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.
Highlights
Nowadays, non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to treat several diseases, such as arthritis, fever and pain
Few data are available about the interaction of monocytes with the brain under physiological conditions, it was seen that in pathological conditions, such as neurodegenerative diseases, a mobilization of pro-inflammatory monocytes directed to the inflamed brain tissues occurs [27]
U937 cells are pro-monocytic leukemia cells originating from the histiocytic lymphoma of a 37-year-old male, while THP-1 cells are mature monocytic cells derived from the blood of a patient affected by acute leukemia [30]
Summary
Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to treat several diseases, such as arthritis, fever and pain. Their effects are largely attributed to the inhibition of the cyclooxygenase (COX)-mediated synthesis of prostaglandins (PGs) [1]. The selectivity toward the two isoforms of COX-1 and COX-2 varies among different NSAIDs: for example, ibuprofen and naproxen are nonselective COX inhibitors, whereas celecoxib, rofecoxib, diclofenac, and nimesulide are COX-2 selective inhibitors [2]. In addition to arthritis and pain, cancer and neurodegenerative diseases (e.g., Alzheimer’s disease (AD)) could be treated with some NSAIDs [3,4]. The brain in AD is characterized by a chronic inflammatory status due to activated glial cells.
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