Selective ER-β agonists alleviate neuronal deficits in insulin-resistant estrogen-deficient rats

Abstract

Objective

The present study aimed to determine the effect of estrogen receptor (ER) agonists on depression and memory impairment in insulin-resistant ovariectomized (OVX) rats.

Methods

Rats underwent bilateral ovariectomy, and low-dose streptozotocin (STZ) and a high-fat diet (58% fat, 25% protein, and 17% carbohydrates as a percentage of kilocalories) were administered to induce an estrogen-deficient insulin-resistant state. After 1 week of STZ administration, rats were treated with 17β-estradiol (17βE2) and selective ER-α (propylpyrazoletriol) and ER-β (diarylpropionitrile) agonists (10 μg/kg subcutaneously). Memory was evaluated using the Morris water maze and depression using the forced swim test.

Results

Treatment with selective ER-β agonist and 17βE2 but not with selective ER-α agonist significantly modulated the neurobehavioral deficits in insulin-resistant OVX rats. These neurobehavioral parameters were further correlated with brain-derived neurotrophic factor (BDNF) levels and acetylcholinesterase (AChE) activity. Selective ER-β agonist and 17βE2 significantly modulated BDNF levels and AChE activity in insulin-resistant OVX rats. Significant increases in estradiol and uterine weight were observed in 17βE2-treated rats, but selective ER agonists did not show any effect.

Conclusion

ER-β agonist can be an effective strategy for the mitigation of memory loss and depression in an estrogen-deficient insulin-resistant state without all of the deleterious feminizing effects that occur with the use of 17βE2.

摘要

目的：研究雌激素受体（ER）激动剂对胰岛素抵抗去势（OVX）大鼠抑郁和记忆障碍的影响。

方法：大鼠进行双侧卵巢切除术, 予低剂量链脲佐菌素（streptozotocin, STZ）和高脂饮食（热量百分比为58%脂肪, 25%蛋白质, 17%碳水化合物）从而诱导雌激素缺乏型胰岛素抵抗状态。给药1周后, 大鼠用17β-雌二醇（17βE2）和选择性ER-α (丙基吡唑三醇）和ER-β (二芳基丙腈）激动剂（皮下注射10 ug/kg）。采用莫里斯水迷宫测试大鼠记忆, 强迫游泳测试抑郁情况。

结果：选择性ER-β 激动剂和17βE2治疗可显著调节胰岛素抵抗OVX大鼠的神经行为缺陷, 选择性ER-a激动剂无此作用。神经行为参数与脑源性神经营养因子（BDNF）水平和乙酰胆碱酯酶（AChE）活性相关。选择性ER-β 激动剂和17βE2显著调节胰岛素抵抗OVX大鼠BDNF水平和AChE活性。17βE2治疗的大鼠中雌二醇和子宫重量显著增加, 但选择性ER激动剂无明显作用。

结论：雌激素缺乏的胰岛素抵抗状态, ER-β激动剂可能是缓解记忆丧失和抑郁的有效方法, 而不会产生使用17βE2带来的负面女性化。

Keywords:

• Ovariectomy
• type 2 diabetes
• estrogen receptor modulators
• menopause
• brain-derived neurotrophic factor

Acknowledgements

The Senior Research Fellowship granted to S. Bansal by the University Grant Commission – Research Fellowship in Science for Meritorious Students is gratefully acknowledged. Bavneet Kaur Sidhu (Research scholar, Department of statistics, Panjab University, Chandigarh) is highly acknowledged to analyze the data statistically. The first draft of the manuscript was written by S. Bansal and was thoroughly checked and reviewed by Prof. K. Chopra. All animal experiments were performed according to policies of institutional animal ethics committee of Panjab University (approval no. IAEC/346-356; dated 11 February 2013).

Potential conflict of interest

The authors declare no conflict of interest.

Source of funding

Additional information

Funding

The present research was financially supported by University Grant Commission.