PPT Improved Long-term Ovariectomy Induced Spatial Cognition Deficit In Young Rats

Ovariectomy is known as―surgical menopause‖with decreased levels of estrogen in femalerodents. And its reported risks and adverse effects include cognitive impairment. In thebrain, estrogen exerts effects through its receptors, estrogen receptor (ER) and (ER).However, the mechanism of ER or ER in ovariectomy-induced cognitive impairmentneeds further investigation. Here, we observed that bilateral ovariectomized3-month-oldrats showed obvious spatial learning and memory deficit in Morris water maze withsignificant loss of neurons and synapses in the hippocampus. Meanwhile with the quicklydeclined serum estradiol levels, the expression of ER in hippocampus, but not ER, wasdecreased since1week after ovariectomy. Prompt4,4,4-(4-propyl-[1H]-pyrazole-1,3,5-triyl) trisphenol (PPT) treatment (1mg/kg/day), anagonist of ER, improved spatial learning and memory ability of ovariectomized rats andrescued ovariectomy-induced neurons loss by keeping the expression of BCLxl, animportant anti-apoptosis protein. Furthermore, ER rescue also improvedovariectomy-induced the loss of hippocampal synapses and up-regulated synapstic proteins(synapsin, NR2A and GluR1) and activating CaMK, ERK, and Akt. Thus, these resultsdemonstrated that ER plays an important role in neuroprotection and that prompt ER rescue is effective to improving hippocampal-dependent cognition deficit afterovariectomy. Long-term estrogen deprivation has a significantly high risk of cognitive dysfunction.Experimental and basic studies show a modulatory role of estrogens in the brain andsuggest their beneficial action in cognitive ability and memory of neurodegenerativediseases. Estrogen is exerts its effects via genomic signaling mediated by interaction withnuclear estrogen receptor. But the mechanism of estrogen receptor on brain is complicated.In previous research, we investigated the effect of estrogen receptor in brain ofovariectomized rats, the results shown us estrogen receptor (ER) was declined afterovariectomy. Here, we found that GSK-3, a key enzyme with complicated signalingpathway in Alzheimer’s disease was activated corresponding with increased phosphorylatedserine-118(p-Ser118ER, activated form of ER) afer ovariectomy, and the GSK-3levelalso was up-regulated. Then, we use an agonist of ER, PPT and inhibitor of GSK-3, LiClrespectively, or combine PPT with LiCl to find the relationship about ER and GSK-3after ovariectomy. In this study, we found that PPT or LiCl treatment improved the deficitsof cognitive ability and memory through activation of GSK-3regulated or was regulatedby ER rescued in ovariectomzied rats. These data indicated that ER and GSK3β maybetwo drug targets to preserve cognitive ability and memory after long-term ovariectomy.