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

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 H2O2via 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. Antioxid Redox Signal. 12, 125–169. Introduction The Biological Membrane Structure and Function Lipid synthesis Fatty acid synthesis Phospholipid synthesis Cholesterol is the precursor for neurosteroid synthesis Phospholipid metabolism ROS and Lipid Peroxidation Stroke Stroke or "brain attack": A problem of vast clinical importance Atherosclerosis is a risk factor for stroke Niemann–Pick C1 (NPC1) and atherosclerosis Nuclear factor erythroid 2-related factor 2 (Nrf2) Nrf2 and atherosclerosis Lp-PLA2, also known as platelet activating factor (PAF) acetylhydrolase Atherosclerosis and group IIA secretory PLA2 (inflammatory PLA2) Sphingomyelinases (SMase) and ceramide: More culprits in atherosclerosis 126Therapeutic potential Cytokines and stroke Antioxidants and stroke Stroke clinical trials Oxidized PC (OxPC) is an inflammatory marker Inflammation and resolution Traumatic Brain Injury (TBI) TBI and lipid peroxidation TBI and ApoE Spinal Cord Injury (SCI) Clinical trials Wallerian Degeneration Neurodegenerative Disorders with High Brain Iron Brain uptake of iron Neurodegeneration with brain iron accumulation (NBIA) and infantile neuroaxonal dystrophy (INAD) Ferritinopathy Aceruloplasminemia Alzheimer's Disease (AD) AD and iron AD, oxidative stress, and lipid peroxidation Parkinson's Disease (PD) PD and iron Dopaminergic neurotoxins PD and α-synuclein Treatment of PD Niemann–Pick Diseases (NPD) Peroxisomal Biogenesis Disorders X-linked adrenoleukodistrophy (ALD) Zellweger syndrome Friedreich's Ataxia Multiple Sclerosis (MS) Experimental autoimmune encephalomyelitis (EAE) Huntington's Disease (HD) HD, iron, and lipid peroxidation Amyotrophic Lateral Sclerosis (ALS) ALS, iron, and lipid peroxidation Schizophrenia and Bipolar Disorder Epilepsy Conclusions