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

J. Neurochem. (2012) 122, 952–961. 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 E2 (PGE2)‐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 PGE2 synthase‐1 (mPGES‐1) activity in response to both lipopolysaccharide‐treated BV2 cell with IC50 of 230 nM and recombinant human mPGES‐1 protein with IC50 of 249 nM in vitro. In superoxide dismutase 1G93A transgenic mouse model of ALS, AAD‐2004 blocked free radical production, PGE2 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 1G93A. Targeting both mPGES‐1‐mediated PGE2 and free radicals may be a promising approach to reduce neurodegeneration in ALS and possibly other neurodegenerative diseases.

Characterization of Motor Neuron Prostaglandin E2 EP3 Receptor Isoform in a Mouse Model of Amyotrophic Lateral Sclerosis

“…9) Furthermore, inhibition of mPGES-1 by AAD-2004, a dual-function drug derived from aspirin and sulfasalazine, prevented the elevation of PGE2 content in the spinal cord of ALS model mice, and improved both motor function and survival. 10) These results suggest that PGE2 plays a pivotal role in the pathogenesis of ALS.…”

AAD-2004 Attenuates Progressive Neuronal Loss in the Brain of Tg-betaCTF99/B6 Mouse Model of Alzheimer Disease

“…Beginning from 10 months of age, Tg-βCTF99/B6 mice and their non-transgenic control mice were fed either lab chow containing AAD-2004 or no drug (control group). AAD-2004 was prepared as described previously [14] and was provided by GNT Pharma Inc. (Yongin, Korea). We prepared the lab chow containing AAD-2004 and control food.…”

“…Recently, it was demonstrated that AAD-2004 had an anti-oxidant property in primary cortical culture, and its anti-oxidant capacity was similar to that by its analog neu2000 [13]. AAD-2004 reduced autophagosome formation, axonopathy, and motor neuron degeneration, improving motor function and increasing life span in in a mouse model of amyotrophic lateral sclerosis [14]. In the present study, we investigated whether AAD-2004 produces a beneficial effect against neuronal loss in the brain of Tg-βCTF99/B6 mice.…”

Roles of vitamin D in amyotrophic lateral sclerosis: possible genetic and cellular signaling mechanisms

“…In SOD G93A transgenic mice, AAD-2004, 2-hydroxy-5-[2-(4-trifluoromethylphenyl)-ethylaminobenzoic acid] blocked free radical production and PGE 2 formation and inhibits mPGES1 and microglial activation in the spinal cord. As a consequence, AAD-2004 reduces auto-phagosome formation, axonopathy, and motor neuron degeneration, improving motor function and increasing life span [122]. These results suggest that mPGES-1 in motor neurons could play a role in the pathogenesis of ALS and that mPGES-1 could work sequentially in motor neurons and activated microglia to produce ALS symptoms in SOD G93A mice.…”