Inflammation, Oxidative Stress, Insulin Resistance, and Hypertension as Mediators for Adverse Effects of Obesity on the Brain: a Review

Abstract Dexamethasone (DEX) is frequently used to treat women at risk of preterm delivery, but although indispensable for completion of organ maturation in fetus, antenatal DEX treatment may exert adverse sex-dimorphic neurodevelopmental effects. Literature findings implicated oxidative stress in adverse effects of DEX treatment.. Purinergic signalling is involved in neurodevelopment, and controled by ectonucleotidases, among which in the brain are most abundant ectonucleoside triphosphate diphosphohydrolase 1 (NTPDase1/CD39) and ecto-5ʹ-nucleotidase (e5ʹNT/CD73), which jointly dephosphorylate ATP to adenosine. They are also involved in cell adhesion and migration, critical for brain development. Up-regulation of CD39 and CD73 after DEX treatment was reported in adult rat hippocampus. We investigated the effects of maternal DEX treatment on CD39 and CD73 expression and enzymatic activity in the rat fetal brain of both sexes, in the context of oxidative status of the brain tissue. Fetuses were obtained at embryonic day (ED) 21, from Wistar rat dams treated with 0.5 mg DEX/kg/day, at ED 16, 17, and 18, and brains were processed and used for further analysis. Sex-specific increase in CD39 and CD73 expression and in the corresponding enzyme activities was induced in the brain of antenatally DEX-treated fetuses, more prominently in males. The oxidative stress induction after antenatal DEX treatment, was confirmed in both sexes, altghough showing a slight bias in males. Due to involvement of purinergic system in crucial neurodevelopmental processes, future investigations are needed to determine the role of observed changes in the adverse effects of antenatal DEX treatment.

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The role of metabolic syndrome in Alzheimer’s disease

10.5327/1516-3180.319 ◽

2021 ◽

Author(s):

Gláucia Maria Senhorinha ◽

Arlys Emanuel Mendes da Silva Santos ◽

Douglas Daniel Dophine

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Insulin Resistance ◽

Alzheimer's Disease ◽

Metabolic Syndrome ◽

Brain Regions ◽

Alzheimer Dementia ◽

The Metabolic Syndrome ◽

The Brain

Background: Metabolic syndrome (MS) leads to the deposits formation of insoluble protein aggregates, neuroinflammation, oxidative stress, neuronal insulin resistance, progressive insulin resistance, desensitization and β-amyloid amyloidosis in the brain, besides direct ischemic effects which are closely associated with Alzheimer’s disease (AD).1 Objectives: The present study seeks to understand the role of the metabolic syndrome in the pathophysiology of Alzheimer’s disease and to describe preventive and therapeutic interventions. Methods: PUBMED and Web of Science were the databases used, the following descriptors were used to search the articles: “Alzheimer Disease” OR “Alzheimer Dementia” AND “Metabolic Syndrome”. Results: The studies in general have shown that MS is related to AD through brain insulin resistance, triggered by oxidative stress and neuroinflammation. It is related to the progressive atrophy of brain regions involved in the progression of AD. Insulin resistance in the brain is related to the progressive atrophy of the brain regions from initial progression of AD. These regions are cingulate cortices, medial temporal lobe, prefrontal gyri and other regions.³ Thus, there is an inhibition of the mechanisms of beta-amyloid removal, leading to its accumulation, which generates neuroinflammation, that in turn potentiates insulin resistance in the central nervous system, contributing to the genesis and progression of cognitive damage.2,3 Conclusions: Insulin resistance plays a major role in the initiation and perpetuation of cognitive impairment in AD. Furthermore, the components of the MS associated with AD, when treated with preventive and therapeutic measures, break this association by promoting rebalancing of the metabolism.

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Insulin Resistance and Oxidative Stress in the Brain: What’s New?

International Journal of Molecular Sciences ◽

10.3390/ijms20040874 ◽

2019 ◽

Vol 20 (4) ◽

pp. 874 ◽

Cited By ~ 40

Author(s):

Mateusz Maciejczyk ◽

Ewa Żebrowska ◽

Adrian Chabowski

Keyword(s):

Oxidative Stress ◽

Insulin Resistance ◽

Strong Relationship ◽

Whole Body ◽

Systemic Insulin Resistance ◽

Amyloid Accumulation ◽

Brain Oxidative Stress ◽

Chronic Hyperglycaemia ◽

Ceramide Generation ◽

The Brain

The latest studies have indicated a strong relationship between systemic insulin resistance (IR) and higher incidence of neurodegeneration, dementia, and mild cognitive impairment. Although some of these abnormalities could be explained by chronic hyperglycaemia, hyperinsulinemia, dyslipidaemia, and/or prolonged whole-body inflammation, the key role is attributed to the neuronal redox imbalance and oxidative damage. In this mini review, we provide a schematic overview of intracellular oxidative stress and mitochondrial abnormalities in the IR brain. We highlight important correlations found so far between brain oxidative stress, ceramide generation, β-amyloid accumulation, as well as neuronal apoptosis in the IR conditions.

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Abstract 113: Glucose Metabolic Disorders in Aging-Associated Microglial NADPH Oxidase 2 Activation and Oxidative Damage of Cerebral Microvasculature and Neurons

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.37.suppl_1.113 ◽

2017 ◽

Vol 37 (suppl_1) ◽

Author(s):

Li Geng ◽

Jian-Mei Li

Keyword(s):

Oxidative Stress ◽

Insulin Resistance ◽

Blood Pressure ◽

Nadph Oxidase ◽

Metabolic Disorders ◽

Aging Brain ◽

Ros Generation ◽

Ros Production ◽

The Brain

Aging has been recognised to be a major risk factor for the development of cardiovascular and neurodegenerative diseases and growing evidence suggests a role for oxidative stress. A Nox2-containing NADPH oxidase has been reported to be a major source of reactive oxygen species (ROS) generation in the vascular system and in the brain. However, the role of Nox2 enzyme in aging-related metabolic disorders and vascular neurodegeneration remains unclear. In this study, we used age-matched wild-type (WT) and Nox2-deficient (Nox2 -/- ) mice on a C57BL/6 background at young (3-4 month) and aging (20-24 month) to investigate the role of Nox2 in aging-related oxidative stress, metabolic disorders and cerebral vascular dysfunction. There was an aging-related increase in blood pressure in WT mice (126 mmHg for young and 148 mmHg for aging) (P<0.05); however the blood pressure was well maintained without significant change in Nox2 -/- aging mice. Compared to young WT mice, WT aging mice had significantly high levels of fasting serum insulin and this was accompanied with delayed clearance of glucose (P<0.05) indicating insulin resistance. In contrast, there was no indication of insulin resistance for Nox2 -/- aging mice. We then examined aging-related brain oxidative stress. Compared to WT young mice, there were significant increases (2.7±0.7 folds) in the levels of ROS production by WT aging brain tissue homogenates as detected by lucigenin-chemiluminescence and DHE fluorescence. Increased ROS production in WT aging brain was accompanied by a significant increase (1.8±0.3 folds) in the Nox2 expression detected mainly in the microglial cells (labelled by Iba-1) and decreases in brain capillaries (labelled by CD31) (2.4±0.8 folds) and neurons (labelled by Neu-N) (2.9±0.5 folds) (all P<0.05). Knockout of Nox2 abolished aging-associated increases in brain ROS production and significantly reduced the aging-related pathophysiological changes in the brain. In conclusion, aging-associated metabolic disorders play a crucial role in aging-associated Nox2 activation and vascular neurodegeneration. Nox2-containing NADPH oxidase represents a valuable therapeutic target for oxidative stress-related brain microvascular damage and neurodegeneration.

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Mechanisms of neurodegeneration in Alzheimer’s disease

Medicinski pregled ◽

10.2298/mpns1208301j ◽

2012 ◽

Vol 65 (7-8) ◽

pp. 301-307 ◽

Cited By ~ 9

Author(s):

Zorica Jovanovic

Keyword(s):

Oxidative Stress ◽

Insulin Resistance ◽

Reactive Oxygen Species ◽

Cell Death ◽

Microglial Activation ◽

Reactive Oxygen ◽

Amyloid Peptide ◽

Oxygen Species ◽

Disease Pathogenesis ◽

The Brain

Introduction. Recent research into mechanisms of neurodegeneration in Alzheimer?s disease has lead to a dramatic increase in our understanding of the mechanisms of cell death and neuroprotection. Alzheimer?s disease is a complex disease with multiple etiological factors involved in disease pathogenesis. Oxidative stress and mitochondrial dysfunction in Alzheimer?s disease. Amyloid-? peptide toxicity is mediated at least in part by oxidative stress. Amyloid-? peptide directly generates reactive oxygen species in the presence of redox-active metal ions. In Alzheimer?s disease, oxidative stress is present early in pathogenesis and contributes to disease pathogenesis. Unlike other organs, the brain is especially vulnerable to reactive oxygen species due to neurons having relatively low levels of endogenous antioxidants. Overly abundant oxygen radicals cause the destruction of cellular macromolecules and participate in signaling mechanisms that result in apoptotic cell death. Microglial activation and nicotinamide adenine dinucleotide phosphate oxidase in Alzheimer?s disease. There is a wealth of evidence demonstrating that microglia, the resident innate immune cells in the brain, can become deleterious and damage neurons. Microglial activation causes neuron damage through the production of neurotoxic factors, such as reactive oxygen species and cytokines that are toxic to neurons. The neuron also has strong homeostatic mechanisms that can delay or prevent activation of apoptosis and necrosis. Insulin resistance and Alzheimer?s disease. Insulin plays a role in Alzheimer?s disease, as it is involved in the metabolism of ?-amyloid. Hyperinsulinemia and type-2 diabetes mellitus results in an increased risk of developing Alzheimer?s disease, but its implications when the disease is already well established remain unknown. Treatment of central insulin resistance may be a promising avenue, not only in metabolic syndrom, but also in Alzheimer?s disease. Conclusion. Increasing evidence suggests a role for oxidative stress, mitochondrial dysfunction, microglial activation and insulin resistance in pathogenesis of neurodegenerative diseases including Alzheimer?s disease.

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