Arachidonic Acid Mediators and Nrf2 in Neurodegenerative Diseases

Malvina Hoxha^1,*, Domenico Tricarico², Loredana Capobianco³
1 Department of the Chemical-Toxicological and Pharmacologic Evaluation of Drugs, Faculty of Pharmacy, Catholic University Our Lady of Good Counsel, Tirana, Albania
2 Department of Pharmacy-Pharmaceutical Sciences, University of Bari “Aldo Moro”, Bari, Italy
3 Department of Biological and Environmental Sciences and Technologies (DiSTeBA), Università del Salento, Lecce, Italy
* Corresponding Author: Malvina Hoxha. Email: email
(This article belongs to the Special Issue: Advances in Nrf2 Signaling Pathway in Neurodegenerative Diseases)

BIOCELL https://doi.org/10.32604/biocell.2026.080846

Received 16 February 2026; Accepted 09 April 2026; Published online 24 April 2026

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Abstract

Arachidonic acid (AA) and its mediators, including prostaglandins (PGs) and lipoxygenase (LOX) products, have different and sometimes opposing effects on neuronal survival and inflammatory signaling. Evidence indicates a functional and dynamic interaction between AA-derived lipid mediators and the nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of antioxidant and cytoprotective responses. Certain AA metabolites, such as the cyclopentenone prostaglandin 15-deoxy-Δ^12,14-prostaglandin J₂ (15d-PGJ₂) and LOX-derived products including 5-oxo-eicosatetraenoic acid (5-oxo-ETE), have been shown to activate Nrf2 signaling. This activation enhances antioxidant defenses, promotes redox homeostasis, and mitigates inflammatory responses in neuronal and glial cells. In contrast, other AA metabolites contribute to sustained neuroinflammation and cytotoxicity, highlighting the dual and context-dependent role of AA signaling in the central nervous system. This duality positions AA mediators as both drivers of pathology and modulators of endogenous protective pathways. Pharmacological strategies targeting cyclooxygenase (COX) enzymes or downstream prostaglandin signaling have therefore been explored for neuroprotective potential; however, clinical translation has been limited by the complex functions of COX-derived products. Arachidonic acid-derived mediators regulating Nrf2 may offer anti-inflammatory yet protective strategies.