Bansal Seema, Chopra Kanwaljit
University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India.
Menopause. 2015 Oct;22(10):1117-24. doi: 10.1097/GME.0000000000000435.
Diabetes and menopause are frequent comorbidities. The objective of the present study was to delineate the effects of nonselective and selective estrogen receptor (ER) agonists (α and β) on cognitive function and depressive behavior in ovariectomized diabetic (Ovx-Dia) rats.
Bilateral ovariectomy was performed in female Sprague-Dawley rats (200-250 g), and streptozotocin was used to induce experimental diabetes. Rats were administered (10 μg/kg SC) a nonselective ER agonist, 17β-estradiol (E2); a selective ER-α agonist, propionitrile (PPT; 4,4',4″-(4-propyl-[1H] pyrazole-1,3,5-triyl) tris phenol); and a selective ER-β agonist, 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN) for 4 weeks after streptozotocin injection.
Marked impairment in memory indicated by increased transfer latency on the fifth day (363%) and increased immobility time (90.5%), coupled with a marked decrease in brain-derived neurotrophic factors (22.5%) and increase in acetylcholinesterase activity (58.1%), were observed in Ovx-Dia rats compared with sham rats. However, a partial change in all these parameters was observed in ovariectomized or diabetic rats compared with sham rats. Treatment with DPN and E2 markedly prevented--whereas treatment with PPT partially prevented--changes induced in Ovx-Dia rats. To assess feminizing action, we measured serum estradiol levels and uterine weights. E2 reversed the ovariectomy-induced decrease in serum estradiol levels and uterine weights, but PPT and DPN treatment did not show any effect.
Results reveal that specific ER-β agonists can ameliorate memory dysfunction and depressive behavior associated with postmenopausal diabetes and are devoid of the feminizing adverse effects of nonselective ER agonists.
糖尿病和更年期是常见的合并症。本研究的目的是描述非选择性和选择性雌激素受体（ER）激动剂（α和β）对去卵巢糖尿病（Ovx-Dia）大鼠认知功能和抑郁行为的影响。
对雌性Sprague-Dawley大鼠（200-250克）进行双侧卵巢切除术，并用链脲佐菌素诱导实验性糖尿病。在注射链脲佐菌素后4周，给大鼠皮下注射（10μg/kg）非选择性ER激动剂17β-雌二醇（E2）、选择性ER-α激动剂丙腈（PPT；4,4',4″-(4-丙基-[1H]吡唑-1,3,5-三基)三苯酚）和选择性ER-β激动剂2,3-双(4-羟基苯基)-丙腈（DPN）。
与假手术大鼠相比，Ovx-Dia大鼠在第5天转移潜伏期增加（363%）、不动时间增加（90.5%），表明记忆明显受损，同时脑源性神经营养因子明显减少（22.5%），乙酰胆碱酯酶活性增加（58.1%）。然而，与假手术大鼠相比，去卵巢或糖尿病大鼠的所有这些参数都有部分变化。DPN和E2治疗可明显预防——而PPT治疗可部分预防——Ovx-Dia大鼠诱导的变化。为了评估雌性化作用，我们测量了血清雌二醇水平和子宫重量。E2可逆转卵巢切除引起的血清雌二醇水平和子宫重量下降，但PPT和DPN治疗没有显示任何效果。
结果表明，特异性ER-β激动剂可改善绝经后糖尿病相关的记忆功能障碍和抑郁行为，且无非选择性ER激动剂的雌性化不良反应。
