Arachidonic acid: reconciling the dichotomy of its oxidative cascade through specific deuteration

Abstract

A new approach to attenuating pathological inflammatory reactions by buffering the eicosanoid pathways with oxidation-resistant hexadeuterated arachidonic acid (D-ARA) is discussed. Enzymatic processing of ARA, released by phospholipase A2, by lipoxygenases, cyclooxygenases, and cytochromes yields a wide range of bioactive eicosanoids, including pro-inflammation, pro-angiogenesis and pro-thrombosis species that, when produced in excess, are an underlying cause of pathology. Conversely, some products of ARA oxidation possess pro-resolving properties. Non-enzymatic free radical oxidation of ARA generates another large group of products such as isoprostanes and their metabolites, associated with inflammation, ischemia-reperfusion stress, and atherosclerosis. A separate group comprises reactive carbonyl derivatives that irreversibly damage diverse biomolecules. Being resistant to both enzymatic and non-enzymatic oxidation pathways due to large kinetic isotope effects, D-ARA may play a role in mitigating inflammation-related disorders and conditions, including inflammaging.

Keywords:

• Arachidonic acid
• cardiovascular pathologies
• bacterial infections
• eicosanoids

Author contributions

J.T.B. – manuscript writing and editing; M.G.S., N.B.P. – manuscript writing; T.V.K – figure preparation and manuscript editing; M.S.S. – conceptualization and editing. We are grateful to Valerian Kagan for critical reading of the manuscript.

Disclosure statement

M.S.S. is the Chief Scientific Officer of Biojiva, Inc.

Additional information

Funding

This work was financed by the Ministry of Science and Higher Education of the Russian Federation within the framework of state support for the creation and development of World-Class Research Centers “Digital Biodesign and Personalized Healthcare” No 75-15-2020-913 (to N.B.P.).