Oxidative and nitrative stress in neurodegeneration

Abstract

Aerobes require oxygen for metabolism and normal free radical formation. As a result, maintaining the redox homeostasis is essential for brain cell survival due to their high metabolic energy requirement to sustain electrochemical gradients, neurotransmitter release, and membrane lipid stability. Further, brain antioxidant levels are limited compared to other organs and less able to compensate for reactive oxygen and nitrogen species (ROS/RNS) generation which contribute oxidative/nitrative stress (OS/NS). Antioxidant treatments such as vitamin E, minocycline, and resveratrol mediate neuroprotection by prolonging the incidence of or reversing OS and NS conditions. Redox imbalance occurs when the antioxidant capacity is overwhelmed, consequently leading to activation of alternate pathways that remain quiescent under normal conditions. If OS/NS fails to lead to adaptation, tissue damage and injury ensue, resulting in cell death and/or disease. The progression of OS/NS-mediated neurodegeneration along with contributions from microglial activation, dopamine metabolism, and diabetes comprise a detailed interconnected pathway. This review proposes a significant role for OS/NS and more specifically, lipid peroxidation (LPO) and other lipid modifications, by triggering microglial activation to elicit a neuroinflammatory state potentiated by diabetes or abnormal dopamine metabolism. Subsequently, sustained stress in the neuroinflammatory state overwhelms cellular defenses and prompts neurotoxicity resulting in the onset or amplification of brain damage.

Keywords: Brain; Dopamine metabolism; Lipid peroxidation; Lipid/protein modification; Microglial activation; Neurodegeneration; Nitrative stress; Oxidative stress; Reactive nitrogen species; Reactive oxygen species.

Figure 1. General mechanism of lipid peroxidation

Lipid peroxidation requires three major steps. After free radicals are formed, the initation step begins via free radical attack and proton abstraction from an unsaturated lipid to form a lipid radical. Propagation ensues when the lipid radical reacts with molecular oxygen or another unsaturated lipid to form a lipoperoxyl radical or regenerate a new lipid radical, respectively. It is during propagation that reactive aldehydes are formed. Propagation continues until termination is reached to form non-radical end products (underlined). The coupled reactions (dashed box) require two rounds of (1) to take place for (2) to succeed it and terminate lipid peroxidation by production of 2L. X and L refer to any reactive species or lipid species, respectively.

Figure 2. Mechanisms of ROS/RNS generation and downstream modifications

Molecular oxygen is a substrate for xanthine oxidase, NADPH oxidases, mitochondrial complexes I and III, and uncoupled nitric oxide synthases to form superoxide. Superoxide is detoxified by forming hydrogen peroxide via superoxide dismutase activity or can react with nitric oxide to form peroxynitrite. Hydrogen peroxide is cleared by cells through catalase, glutathione peroxidase/glutathione reductase (GR), and iron. Nitric oxide is formed from dietary nitrate to nitrite or from coupled nitric oxide synthases. Nitrite decomposition and peroxynitrite acidification form nitrogen dioxide radicals. Nitrogen dioxide in the presence of water and sulfuric acid results in nitronium or nitryl ion formation and is reversible. Nitronium ions also result from peroxynitrite's reaction with a transition metal. Species responsible for protein S-nitrosylation, lipid nitration, and 3-nitrotyrosine production are indicated as marked with *, ^@, ^# , respectively.

Figure 3. A model for oxidative stress-induced microglial activation in regulating neurodegeneration

In a redox balanced state, both neurons and their support cells coexist in a healthy environment with ROS/RNS in homeostasis. Neurons exhibit normal morphology while microglial cells are in their inactive resting state (a). Upon induction of oxidative/nitrative stress in a redox imbalanced state, a neuroinflammatory condition is established by activation of microglia which undergo morphological changes as ROS/RNS-producing factories through upregulation and release of cytokines such as interleukin-1, interleukin-6, tumor necrosis factor-α, and interferon-γ; iNOS upregulation, which increases NO levels; increased ROS production; and stimulation of dopaminequinone formation where dopamine-quinones down regulate neuroprotective gene expression (b, c). Activated microglia function in two ways: (1) to activate neighboring microglial cells or sustain activation of already activated microglia in a positive feedback mechanism (denoted by the circled + sign) and (2) to act on neurons causing several characteristic changes. In the presence of activated microglia, neurons can exhibit cell shrinkage and reduced axonal and dendrite length, myelin insulation, spine density, nerve conductance, and neurotransmitter transmission. These effects mediate the transition into the neurotoxic state and are initiated by activated microglia.

Figure 4. A model for the interplay among oxidative stress, microglial activation, dopamine metabolism, and diabetes

The process by which OS leads to neurodegeneration is detailed in the solid black arrows, whereas the details of each are noted in solid gray to the left and right. (1) An oxidative/nitrative stress-inducing stimulus, for example antioxidant depletion or altered dopamine metabolism, occurs in the brain. (2) Consequent stress follows, mediated by redox cycling through ROS/RNS, LPO products, or lipid or protein modifications. (3) Once oxidative/nitrative stress mediators are present, cellular processes undergo modifications and/or fluctuations, such as declines in autophagy or PARP1 over activation. (4) Oxidative/nitrative stress and changes in these processes lead to microglial activation, which causes secretion of several pro-inflammatory cytokines, iNOS upregulation, dopamine-quinone production, and potentiated ROS/RNS production, all of which can alone cause further microglial activation. (5) Microglial activation acts on dopamine metabolism. Examples of vacillations in dopamine metabolism are caused by shifts in the extracellular and intracellular dopamine pools, dopamine autooxidation, decreased acetylcholine synthesis or availability, tyrosine hydroxylase nitration, and onset of diabetes.