Proprotein convertase subtilisin/kexin type 9 inhibitor and atorvastatin exert greater efficacy than estrogen on attenuating brain pathology and learning deficit in obesity with estrogen‐deprived condition

Abstract

During estrogen-deprived periods, an increase in the development of obesity and dyslipidemia has occurred. Previous studies found that obesity aggravated metabolic disturbances, leading to brain pathology and cognitive decline in estrogen-deprived condition. Although estrogen and atorvastatin which is the recommended first-line drugs for lipid-lowering treatment have been shown to improve the metabolic and brain function in estrogen-deprived condition, both drugs can lead to several adverse effects. The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor has recently been approved as an effective therapeutic drug for patients with dyslipidemia. However, the comparative efficacy of PCSK9 inhibitor, atorvastatin, and estrogen in obesity with the estrogen-deprived model for improving metabolic and brain function has not been elucidated. Thirty female rats were fed with either a normal diet (ND) or a high-fat diet (HFD) for 16 weeks. At week 13, ND-fed rats were assigned to sham-operated (Sham; n=6), HFD-fed rats were assigned to estrogen-deprived group by ovariectomy (OVX; n=24). Six weeks after surgery period, sham was received vehicle (normal saline; n=6) for additional 4 weeks. OVX groups were divided into four subgroups to receive either vehicle (normal saline; n=6), PCSK9 inhibitor (4 mg/kg/day; n=6), atorvastatin (40mg/kg/day; n=6) and estrogen (50 µg/kg/day; n=6) for additional 4 weeks. At the end of experimental period, all animals were taken to test learning process with a Morris water maze test. After that, blood and brain were collected to determine metabolic and brain functions. Metabolic disturbance, brain oxidative stress, brain apoptosis, brain insulin receptor dysfunction, dendritic spine loss, and learning deficit were found in obese-ovariectomized rats. PCSK9 inhibitor, atorvastatin and estrogen equally attenuated metabolic disturbance, brain oxidative stress, and brain apoptosis in obese-ovariectomized rats. Interestingly, PCSK9 inhibitor and atorvastatin had the better efficacy than estrogen in ameliorating brain insulin receptor dysfunction, dendritic spine loss, and learning deficit in obese-ovariectomized rats. These findings suggest that PCSK9 inhibitor and atorvastatin, instead of estrogen, may be another drug of choice for improving metabolic and brain function in the case of obesity with estrogen deprivation.