Chapter 8

Interplay Between Oxidative Stress and Meta- Inflammation in Obesity-Related Neurodegeneration

Orhan Lepara

Abstract

Neurodegeneration refers to the gradual deterioration of neuron structure and function and can lead to debilitating neurological conditions such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Common pathogenic mechanisms on which many neurodegenerative disorders (NDDs) are based include abnormal protein dynamics of malfolding, degradation, proteasomal instability, and aggregation; often with molecular chaperone actions and mutations; free radical/reactive oxygen species (ROS) formation and OxS; bioenergetic weakness, mitochondrial dysfunction and damage to DNA, neuronal Golgi system fragmentation, disruption of the movement of cellular/axonal, neurotrophin (NTF) dysfunction and neuroinflammatory/neuroimmune processes. Oxidative stress is a phenomenon caused by an imbalance between production and accumulation of ROS/reactive nitrogen species (RNS) and/or a deficiency of enzymatic and nonenzymatic antioxidants. Oxidative stress can be a result, but also an obesity trigger. It has shown that obesity is coupled with an altered redox state and increased metabolic risk. Antioxidant defenses in obese patients are decreased compared to the control group, and their concentrations correlate inversely with core adiposity. Moreover, obesity is also defined by increased concentrations of reactive oxygen or nitrogen species. Metabolic changes caused by weight are associated with damage to the central nervous system (CNS), which can result in neuronal death, either through apoptosis or cell necrosis, or by modifying the neuron's synaptic plasticity. Adipose tissue dysfunction associated with obesity has been correlated with abnormal brain metabolism, neuroinflammation, brain atrophy, neural impairment, diminished mood, and cognitive decline. Due to their high metabolic rate, visceral fat tissues function as endocrine organs, which secrete adipokines (leptin, adiponectin, visfatin, resistin, apelin, and plasminogen activator inhibitor type 1) and cytokines (TNF-α, IL-6, IL-1β). Inflammatory cytokines bind to their receptors by activating the pathway of the nuclear factor-kappaB, which induces a pro-inflammatory state. Inflammatory pathways and DNA damage may also be triggered by nutritional imbalance, adversely affecting redox control [via glutathione peroxidase (GPx); glutathione (GSH), and oxidized glutathione (GSSG) levels] and thus fostering oxidative stress. Obesity also impacts the glucose and energy metabolism of brain cells, and by secreting pro-inflammatory agents causes neuroinflammation primarily in the brain's hypothalamic area. The general effect is the loss of neuronal activity and its internal molecular machinery, resulting in intracellular or extracellular or both aberrant protein deposition, contributing to neurodegeneration.

Total Pages: 152-177 (26)

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