| Autor: |
Bok Sun Yun, yong lee, Young Lee, Sun Son, Woong Cho, Byoung Joo Gwag, Soo Young Byun, Doo Im, Jin Shin, Joe E. Springer, Park Sun, Jin Lee, Jae Lee |
| Rok vydání: |
2010 |
| Předmět: |
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| Zdroj: |
Nature Precedings |
| ISSN: |
1756-0357 |
| DOI: |
10.1038/npre.2010.5237.1 |
| Popis: |
While free radicals and inflammation constitute major routes of neuronal injury occurring in neurodegenerative diseases, neither antioxidants nor nonsteroidal anti-inflammatory drugs (NSAIDs) have shown significant efficacy in human clinical trials. To explore the possibility that concurrent blockade of free radicals and PGE2-mediated inflammation might constitute a safe and effective therapeutic approach to certain neurodegenerative diseases, we have developed 2-hydroxy-5-[2-(4-trifluoromethylphenyl)-ethylaminobezoic 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 prostaglandin E synthase-1 (mPGES-1) with an IC50 of 230 nM. Oral administration of AAD-2004 blocked free radical formation, PGE2 formation, and microglial activation in the spinal motor neurons of SOD1G93A mice. 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 ibuprofen or riluzole. Gastric bleeding was not induced by AAD-2004 even at a dose 400-fold higher than that required to obtain maximal therapeutic efficacy in SOD1G93A mice. Targeting both mPGES-1 and free radicals may be a promising approach to reduce neurodegeneration in ALS and possibly other neurodegenerative diseases. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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Full text from SpringerLink