Concurrent blockade of free radical and microsomal prostaglandin e synthase-1-mediated PGE 2 production improves safety and efficacy in a mouse model of amyotrophic lateral sclerosis

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

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

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 languageEnglish
Pages (from-to)952-961
Number of pages10
JournalJournal of Neurochemistry
Volume122
Issue number5
DOIs
StatePublished - Sep 2012

Keywords

  • ALS
  • PGE
  • SOD1
  • inflammation
  • mPGES-1
  • oxidative stress

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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