D-galactose-induced aging does not cause further deterioration in brain pathologies and cognitive decline in the obese condition.

Largely as a consequence of changes in modern lifestyle, a significant proportion of global population have become obese. When obese people grow old, pathologies aggravate neurodegeneration. Several studies have demonstrated that both aging and obesity have deleterious impact on brain. However, the time course effects of combined aging-induced by d-galactose and obesity caused by high-fat diet on cognitive and brain function have not been explored. We hypothesize that D-galactose accelerates and aggravates brain pathologies and cognitive dysfunction in the state of obesity. Ninety-six Wistar rats were separated into two groups to be fed with either a normal diet (ND) or a high-fat diet (HFD) for 16 to 20 weeks. At the end of 12 weeks, ND and HFD-fed rats were injected with vehicle (0.9% NSS, s.c) or d-galactose (150 mg/kg/d, s.c) for 4 or 8 weeks. Data from behavioral test, metabolic parameters and brain pathologies were determined at 4 and 8-weeks after d-galactose administration. The results from both d-galactose-treated rats and HFD-fed rats showed that there was an equal increase in advanced glycation end products, and microglial activation, and an impairment in long-term depression, long-term potentiation, and synaptic protein and dendritic spine density in hippocampus, resulting in cognitive decline. However, d-galactose did not accelerate or aggravate these parameters and cognitive decline in HFD-fed rats. These results suggest that aging, obesity, and combined model have equally adverse effects on cognition. These findings can be used to increase public awareness of the negative impact of both aging and obesity on neurodegeneration.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor exerts greater efficacy than atorvastatin on improvement of brain function and cognition in obese rats.

The accumulation of lipid as a result of long-term consumption of a high-fat diet (HFD) may lead to metabolic and brain dysfunction. Atorvastatin, a recommended first-line lipid-lowering agent, has shown beneficial effects on metabolic and brain functions in several models. Recently, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor was approved as an effective therapeutic drug for dyslipidemia patients. However, few studies have reported on the effect of this PCSK9 inhibitor on brain function. In addition, the comparative efficacy on the improvement of metabolic and brain functions between PCSK9 inhibitor and atorvastatin in obese models have not been elucidated. We hypothesized that PCSK9 inhibitor improves metabolic and brain functions in an obese model to a greater extent than atorvastatin. Thirty-two female rats were fed with either a normal diet (ND) or HFD for 15 weeks. At week 13, ND rats were given normal saline and HFD rats were given either normal saline, atorvastatin (40 mg/kg/day) or PCSK9 inhibitor (4 mg/kg/day) for 3 weeks. Oxidative stress, blood brain barrier breakdown, microglial hyperactivity, synaptic dysplasticity, apoptosis, amyloid proteins production in the hippocampus and cognitive decline were found in HFD-fed rats. Atorvastatin and PCSK9 inhibitor therapies equally attenuated hippocampal apoptosis and amyloid protein production in HFD-fed rats. Interestingly, PCSK9 inhibitor had the greater efficacy than atorvastatin on the amelioration of hippocampal oxidative stress, blood brain barrier breakdown, microglial hyperactivity, synaptic dysplasticity in the hippocampus and cognitive decline. These findings suggest that PCSK9 inhibitor may be another drug of choice for improving brain function in the obese condition with discontinued statin therapy.

Combined dipeptidyl peptidase-4 inhibitor with low-dose testosterone exerts greater efficacy than monotherapy on improving brain function in orchiectomized obese rats.

Both obesity and orchiectomy lead to the development of brain pathologies and cognitive decline. Testosterone replacement therapy (2 mg/kg/day TRT) and dipeptidyl peptidase-4 inhibitor (vildagliptin) improved cognition in orchiectomized rats, and obese rats. However, both had no beneficial effects in brain of orchiectomized-obese rats. TRT (>2 mg/kg/day) is possible to attenuate brain defects in those rats, but high dose of TRT causes adverse effects. Then, combined effect of low-dose TRT (1 mg/kg/day) and vildagliptin on brain and cognitive functions in orchiectomized-obese rats should be investigated. Sixty male rats were fed with either a normal diet (ND) or a high-fat diet (HFD) for 28 weeks. At week 13, both ND and HFD-fed rats had either a sham-operation or an orchiectomy. At week 25, orchiectomized rats were treated with either: a vehicle, 2 mg/kg/day TRT, vildagliptin (3 mg/kg/day) or a combined vildagliptin with 1 mg/kg/day TRT for 4 weeks. Then, metabolic parameters, brain and cognitive functions were determined. Hippocampal oxidative stress, apoptosis, dendritic spine loss, microglial hyperactivity, and cognitive decline were found in orchiectomized ND-fed rats and sham-operated HFD-fed rats. Interestingly, orchiectomy aggravated these brain pathologies and cognitive decline in HFD-fed rats. In orchiectomized ND-fed rats, all treatments restored brain and cognitive functions. In orchiectomized HFD-fed rats, monotherapies ameliorated these brain pathologies, while the combined therapies had the greatest beneficial effect on the brains. These findings suggest the combined therapies may be the best therapeutic approach for restoring brain functions in the orchiectomized-obese condition.

N-acetylcysteine with low-dose estrogen reduces cardiac ischemia-reperfusion injury.

Myocardial damage and mitochondrial dysfunction caused by cardiac ischemia-reperfusion (I/R) injury are intensified by endogenous estrogen deprivation. Although N-acetylcysteine (NAC) exerted cardioprotective effects, its benefits when used in combination with hormone therapy are unknown. We tested the hypothesis that a combination of NAC with low-dose estrogen improves cardiometabolic function and protects cardiac mitochondria against I/R injury, to a similar extent to regular-dose estrogen treatment, in estrogen-deprived rats. Female Wistar rats had a bilateral ovariectomy (OVX) or sham operation. Twelve weeks after the operation, OVX rats were treated with regular-dose estrogen (E; 50 µg/kg/day), low-dose estrogen (e; 25 µg/kg/day), NAC (N; 100 mg/kg/day) or combined low-dose estradiol with NAC (eN) for 4 weeks (n = 6/group). Metabolic parameters, echocardiography, heart rate variability and then cardiac I/R protocol involving 30-min coronary artery ligation, followed by 120-min reperfusion, were performed. OVX rats had increased body weight, visceral fat, fasting plasma glucose, HOMA-IR index, triglycerides, cholesterol and LDL levels (P < 0.05 vs sham). Only OVX-E and OVX-eN had a similarly improved HOMA-IR index. LVEF was increased in all treatment groups, but HRV was restored only by OVX-E and OVX-eN. After I/R, myocardial infarct size was decreased in both OVX-E and OVX-eN groups. OVX-E and OVX-eN rats similarly had a reduced mitochondrial ROS level and increased mitochondrial membrane potential in the ischemic myocardium. In conclusion, combined NAC with low-dose estrogen and regular-dose estrogen therapy similarly improve cardiometabolic function, prevent cardiac mitochondrial dysfunction and reduces the infarct size in estrogen-deprived rats with cardiac I/R injury.

Both oophorectomy and obesity impaired solely hippocampal-dependent memory via increased hippocampal dysfunction.

Our previous study demonstrated that obesity aggravated peripheral insulin resistance and brain dysfunction in the ovariectomized condition. Conversely, the effect of obesity followed by oophorectomy on brain oxidative stress, brain apoptosis, synaptic function and cognitive function, particularly in hippocampal-dependent and hippocampal-independent memory, has not been investigated. Our hypothesis was that oophorectomy aggravated metabolic impairment, brain dysfunction and cognitive impairment in obese rats. Thirty-two female rats were fed with either a normal diet (ND, n = 16) or a high-fat diet (HFD, n = 16) for a total of 20 weeks. At week 13, rats in each group were subdivided into sham and ovariectomized subgroups (n = 8/subgroup). At week 20, all rats were tested for hippocampal-dependent and hippocampal-independent memory by using Morris water maze test (MWM) and Novel objective recognition (NOR) tests, respectively. We found that the obese-insulin resistant condition occurred in sham-HFD-fed rats (HFS), ovariectomized-ND-fed rats (NDO), and ovariectomized-HFD-fed rats (HFO). Increased hippocampal oxidative stress level, increased hippocampal apoptosis, increased hippocampal synaptic dysfunction, decreased hippocampal estrogen level and impaired hippocampal-dependent memory were observed in HFS, NDO, and HFO rats. However, the hippocampal-independent memory, cortical estrogen levels, cortical ROS production, and cortical apoptosis showed no significant difference between groups. These findings suggested that oophorectomy and obesity exclusively impaired hippocampal-dependent memory, possibly via increased hippocampal dysfunction. Nonetheless, oophorectomy did not aggravate these deleterious effects under conditions of obesity.