Menopause is associated with dyslipidemia and an increased risk of cardio-cerebrovascular disease. The classic view assumes that the underlying mechanism of dyslipidemia is attributed to an insufficiency of estrogen. In addition to a decrease in estrogen, circulating follicle-stimulating hormone (FSH) levels become elevated at menopause. In this study, we find that blocking FSH reduces serum cholesterol via inhibiting hepatic cholesterol biosynthesis. First, epidemiological results show that the serum FSH levels are positively correlated with the serum total cholesterol levels, even after adjustment by considering the effects of serum estrogen. In addition, the prevalence of hypercholesterolemia is significantly higher in peri-menopausal women than that in premenopausal women. Furthermore, we generated a mouse model of FSH elevation by intraperitoneally injecting exogenous FSH into ovariectomized (OVX) mice, in which a normal level of estrogen (E2) was maintained by exogenous supplementation. Consistently, the results indicate that FSH, independent of estrogen, increases the serum cholesterol level in this mouse model. Moreover, blocking FSH signaling by anti-FSHβ antibody or ablating the FSH receptor (FSHR) gene could effectively prevent hypercholesterolemia induced by FSH injection or high-cholesterol diet feeding. Mechanistically, FSH, via binding to hepatic FSHRs, activates the Gi2α/β-arrestin-2/Akt pathway and subsequently inhibits the binding of FoxO1 with the SREBP-2 promoter, thus preventing FoxO1 from repressing SREBP-2 gene transcription. This effect, in turn, results in the upregulation of SREBP-2, which drives HMGCR nascent transcription and de novo cholesterol biosynthesis, leading to the increase of cholesterol accumulation. This study uncovers that blocking FSH signaling might be a new strategy for treating hypercholesterolemia during menopause, particularly for women in peri-menopause characterized by FSH elevation only.

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To discover novel BChE inhibitors, a hierarchical virtual screening protocol followed by biochemical evaluation was applied. The most potent compound 8012-9656 (eqBChE IC 50 = 0.18 ± 0.03 μM, hBChE IC 50 = 0.32 ± 0.07 μM) was purchased and synthesized. It inhibited BChE in a noncompetitive manner and could occupy the binding pocket forming diverse interactions with the target. 8012-9656 was proven to be safe in vivo and in vitro and showed comparable performance in ameliorating the scopolamine-induced cognition impairment to tacrine. Additionally, treatment with 8012-9656 could almost entirely recover the Aβ 1−42 (icv)-impaired cognitive function to the normal level and showed better behavioral performance than donepezil. The evaluation of the Aβ 1−42 total amount confirmed its anti-amyloidogenic profile. Moreover, 8012-9656 possessed blood−brain barrier (BBB) penetrating ability, a long T 1/2 , and low intrinsic clearance. Hence, the novel potential BChE inhibitor 8012-9656 can be considered as a promising lead compound for further investigation of anti-AD agents.

PURPOSE. To determine the roles of dopamine D2 receptors (D2Rs) and dopamine D1 receptors (D1Rs) in the inhibition of form-deprivation myopia (FDM) by the nonselective dopamine agonist apomorphine (APO) in D2R-knockout (D2R-KO) and D1R-KO mice. METHODS.Retinal layer thicknesses and electroretinograms (ERGs) were analyzed in KO mice and in D2R and D1R antagonist-treated mice. D2R-KO or D1R-KO mice and wild-type (WT) littermates were subjected to form deprivation during postnatal weeks 5 to 8. Both groups were intraperitoneally injected daily with either APO (5 lg/g body weight) dissolved in 1 lg/ lL ascorbic acid or vehicle alone. Refraction, vitreous chamber depth (VCD), and axial length (AL), among other parameters, were measured prior to and at the end of the treatment period.RESULTS. The retinal layer thicknesses and ERGs in KO mice were similar to those treated with D2R and D1R antagonists. APO administration in WT mice inhibited the development of FDM by approximately 80%. FDM in D2R-KO mice was inhibited approximately 50% compared with WT mice and was further inhibited by APO to a level similar to that in APO-treated WT mice. FDM development in D1R-KO mice was similar to that in WT mice and was not affected by APO administration. The changes in VCD and AL were consistent with refraction data.CONCLUSIONS. In mice, APO-mediated FDM inhibition was abolished by D1R KO but not D2R KO. This indicates the specificity of D1Rs for the pharmacologic inhibitory effect of APO on FDM and a nonessential role of D2Rs in this process in mice.