SELECTIVE ER-B ACTIVATION MITIGATES COGNITIVE IMPAIRMENT IN TYPE 2 DIABETIC OVARIECTOMIZED RATS

Abstract

Type 2 diabetes mellitus is common in postmenopausal women and is a major risk factor for cognitive loss. Neuroprotective effects of estrogen appear to be absent in women with diabetes, may be due to, differential expression as well as activation of ER-α and β during disease conditions. This study attempts to characterize the specific estrogen receptor which could be selectively targeted to mitigate memory impairment in postmenopausal diabetic situation. Young female wistar rats aged 3-4 months (150-200g) were divided in nine groups (n=6-8). To induce postmenopausal diabetic stage, rats were bilaterally ovariectomized, and after 1 week of ovariectomy, HFD was given for 2 weeks, followed by a single injection of STZ (35 mg/kg/i.p.) and rats were continued on HFD diet for another 8 weeks. Rats were administered with 10 μg/kg/s.c. of a nonselective estrogen receptor agonist, 17-β estradiol (17βE2), selective ER-α agonist (4, 4’, 4’’-(4-propyl-[1H] pyrazole-1, 3, 5-triyl) tris phenol (PPT) and selective ER-β agonist, 2, 3-bis (4-hydroxyphenyl)-propionitrile (DPN) for eight weeks after STZ injection. Marked impairment in memory [increased transfer latency and pathlength (4 fold) and decreased time spent in target quadrant (3 fold)] coupled with a marked decrease in brain derived neurotrophic factors (BDNF) (3 fold) and increase in acetylcholinesterase activity (2.5 fold) were observed in ovariectomized type 2-diabetic rats as compared to sham rats. However, partial change in all these parameters were observed in ovariectomized or diabetic rats as compared to sham rats. Treatment with DPN and 17-βE2 markedly while PPT treatment partially prevented transfer latency, BDNF and acetylcholinesterase activity changes induced in ovariectomized diabetic rats. To assess feminizing action of all the agents, we also assessed serum estradiol levels and uterine weights. 17-βE2 reversed ovariectomy-induced decrease in serum estradiol levels and uterine weights but PPT and DPN treatment did not show any effect. Our data suggests that ER-β could be an important pharmacological target, to mimic the beneficial effect of estradiol in memory impairment, especially in postmenopausal diabetes.