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Int. J. Mol. Sci. 2016, 17(7), 1035;

Novel NSAID-Derived Drugs for the Potential Treatment of Alzheimer’s Disease

Department of Pharmacy, University “G. d’Annunzio” of Chieti-Pescara, Via dei Vestini 31, 66100 Chieti Scalo (CH), Italy
Department of Molecular Biology and Genetics, Erzurum Technical University, Erzurum 25240, Turkey
Dompé Farmaceutici S.p.A.,Via Campo di Pile, 67100 L’Aquila (AQ), Italy
Department of Medical Oral and Biotechnological Sciences, University “G. d’Annunzio” of Chieti-Pescara, Via dei Vestini 31, 66100 Chieti Scalo (CH), Italy
Author to whom correspondence should be addressed.
Academic Editor: Katalin Prokai-Tatrai
Received: 12 April 2016 / Revised: 13 June 2016 / Accepted: 20 June 2016 / Published: 30 June 2016
(This article belongs to the Special Issue Neuroprotective Strategies 2016)
Full-Text   |   PDF [1374 KB, uploaded 30 June 2016]   |  


Nonsteroidal anti-inflammatory drugs (NSAIDs) have been suggested for the potential treatment of neurodegenerative diseases, such as Alzheimer’s disease (AD). Prolonged use of NSAIDs, however, produces gastrointestinal (GI) toxicity. To overcome this serious limitation, the aim of this study was to develop novel NSAID-derived drug conjugates (Anti-inflammatory-Lipoyl derivatives, AL49) that preserve the beneficial effects of NSAIDS without causing GI problems. As such, we conjugated selected well-known NSAIDs, such as (S)-naproxen and (R)-flurbiprofen, with (R)-α-lipoic acid (LA) through alkylene diamine linkers. The selection of the antioxidant LA was based on the proposed role of oxidative stress in the development and/or progression of AD. Our exploratory studies revealed that AL7 containing the diaminoethylene linker between (R)-flurbiprofen and LA had the most favorable chemical and in vitro enzymatic stability profiles among the synthesized compounds. Upon pretreatment, this compound exhibited excellent antioxidant activity in phorbol 12-miristate 13-acetate (PMA)-stimulated U937 cells (lymphoblast lung from human) and Aβ(25–35)-treated THP-1 cells (leukemic monocytes). Furthermore, AL7 also modulated the expression of COX-2, IL-1β and TNF-α in these cell lines, suggesting anti-inflammatory activity. Taken together, AL7 has emerged as a potential lead worthy of further characterization and testing in suitable in vivo models of AD. View Full-Text
Keywords: anti-inflammatory drugs; Alzheimer’s disease; lipoic acid; neuroinflammation anti-inflammatory drugs; Alzheimer’s disease; lipoic acid; neuroinflammation

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Cacciatore, I.; Marinelli, L.; Fornasari, E.; Cerasa, L.S.; Eusepi, P.; Türkez, H.; Pomilio, C.; Reale, M.; D’Angelo, C.; Costantini, E.; Di Stefano, A. Novel NSAID-Derived Drugs for the Potential Treatment of Alzheimer’s Disease. Int. J. Mol. Sci. 2016, 17, 1035.

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