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.
Original language | English |
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Pages (from-to) | 952-961 |
Number of pages | 10 |
Journal | Journal of Neurochemistry |
Volume | 122 |
Issue number | 5 |
DOIs | |
State | Published - Sep 2012 |
Keywords
- ALS
- PGE
- SOD1
- inflammation
- mPGES-1
- oxidative stress
ASJC Scopus subject areas
- Biochemistry
- Cellular and Molecular Neuroscience