Concurrent blockade of free radical and microsomal prostaglandin E synthase-1-mediated PGE2 production improves safety and efficacy in a mouse model of amyotrophic lateral sclerosis.

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.

• Authors: Jin Hee Shin, Young Ae Lee, Jae Keun Lee, Yong Beom Lee, Woong Cho, Doo Soon Im, Jin Hwan Lee, Bok Sun Yun, Joe E Springer, Byoung Joo Gwag
• Journal: Journal of neurochemistry (J Neurochem) Vol. 122 Issue 5 Pg. 952-61 (Sep 2012) ISSN: 1471-4159 [Electronic] England
• PMID: 22537108 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2012 The Authors. Journal of Neurochemistry © 2012 International Society for Neurochemistry.

Chemical References

• AAD-2004
• Aif1 protein, mouse
• Anti-Inflammatory Agents, Non-Steroidal
• Calcium-Binding Proteins
• Free Radical Scavengers
• Free Radicals
• Microfilament Proteins
• 3-nitrotyrosine
• Sulfasalazine
• Tyrosine
• Riluzole
• 8-Hydroxy-2'-Deoxyguanosine
• SOD1 G93A protein
• Superoxide Dismutase
• Deoxyguanosine
• Dinoprostone
• Aspirin
• Ibuprofen

Topics

• 8-Hydroxy-2'-Deoxyguanosine
• Amyotrophic Lateral Sclerosis (drug therapy, genetics, metabolism, physiopathology)
• Analysis of Variance
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology, therapeutic use)
• Aspirin (analogs & derivatives, pharmacology, therapeutic use)
• Calcium-Binding Proteins (metabolism)
• Cerebral Cortex (pathology)
• Deoxyguanosine (analogs & derivatives, metabolism)
• Dinoprostone (metabolism)
• Disease Models, Animal
• Encephalitis (chemically induced, drug therapy)
• Free Radical Scavengers (metabolism)
• Free Radicals (antagonists & inhibitors, metabolism)
• Gene Expression Regulation (drug effects, genetics)
• Humans
• Ibuprofen (pharmacology, therapeutic use)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Microfilament Proteins (metabolism)
• Microglia (drug effects, metabolism)
• Motor Neurons (drug effects, pathology)
• Oxidative Stress (drug effects)
• Riluzole (pharmacology, therapeutic use)
• Spinal Cord (pathology)
• Sulfasalazine (pharmacology, therapeutic use)
• Superoxide Dismutase (genetics)
• Tyrosine (analogs & derivatives, metabolism)