Mitochondrial Link Between Metabolic Syndrome and Pre-Alzheimer’s Disease

There is much evidence to demonstrate that the presence of the metabolic syndrome (MetS) is associated with an increase in the incidence of pre-Alzheimer’s disease. The possible underlying mechanisms linking pre-Alzheimer’s disease and MetS are still unclear. This study summarizes and discusses the potential mechanisms involved in pre-Alzheimer’s disease under MetS conditions, including an increased brain oxidative stress, brain inflammation, brain mitochondrial dysfunction, hyper-phosphorylated tau protein, and amyloid beta production. This report focuses on brain mitochondrial alterations in cases of pre-Alzheimer’s disease where MetS is also extant. The data from in vitro, in vivo, and clinical studies are included. In addition, potential interventions against pre-Alzheimer’s disease in conjunction with MetS are summarized and discussed

Acetylcholine Attenuates Hydrogen Peroxide-Induced Intracellular Calcium Dyshomeostasis Through Both Muscarinic and Nicotinic Receptors in Cardiomyocytes

Background/Aims: Oxidative stress induced intracellular Ca2+ overload plays an important role in the pathophysiology of several heart diseases. Acetylcholine (ACh) has been shown to suppress reactive oxygen species generation during oxidative stress. However, there is little information regarding the effects of ACh on the intracellular Ca2+ regulation in the presence of oxidative stress. Therefore, we investigated the effects of ACh applied before or after hydrogen peroxide (H2O2) treatment on the intracellular Ca2+ regulation in isolated cardiomyocytes. Methods: Single ventricular myocytes were isolated from the male Wistar rats for the intracellular Ca2+ transient study by a fluorimetric ratio technique. Results: H2O2 significantly decreased both of intracellular Ca2+ transient amplitude and decay rate. ACh applied before, but not after, H2O2 treatment attenuated the reduction of intracellular Ca2+ transient amplitude and decay rate. Both atropine (a muscarinic acetylcholine receptor blocker) and mecamylamine (a nicotinic acetylcholine receptor blocker) significantly decreased the protective effects of acetylcholine on the intracellular Ca2+ regulation. Moreover, the combination of atropine and mecamylamine completely abolished the protective effects of acetylcholine on intracellular Ca2+ transient amplitude and decay rate. Conclusion: ACh pretreatment attenuates H2O2-induced intracellular Ca2+ dyshomeostasis through both muscarinic and nicotinic receptors

Fetal hemodynamic changes and mitochondrial dysfunction in myocardium and brain tissues in response to anemia: a lesson from hemoglobin Bart’s disease

Abstract Objective Whether or not the effects of anemia in the early phase, while the fetuses attempts to increase cardiac output to meet oxygen requirement in peripheral organs, is detrimental to the fetal developing vital organs is little-known. The objective of this is to compare prenatal cardiovascular changes and post-abortal cellular damages in the myocardium as a pumping organ and the brain as a perfused organ between anemic fetuses (using fetal Hb Bart’s disease as a study model) in pre-hydropic phase and non-anemic fetuses. Methods Fetuses affected by Hb Bart’s disease and non-anemic fetuses at 16–22 weeks were recruited to undergo comprehensive fetal echocardiography. Cord blood analysis was used to confirm the definite diagnosis of fetal Hb Bart’s disease and normal fetuses. Fetal cardiac and brain tissues were collected shortly after pregnancy termination for the determination of oxidative stress and mitochondrial function, including mitochondrial ROS production and mitochondrial membrane changes. Results A total of 18 fetuses affected by Hb Bart’s disease and 13 non-anemic fetuses were recruited. The clinical characteristics of both groups were comparable. The affected fetuses showed a significant increase in cardiac dimensions, cardiac function, cardiac output and brain circulation without deteriorating cardiac contractility and preload. However, in the affected fetuses, mitochondrial dysfunction was clearly demonstrated in brain tissues and in the myocardium, as indicated by a significant increase in the membrane potential change (p-value < 0.001), and a significant increase in ROS production in brain tissues, with a trend to increase in myocardium. The findings indicated cellular damage in spite of good clinical compensation. Conclusion The new insight is that, in response to fetal anemia, fetal heart increases in size (dilatation) and function to increase cardiac output and blood flow velocity to provide adequate tissue perfusion, especially brain circulation. However, the myocardium and brain showed a significant increase in mitochondrial dysfunction, suggesting cellular damage secondary to anemic hypoxia. The compensatory increase in circulation could not completely prevent subtle brain and heart damage

Effects of vildagliptin, metformin, and combination of vildagliptin and metformin on metabolic parameters (n = 11/group).

<p>*<i>P</i><0.05 vs. NDV, ^†<i>P</i><0.05 vs. HFDV.</p

Effects of vildagliptin, metformin, combined drugs on arrhythmia, mortality rate, and phosphorylation of Cx43 level.

<p>(A) Combined drugs reduced arrhythmia score in HFD rats.*p<0.05 vs. HFDV, n = 11/group. (B) Combined drugs delayed time to the 1^st VT/VF onset in HFD rats. *p<0.05 vs. HFDV, n = 11/group. (C) Mortality rate was higher in HFDV, and combined drugs reduced mortality rate in both ND and HFD rats. *p<0.05 vs. NDV, ^†p<0.05 vs. HFDV, n = 11/group. (D) Combined drugs increased p-Cx43 in HFD rats. *p<0.05 vs. HFDV, n = 5/group.</p

Effects of vildagliptin, metformin, and combined drugs on infarct size, Bax, and Bcl-2 expression.

<p>(A) Infarct size was increased in HFDV, and all treatments reduced infarct size in both ND and HFD rats. *p<0.05 vs. NDV, ^†p<0.01 vs. HFDV, n = 6/group. (B) Representative images showing TTC staining for infarct size determination. (C) Bax expression was increased in HFDV, and all treatments reduced Bax expression in HFD rats. *p<0.05 vs. NDV, ^†p<0.05 vs. HFDV, n = 5/group. (D) Bcl-2 expression was decreased in HFDV, and all treatments increased Bcl-2 expression in HFD rats. *p<0.05 vs. NDV, ^†p<0.05 vs. HFDV, n = 5/group.</p

Erythropoietin administration exerted neuroprotective effects against cardiac ischemia/reperfusion injury

Acute myocardial infarction (AMI) leads to cardiac dysfunction and also causes brain dysfunction and pathology. The neuroprotective effects of erythropoietin (EPO), the hormone controlling the production of red blood cells, have been shown in case of cerebral ischemic/reperfusion (I/R) injury. However, the effects of EPO on the brain pathologies induced by cardiac I/R injury have not been investigated. We hypothesized that the administration of EPO attenuates brain damage caused by cardiac I/R injury through decreasing peripheral and brain oxidative stress, preserving microglial morphology, attenuating hippocampal necroptosis, and decreasing hippocampal apoptosis, and hippocampal dysplasticity. Male Wistar rats (n ​= ​38) were divided into two groups, sham (n ​= ​6) and cardiac I/R (n ​= ​32). All rats being subjected to the cardiac I/R operation were randomly divided into 4 subgroups (n ​= ​8/group): vehicle, EPO pretreatment, EPO given during ischemia, and EPO given at the onset of reperfusion. The EPO was given at a dosage of 5000 units/kg via intravenous injection. Left ventricle function, oxidative stress, brain mitochondrial function, microglial morphology, hippocampal necroptosis, hippocampal apoptosis, and hippocampal plasticity were measured. EPO administration exerted beneficial anti-oxidative, anti-inflammatory, and anti-apoptotic effects on the brain against cardiac I/R. Giving EPO before cardiac ischemia conferred the greatest neuroprotection against cardiac I/R injury through the attenuation of LV dysfunction, decrease in peripheral and brain oxidative stress, and the attenuation of microglial activation, brain mitochondrial dysfunction, apoptosis, and necroptosis, leading to the improvement of hippocampal dysplasticity under cardiac I/R conditions. EPO pretreatment provided the greatest benefits on brain pathology induced by cardiac I/R

Effects of vildagliptin, metformin, and combined drugs on cardiac mitochondrial function and morphology.

<p>(A) Mitochondrial ROS production was increased in ischemic area of NDV and HFDV, Mitochondrial ROS production was higher in HFDV than NDV, and all treatments reduced mitochondrial ROS production. *p<0.05 vs. remote area, ^†p<0.05 vs. ischemic area of NDV, n = 5/group. (B) Mitochondrial membrane depolarization was found in ischemia area of NDV and HFDV, all treatment prevented mitochondrial membrane depolarization. *p<0.05 vs. remote area of NDV, n = 5/group. (C) An absorbance was decreased in ischemic area of NDV and HFDV. The reduction of absorbance was greater in HFDV than NDV, and all treatments prevented mitochondrial swelling, *p<0.05 vs. remote area of NDV, n = 5/group. (D–M) Cardiac mitochondrial morphology</p

Effects of HFD consumption, vildagliptin, metformin, and combined drugs on HRV and echocardiographic parameters.

<p>(A) The LF/HF ratio was increased at week 8^th and week 12^thof HFD consumption.*p<0.05 vs. baseline, n = 11/group. (B) Vildagliptin, metformin, and combined drugs reduced the LF/HF ratio in HFD rats. *p<0.05 vs. NDV, ^†p<0.05 vs. HFDV, n = 11/group, (C) %FS was decreased after 12 weeks of HFD consumption.*p<0.05 vs. ND, n = 11/group. (D) LVEF was decreased after 12 weeks of HFD consumption.*p<0.05 vs. ND, n = 11/group. (E) Vildagliptin, metformin, and combined drugs increased %FS in HFD rats. *p<0.05 vs. HFDV, n = 11/group. (F) Vildagliptin, metformin, and combined drugs increased LVEF in HFD rats. *p<0.05 vs. HFDV, n = 11/group.</p