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

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

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.

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.

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.