Differential role of estrogen receptor modulators in depression-like behavior and memory impairment in rats with postmenopausal diabetes.

OBJECTIVE: 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.

METHODS: 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.

RESULTS: 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.

CONCLUSIONS: 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.