title: Novel NSAID-Derived Drugs for the Potential Treatment of Alzheimer's Disease.
abstract: 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, AL4-9) 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.
authors.affiliation: Department of Pharmacy, University "G. d'Annunzio" of Chieti-Pescara, Via dei Vestini 31, 66100 Chieti Scalo (CH), Italy. ivana.cacciatore@unich.it.
authors.forename: Ivana
authors.initials: I
authors.lastname: Cacciatore
authors.affiliation: Department of Pharmacy, University "G. d'Annunzio" of Chieti-Pescara, Via dei Vestini 31, 66100 Chieti Scalo (CH), Italy. l.marinelli@unich.it.
authors.forename: Lisa
authors.initials: L
authors.lastname: Marinelli
authors.affiliation: Department of Pharmacy, University "G. d'Annunzio" of Chieti-Pescara, Via dei Vestini 31, 66100 Chieti Scalo (CH), Italy. e.fornasari@unich.it.
authors.forename: Erika
authors.initials: E
authors.lastname: Fornasari
authors.affiliation: Department of Pharmacy, University "G. d'Annunzio" of Chieti-Pescara, Via dei Vestini 31, 66100 Chieti Scalo (CH), Italy. l.cerasa@unich.it.
authors.forename: Laura S
authors.initials: LS
authors.lastname: Cerasa
authors.affiliation: Department of Pharmacy, University "G. d'Annunzio" of Chieti-Pescara, Via dei Vestini 31, 66100 Chieti Scalo (CH), Italy. piera.eusepi@unich.it.
authors.forename: Piera
authors.initials: P
authors.lastname: Eusepi
authors.affiliation: Department of Pharmacy, University "G. d'Annunzio" of Chieti-Pescara, Via dei Vestini 31, 66100 Chieti Scalo (CH), Italy. hasanturkez@gmail.com.|Department of Molecular Biology and Genetics, Erzurum Technical University, Erzurum 25240, Turkey. hasanturkez@gmail.com.
authors.forename: Hasan
authors.initials: H
authors.lastname: Türkez
authors.affiliation: Department of Pharmacy, University "G. d'Annunzio" of Chieti-Pescara, Via dei Vestini 31, 66100 Chieti Scalo (CH), Italy. cristina.pomilio@dompe.it.|Domp&#233; Farmaceutici S.p.A.,Via Campo di Pile, 67100 L'Aquila (AQ), Italy. cristina.pomilio@dompe.it.
authors.forename: Cristina
authors.initials: C
authors.lastname: Pomilio
authors.affiliation: Department of Medical Oral and Biotechnological Sciences, University "G. d'Annunzio" of Chieti-Pescara, Via dei Vestini 31, 66100 Chieti Scalo (CH), Italy. marcella.reale@unich.it.
authors.forename: Marcella
authors.initials: M
authors.lastname: Reale
authors.affiliation: Department of Medical Oral and Biotechnological Sciences, University "G. d'Annunzio" of Chieti-Pescara, Via dei Vestini 31, 66100 Chieti Scalo (CH), Italy. chiara.dangelo@unich.it.
authors.forename: Chiara
authors.initials: C
authors.lastname: D'Angelo
authors.affiliation: Department of Medical Oral and Biotechnological Sciences, University "G. d'Annunzio" of Chieti-Pescara, Via dei Vestini 31, 66100 Chieti Scalo (CH), Italy. erica.costantini@unich.it.
authors.forename: Erica
authors.initials: E
authors.lastname: Costantini
authors.affiliation: Department of Pharmacy, University "G. d'Annunzio" of Chieti-Pescara, Via dei Vestini 31, 66100 Chieti Scalo (CH), Italy. antonio.distefano@unich.it.
authors.forename: Antonio
authors.initials: A
authors.lastname: Di Stefano
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000633:toxicity; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000627:therapeutic use*; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D004355:Drug Stability; D005480:Flurbiprofen / Q000737:chemistry; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D009288:Naproxen / Q000737:chemistry; D010446:Peptide Fragments / Q000633:toxicity; D017382:Reactive Oxygen Species / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity; D008063:Thioctic Acid / Q000737:chemistry; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000975:Antioxidants; D053583:Interleukin-1beta; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; C074636:amyloid beta-protein (25-35); D009288:Naproxen; D005480:Flurbiprofen; D008063:Thioctic Acid; D051546:Cyclooxygenase 2; D013755:Tetradecanoylphorbol Acetate
keywords: Alzheimer’s disease; anti-inflammatory drugs; lipoic acid; neuroinflammation