title: 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.affiliation: Department of Neuroscience, Ajou University School of Medicine, Suwon, South Korea GNT Pharma, Yongin, South Korea.
authors.forename: Jin Hee
authors.initials: JH
authors.lastname: Shin
authors.forename: Young Ae
authors.initials: YA
authors.lastname: Lee
authors.forename: Jae Keun
authors.initials: JK
authors.lastname: Lee
authors.forename: Yong Beom
authors.initials: YB
authors.lastname: Lee
authors.forename: Woong
authors.initials: W
authors.lastname: Cho
authors.forename: Doo Soon
authors.initials: DS
authors.lastname: Im
authors.forename: Jin Hwan
authors.initials: JH
authors.lastname: Lee
authors.forename: Bok Sun
authors.initials: BS
authors.lastname: Yun
authors.forename: Joe E
authors.initials: JE
authors.lastname: Springer
authors.forename: Byoung Joo
authors.initials: BJ
authors.lastname: Gwag
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D000704:Analysis of Variance; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use*; D001241:Aspirin / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002540:Cerebral Cortex / Q000473:pathology; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism*; D004195:Disease Models, Animal; D004660:Encephalitis / Q000139:chemically induced / Q000188:drug therapy; D016166:Free Radical Scavengers / Q000378:metabolism; D005609:Free Radicals / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007052:Ibuprofen / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D009046:Motor Neurons / Q000187:drug effects / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D019782:Riluzole / Q000494:pharmacology / Q000627:therapeutic use; D013116:Spinal Cord / Q000473:pathology; D012460:Sulfasalazine / Q000494:pharmacology / Q000627:therapeutic use*; D013482:Superoxide Dismutase / Q000235:genetics; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: C575912:AAD-2004; C491049:Aif1 protein, mouse; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002135:Calcium-Binding Proteins; D016166:Free Radical Scavengers; D005609:Free Radicals; D008840:Microfilament Proteins; C002744:3-nitrotyrosine; D012460:Sulfasalazine; D014443:Tyrosine; D019782:Riluzole; D000080242:8-Hydroxy-2'-Deoxyguanosine; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; D003849:Deoxyguanosine; D015232:Dinoprostone; D001241:Aspirin; D007052:Ibuprofen