Cyclopentenone Eicosanoids as Mediators of Neurodegeneration: A Pathogenic Mechanism of Oxidative Stress-Mediated and Cyclooxygenase-Mediated Neurotoxicity

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) PGA 2 , PGJ 2 , and 15-deoxy-Δ 12,14 PGJ 2 , enzymatic products of cyclooxygenase-mediated arachidonic acid metabolism, exert a complex array of potent neurodegenerative, neuroprotective, and anti-inflammatory effects. Cyclopentenone isoprostanes (A 2 /J 2 -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.

Prostaglandin J2 Alters Pro-survival and Pro-death Gene Expression Patterns and 26 S Proteasome Assembly in Human Neuroblastoma Cells

“…Furthermore, PGJ2-treatment increased the mRNA levels of genes encoding for calcium-dependent and cytoskeletalrelated proteins, supporting the notion that these eicosanoids exert a complex array of effects that are relevant to neurodegeneration. As conveyed in an excellent recent review (30), the CNS production of highly reactive cyclopentenone prostaglandins, such as the J2 series, may represent a novel pathogenic mechanism common to many neurodegenerative diseases. The temporal and spatial characterization of the effects of these agents may lead to the identification of early biomarkers of these neurodegenerative conditions that are associated with inflammation.…”

“…The CNS production of these cyclopentenone eicosanoids may represent a novel pathogenic mechanism leading to many neurodegenerative conditions (reviewed in Ref. 30). A key question that remains unanswered is whether different forms of neurodegenerative disorders share a common mechanism, i.e.…”

“…Their chemical properties in conjunction with their pro-oxidant and ubiquitin-proteasome pathway disrupting effects render these cyclopentenone prostaglandins extremely neurotoxic and capable of inducing neuronal cell death (reviewed in Ref. 30).…”

Cytoskeleton/Endoplasmic Reticulum Collapse Induced by Prostaglandin J2 Parallels Centrosomal Deposition of Ubiquitinated Protein Aggregates

“…will prevent endangered neurons from dying. Among the many products of arachidonic acid signaling, cyclopentenone prostaglandins such as PGJ2, seem to contribute to pathogenic mechanisms that lead to neurodegeneration (45,46).…”

Pharmacological Evaluation of Cucumber for Cognition Enhancing Effect on Brain of Mice

“…The rise in arachidonic acid coupled with increased lipid peroxidation can promote eicosanoid formation [30] and, if prostaglandins are not quickly removed, they can undergo conversion to neurotoxic agents, the cyclopentenone prostaglandins and the levuglandins. [31] A number of studies confirmed that the redox status of intracellular reduced glutathione (GSH) -the major antioxidant thiol in mammalian cells -would be a critical factor in determining cellular susceptibility to peroxynitrite. Thus, glutathione deficiency facilitates NO and peroxynitrite-dependent neurotoxicity by, possibly, increasing the rate of protein nitration and mitochondrial damage at complex I.…”