteride challenge did not show any further decrease in tear flow. Gene expression analysis also revealed a significant downregulation of sex steroid receptors in ocular tissues after ovariectomy and finasteride challenge.
From this study, it has been concluded that ovariectomized and finasteride treated antiandrogenic models produced a significant tear deficiency in the rats which can be explored for pharmacological screening of topical agents and understanding the disease process in postmenopausal and androgen deficiency dry eye disorders.
本研究旨在建立模拟绝经后/雄激素缺乏性干眼的动物模型，并评估所建立模型眼组织中性类固醇受体（NR3A1、NR3A2和NR3C4）的表达。
研究选用体重180 - 250g的健康Wistar大鼠，雌雄不限。对雌性大鼠进行双侧卵巢切除术，对雄性和雌性大鼠均给予口服非那雄胺（剂量为1.16mg/kg/天）。随着时间推移，采用棉线法和泪膜破裂时间（TBUT）评估泪膜稳定性。在泪液评估过程中，使用奥古斯特 - 罗氏 - 马格努斯近似法计算露点，以关联影响泪液功能测试的环境因素。最后，处死动物，对眼组织（泪腺和角膜）进行NR3A1（雌激素受体α）、NR3A2（雌激素受体β）和雄激素（NR3C4）受体表达的定量分析。
卵巢切除术后，所有雌性大鼠从第20天起出现明显的泪膜缺乏。给予非那雄胺10天也使雄性和雌性大鼠出现明显的泪膜缺乏。然而，对卵巢切除术后60天的大鼠进行非那雄胺激发，泪液流量未进一步减少。基因表达分析还显示，卵巢切除和非那雄胺激发后，眼组织中性类固醇受体显著下调。
本研究得出结论，卵巢切除和非那雄胺处理的抗雄激素模型在大鼠中产生了明显的泪液缺乏，可用于局部药物的药理筛选以及了解绝经后和雄激素缺乏性干眼疾病的发病过程。
