Oxidative Injury In The Pathogenesis Of Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a adult-onset progressive neurodegenerative disease, selectively involving in the upper and lower motor neurons. Charcot described ALS in 1874. The precise causes of this creeping paralysis, known colloquially as Lou Gehrig's disease, are still not elucidated.The sufferer usually died 3-5 years after the first appearance of symptoms. Several mechanisms for the pathogenesis of ALS have been proposed: 1 ) mutations of the copper/zinc superoxide dismutase;2 )glutamate excitotoxicity ;3 )mitochondrial dysfunction;4)oxidative stress;5)exogenous toxin and virus;6)autoimmunity; 7)over phosphorylation of neurofilament; 8) deficiency of neurotrophic factors. et al. Although multiple mechanisms clearly can contribute to the pathogenesis of motor neuron injury, recent advances suggest that oxidative stress may play a significant role in the amplification,and possibly the initiation,of disease.Some peculiarities of motor neurons suggest they may be particularly vulnerable to oxidative stress. They are large cells with a very long axonal process. In the spinal cord, to link with muscle fibres, especially the distal lower limb,the motor neuron needs to support a long axonal process with a robust internal skeleton and therefore has a very high content of neurofilament proteins prone to oxidative injury. Motor neurons have high energy demands, necessitating a high level of mitochondrial activity. Unfortunately,the mitochondrial respiratory chain is one of the main sites for the intracellular generation of free radicals. Therefore motor neurons may well be exposed to oxidative stress.This article reviews potential mechanisms of disease pathogenesis in the context of recent data supporting a major role for oxidative stress throughout the disease course.The generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) leads to oxidative and/or nitrosative damage to cellular proteins, lipids and DNA,a process collectively referred to as oxidative stress. In ALS, oxidative stress increases due to an aberrant generation of ROS/RNS and a gradual decline in cellular antioxidant defense mechanisms.In addition, various genetic mutations and environmental exposures can sensitize individuals to oxidative stress and neurodegeneration.Subsequent events after oxidative stress are glutamate-induced neurotoxicity and increased cytosolic Ca2+ levels, resulting in activation of Ca2+-dependent enzymes including NADPH oxidase, cytosolic phospholipase A2, xanthine oxidase, and neuronal nitric oxide synthase (NOS). These enzymes produce reactive oxygen and nitrogen species (ROS/RNS), which oxidatively modify nucleic acid, lipid, sugar, and protein, leading to nuclear damage, mitochondrial damage, proteasome inhibition, and endoplasmic reticulum (ER) stress. Mitochondria are a major source of oxidative stress. Mitochondrial damage results in both ROS leakage from the electron transport system and Ca2+ release. In addition, ROS can leave the motor neurons and induce oxidation and disruption of glutamate uptake in neighboring astrocytes. These results provide a mechanism that can account for the localized loss of glial glutamate transport seen in the disease. Furthermore, the observations lend support for a feedforward model involving reciprocal interactions between motor neurons and glia, which may prove useful in understanding ALS pathogenesis. Oxidative Stress and SOD1Gene MutantThe mutant Cu/Zn SOD1 gains cytotoxic activity,of which the explanation is that the mutations affect the protein's conformation so that the mutated enzyme becomes a source of free radicals and induces oxidative damage in the motor neuron. Oxidative Stress and ExcitotoxicityThe amino acid L-glutamate is the major excitatory neurotransmitter in the central nervous system and is likely involved in most aspects of normal brain function.Excessive activation of glutamate receptors, however,can harm and damage neurons via a mechanism involving the disruption of calcium homeostasis.In a process termed excitotoxicity,the binding of glutamate to ionotropic receptors leads to an inflow of calcium;this rise in cytosolic calcium then triggers changes in mitochondria that enhance the production of free radicals and may also lead to the activation of programed cell death pathways and subsequent cell death. Recently demonstrated that reactive oxygen species generated within motoneurons in response to glutamate can disrupt the glutamate transport function of neighboring astrocytes.A reactive oxygen species- induced decrease in glutamate transport would cause additional rises in extracellular glutamate,which,in turn,would lead to further excitotoxic activation of neurons.Similarly,this cycle could be initiated by reactive oxygen species arising in microglial cells.Oxidative Stress and Nrf2Nuclear erythroid 2-related factor 2 (Nrf2) is a basic region leucine-zipper transcription factor that binds to the antioxidant response element, thereby regulating the expression of many genes that are involved in cellular antioxidant and anti-inflammatory defense. Under normal conditions, Nrf2 activation is inhibited by Kelch-like ECH- associated protein 1 (Keap1).Many results suggest that there was a reduction of Nrf2 mRNA and protein expression in neurons, whereas Keap1 mRNA expression was increased in the motor cortex and spinal cord.Alterations in this signaling cascade occur in ALS and that they may contribute to chronic motor neuron degeneration.Furthermore,Nrf2 activation in astrocytes protects against neurodegeneration in mouse models of familial amyotrophic lateral sclerosis. Oxidative Stress and Iron HomeostasisIron is essential for normal central nervous system (CNS) development and function. However, imbalances, either excess or deficiency, can result in neuronal injury.Iron can generate highly reactivitve hydroxy radicals through Fenton reaction , lead to oxidative stress, and damage some basic components of organism,such as lipids,proteins,DNA and result in celluar injury. So maintaince of celluar iron balance is very important to body.Dysregulation of iron homeostasis in the CNS contributes to disease progression in amyotrophic lateral sclerosis. Many data suggest that iron chelator therapy might be useful for the treatment of ALS.Accumulating evidence supports the hypothesis that brain iron dysregulation and oxidative stress , resulting in ROS generation from H2O2 trigger a cascade of events leading to apoptotic/ necrotic cell death in ALS.Thus, novel therapeutic approaches aimed at neutralization of oxidative stress-induced neurotoxicity,iron chelators and non-vitamin natural antioxidant polyphenols,in monotherapy,or as part of antioxidant cocktail formulation for these diseases. Oxidative Stress and Immune ActivationThe hallmark of immune activation in ALS is the presence of activated microglia and macrophages in affected areas of the CNS.This immune infiltration is accompanied by an increase in proinflammatory proteins,including prostaglandins and the chemokine,monocyte chemoattractant protein (MCP)-1 ,while serving as a significant source of oxidative stress.Recent evidence suggests that oxidative stress may have a more significant role in modulating immune activation. Oxidative Stress and Susceptibility FactorsALS is likely caused by the interaction of genetic and environmental factors and age-dependent changes that may be involved in lowering the threshold of intrinsically vulnerable motor neurons to injury.Several environmental factors have been investigated,including viral infection, pesticide exposure,and smoking as possible links to ALS.Similarly,gene polymorphisms and mutations have been studied as possible susceptibility factors in ALS.The evidence for the involvement of oxidative stress in the progression of motor neuron injury in ALS seems hard to deny.Oxidative stress may be part of a final common pathway through which degenerative disease evolve. Further studies are required. Accordingly, increased understanding of the involvement of oxidative stress is likely to lead to potential therapeutic strategies for the treatment of ALS.