Cyclopentenone eicosanoids as mediators of neurodegeneration: A pathogenic mechanism of oxidative stress-mediated and cyclooxygenase-mediated neurotoxicity

Erik S. Musiek, Ginger L. Milne, Beth Ann McLaughlin, Jason D. Morrow

Research output: Contribution to journalArticlepeer-review

56 Scopus citations

Abstract

The activation of cyclooxygenase enzymes in the brain has been implicated in the pathogenesis of numerous neurodegenerative conditions. Similarly, oxidative stress is believed to be a major contributor to many forms of neurodegeneration. These 2 distinct processes are united by a common characteristic: the generation of electrophilic cyclopentenone eicosanoids. These cyclopentenone compounds are defined structurally by the presence of an unsaturated carbonyl moiety in their prostane ring, and readily form Michael adducts with cellular thiols, including those found in glutathione and proteins. The cyclopentenone prostaglandins (PGs) PGA2, PGJ2, and 15-deoxy-Δ12,14 PGJ2, enzymatic products of cyclooxygenase-mediated arachidonic acid metabolism, exert a complex array of potent neurodegenerative, neuroprotective, and anti-inflammatory effects. Cyclopentenone isopsrostanes (A2/J2-IsoPs), products of non-enzymatic, free radical-mediated acachidonate oxidation, are also highly bioactive, and can exert direct neurodegenerative effects. In addition, cyclopentenone products of docosahexaenoic acid oxidation (cyclopentenone neuroprostanes) are also formed abundantly in the brain. For the first time, the formation and biological actions of these various classes of reactive cyclopentenone eicosanoids are reviewed, with emphasis on their potential roles in neurodegeneration. The accumulating evidence suggests that the formation of cyclopentenone eicosanoids in the brain may represent a novel pathogenic mechanism, which contributes to many neurodegenerative conditions.

Original languageEnglish
Pages (from-to)149-158
Number of pages10
JournalBrain Pathology
Volume15
Issue number2
DOIs
StatePublished - Apr 2005

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