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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-delta(12,14) PGJ2, enzymatic products of cyclooxygenase-mediated arachidonic acid metabolism, exert a complex array of potent neurodegenerative, neuroprotective, and anti-inflammatory effects. Cyclopentenone isoprostanes (A2/J2-IsoPs), products of non-enzymatic, free radical-mediated arachidonate 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.