Lipid Oxidation and Peroxidation in CNS Health and Disease: From Molecular Mechanisms to Therapeutic Opportunities

Abstract

Reactive oxygen species (ROS) are produced at low levels in mammalian cells by various metabolic processes, such as oxidative phosphorylation by the mitochondrial respiratory chain, NAD(P)H oxidases, and arachidonic acid oxidative metabolism. To maintain physiological redox balance, cells have endogenous antioxidant defenses regulated at the transcriptional level by Nrf2/ARE. Oxidative stress results when ROS production exceeds the cell's ability to detoxify ROS. Overproduction of ROS damages cellular components, including lipids, leading to decline in physiological function and cell death. Reaction of ROS with lipids produces oxidized phospholipids, which give rise to 4-hydroxynonenal, 4-oxo-2-nonenal, and acrolein. The brain is susceptible to oxidative damage due to its high lipid content and oxygen consumption. Neurodegenerative diseases (AD, ALS, bipolar disorder, epilepsy, Friedreich's ataxia, HD, MS, NBIA, NPC, PD, peroxisomal disorders, schizophrenia, Wallerian degeneration, Zellweger syndrome) and CNS traumas (stroke, TBI, SCI) are problems of vast clinical importance. Free iron can react with H(2)O(2) via the Fenton reaction, a primary cause of lipid peroxidation, and may be of particular importance for these CNS injuries and disorders. Cholesterol is an important regulator of lipid organization and the precursor for neurosteroid biosynthesis. Atherosclerosis, the major risk factor for ischemic stroke, involves accumulation of oxidized LDL in the arteries, leading to foam cell formation and plaque development. This review will discuss the role of lipid oxidation/peroxidation in various CNS injuries/disorders.

The Keap1–Nrf2 pathway: promising therapeutic target to counteract ROS-mediated damage in cancers and neurodegenerative diseases

“…As the cerebrum has high lipid content and high oxygen consumption, it is susceptible to oxidative damage (Adibhatla and Hatcher 2010). The high ROS level during reperfusion leads to the pathophysiology of cerebral ischaemia-reperfusion (IR) injury and haemorrhage (Kontos 1989;Flamm et al 1978;Aronowski and Zhao 2011).…”

Application of fatty acid and lipid measurements in neuropsychiatry

“…Pro-inflammatory cytokins (TNF-α, IL-1), secretory phospholipase A2 IIA and lipoprotein-PLA2 are implicated in vascular inflammation. TNF-α and IL-1 alter lipid metabolism and stimulate production of eicosanoids, ceramide and reactive oxygen species leading to potential CNS injures and certain neurological disorders [26].…”

“…The neurochemical system mediating the stress response becomes more "sensitive" to future stressors related to the original experience [25]. Dysregulated lipid metabolism may be of particular importance for central nervous system (CNS) injures and disorders as the CNS has the highest lipid concentration next to adipose tissue [26]. The exact pathophysiological mechanism linking lipids and mental disorders is still debatable.…”

Redox Proteomics in Selected Neurodegenerative Disorders: From Its Infancy to Future Applications

“…Lipid peroxidation, leading to numerous products, including a,b-unsaturated aldehydydes, is highly evident in neurodegenerative diseases (5). As a whole, lipid-peroxidation-derived reactive electrophilic aldehydes are capable of facile covalent attachment to proteins by forming stable adducts with cysteine, lysine, and histidine ( Fig.…”