The Emerging Role of the Double-Edged Impact of Arachidonic Acid-Derived Eicosanoids in the Neuroinflammatory Background of Depression

Eicosanoids are arachidonic acid (AA) derivatives belonging to a family of lipid signalling mediators that are engaged in both physiological and pathological processes in the brain. Recently, their implication in the prolonged inflammatory response has become a focus of particular interest because, in contrast to acute inflammation, chronic inflammatory processes within the central nervous system (CNS) are crucial for the development of brain pathologies including depression. The synthesis of eicosanoids is catalysed primarily by cyclooxygenases (COX), which are involved in the production of pro-inflanunatory AA metabolites, including prostaglandins and thromboxanes. Moreover, eicosanoid synthesis is catalysed by lipoxygenases (LOXs), which generate both leukotrienes and anti-inflammatory derivatives such as lipoxins. Thus, AA metabolites have double-edged pro-inflammatory and anti-inflammatory, pro-resolving properties, and an imbalance between these metabolites has been proposed as a contributor or even the basis for chronic neuroinflammatory effects. This review focuses on important evidence regarding eicosanoid-related pathways (with special emphasis on prostaglandins and lipoxins) that has added a new layer of complexity to the idea of targeting the double-edged AA-derivative pathways for therapeutic benefits in depression. We also sought to explore future research directions that can support a pro-resolving response to control the balance between eicosanoids and thus to reduce the chronic neuroinflammation that underlies at least a portion of depressive disorders.

Automated summary

Eicosanoids are a family of lipid signaling mediators derived from arachidonic acid (AA) and play a role in physiological and pathological processes in the brain. Their synthesis is primarily catalyzed by cyclooxygenases (COX) and lipoxygenases (LOXs). The metabolites of AA have dual properties of pro-inflammatory and anti-inflammatory effects, potentially contributing to chronic neuroinflammation. Targeting Eicosanoid-related pathways may offer therapeutic benefits for depression.