Abstract
While free radicals and inflammation constitute major routes of neuronal injury occurring in amyotrophic lateral sclerosis (ALS), neither antioxidants nor non-steroidal anti-inflammatory drugs have shown significant efficacy in human clinical trials. We examined the possibility that concurrent blockade of free radicals and prostaglandin E(2) (PGE(2))-mediated inflammation might constitute a safe and effective therapeutic approach to ALS. We have developed 2-hydroxy-5-[2-(4-trifluoromethylphenyl)-ethylaminobenzoic acid] (AAD-2004) as a derivative of aspirin. AAD-2004 completely removed free radicals at 50 nM as a potent spin-trapping molecule and inhibited microsomal PGE(2) synthase-1 (mPGES-1) activity in response to both lipopolysaccharide-treated BV2 cell with IC(50) of 230 nM and recombinant human mPGES-1 protein with IC(50) of 249 nM in vitro. In superoxide dismutase 1(G93A) transgenic mouse model of ALS, AAD-2004 blocked free radical production, PGE(2) formation, and microglial activation in the spinal cords. As a consequence, AAD-2004 reduced autophagosome formation, axonopathy, and motor neuron degeneration, improving motor function and increasing life span. In these assays, AAD-2004 was superior to riluzole or ibuprofen. Gastric bleeding was not induced by AAD-2004 even at a dose 400-fold higher than that required to obtain maximal therapeutic efficacy in superoxide dismutase 1(G93A). Targeting both mPGES-1-mediated PGE(2) and free radicals may be a promising approach to reduce neurodegeneration in ALS and possibly other neurodegenerative diseases.
© 2012 The Authors. Journal of Neurochemistry © 2012 International Society for Neurochemistry.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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8-Hydroxy-2'-Deoxyguanosine
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Amyotrophic Lateral Sclerosis / drug therapy*
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Amyotrophic Lateral Sclerosis / genetics
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Amyotrophic Lateral Sclerosis / metabolism*
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Amyotrophic Lateral Sclerosis / physiopathology
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Analysis of Variance
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology
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Anti-Inflammatory Agents, Non-Steroidal / therapeutic use*
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Aspirin / analogs & derivatives
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Aspirin / pharmacology
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Aspirin / therapeutic use
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Calcium-Binding Proteins / metabolism
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Cerebral Cortex / pathology
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Deoxyguanosine / analogs & derivatives
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Deoxyguanosine / metabolism
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Dinoprostone / metabolism*
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Disease Models, Animal
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Encephalitis / chemically induced
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Encephalitis / drug therapy
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Free Radical Scavengers / metabolism
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Free Radicals / antagonists & inhibitors
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Free Radicals / metabolism*
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / genetics
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Humans
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Ibuprofen / pharmacology
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Ibuprofen / therapeutic use
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Microfilament Proteins / metabolism
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Microglia / drug effects
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Microglia / metabolism
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Motor Neurons / drug effects
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Motor Neurons / pathology
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Oxidative Stress / drug effects
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Riluzole / pharmacology
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Riluzole / therapeutic use
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Spinal Cord / pathology
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Sulfasalazine / pharmacology
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Sulfasalazine / therapeutic use*
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Superoxide Dismutase / genetics
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Tyrosine / analogs & derivatives
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Tyrosine / metabolism
Substances
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AAD-2004
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Aif1 protein, mouse
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Anti-Inflammatory Agents, Non-Steroidal
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Calcium-Binding Proteins
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Free Radical Scavengers
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Free Radicals
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Microfilament Proteins
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3-nitrotyrosine
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Sulfasalazine
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Tyrosine
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Riluzole
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8-Hydroxy-2'-Deoxyguanosine
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SOD1 G93A protein
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Superoxide Dismutase
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Deoxyguanosine
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Dinoprostone
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Aspirin
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Ibuprofen