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Biochem Pharmacol. 2018 Dec;158:161-173. doi: 10.1016/j.bcp.2018.10.007. Epub 2018 Oct 11.

Two-pronged approach to anti-inflammatory therapy through the modulation of the arachidonic acid cascade.

Author information

1
Department of Pharmacological and Biomolecular Sciences, University of Milan, Via Balzaretti 9, 20133 Milano, Italy; IBIM, Consiglio Nazionale delle Ricerche, via Ugo la Malfa 153, 90146 Palermo, Italy.
2
Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany.
3
Department of Pharmacological and Biomolecular Sciences, University of Milan, Via Balzaretti 9, 20133 Milano, Italy. Electronic address: genrico.rovati@unimi.it.

Abstract

Chronic inflammation and pain is a major global health problem, and nonsteroidal anti-inflammatory drugs (NSAIDs) remain the most frequently prescribed drugs and common option for the treatment of inflammatory pain. However, they have the potential to cause serious complications, such as gastrointestinal (GI) lesions, bleeding and cardiovascular (CV) problems. NSAIDs exert their anti-inflammatory, analgesic and anti-pyretic actions by inhibiting the cyclooxygenases (COX)-1 and COX-2, key enzymes of the arachidonic acid (AA) cascade. However, not all the AA products or their receptors are pro-inflammatory. Therefore, given the multifaceted interactions of these lipid mediators where a single precursor can trigger multiple events with synergic or opposed function, it is easy to predict that any perturbation of this interplay will cause several unavoidable side effects. Today, we do not have a truly safe NSAID that minimizes GI damage and CV toxicity. One possibility to interfere with this intricate network, while trying to keep its fine balance, is to develop molecules affecting several targets. Different strategies have been proposed for a multitargeted intervention at different levels of the AA cascade, like inhibition of multiple upstream enzymes, such as COX, 5-lipoxygenase, or even soluble epoxide hydrolase and prostaglandin E synthase. Alternative strategies are more focused in the inhibition of targets downstream in the metabolic pathway, such as thromboxane synthase and/or blocking selective receptors. In this review we will briefly summarize the new strategies that have been proposed for a multitargeted pharmacological intervention on this metabolic cascade aimed at developing novel anti-inflammatory therapeutics.

KEYWORDS:

Cyclooxygenase; Eicosanoids; Lipoxygenase; Nonsteroidal anti-inflammatory drugs

PMID:
30315753
DOI:
10.1016/j.bcp.2018.10.007

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