Physiological and Pathological Roles of 15-Deoxy-Δ12,14-Prostaglandin J2 in the Central Nervous System and Neurological Diseases

Abstract

Prostaglandins (PGs) are divided into conventional PGs, e.g., PGD₂, and cyclopentenone-type PGs, e.g., 15-deoxy-Δ^12,14 prostaglandin J₂ (15d-PGJ₂). PGD₂ is non-enzymatically metabolized to PGJ₂, Δ¹²-PGJ₂, and 15d-PGJ₂. In the central nervous system, 15d-PGJ₂ differentiates embryonic midbrain cells into dopaminergic neuronal cells via its nuclear peroxysome proliferator-activated receptor-γ (PPARγ). 15d-PGJ₂ exerts conflict actions: proinflammatory and anti-inflammatory activities. In the brain, 15d-PGJ₂ possesses opposite functions as a neuroprotectant at low concentrations and a neurotoxicant at high concentrations in the brain. PPARγ contributes to the neuroprotective effect of 15d-PGJ₂ but not to the neurotoxic effect. Its membrane receptor, chemoattractant receptor-homologous molecule expressed on T-helper type 2 cells (CRTH2), is not also involved in the neurotoxicity of 15d-PGJ₂. 15d-PGJ₂ induces neuronal apoptosis via inactivating ubiquitin proteasome pathway and activating caspase cascade. Alternatively, 15d-PGJ₂ downregulates phosphoinositide 3-kinase (PI3K)-Akt pathway and suppresses neurite outgrowth. 15d-PGJ₂ possesses α,β-unsaturated ketone moiety in its cyclopentenone ring and acts an endogenous electrophile. By the Michael addition reaction, 15d-PGJ₂ is covalently bound to cellular nucleophiles, such as free cysteine residues of proteins that regulate intracellular signaling pathways. There are specific binding sites of [³H]15d-PGJ₂ in the plasma membrane of cerebral cortices. Besides CRTH2, plasmalemmal glycolytic enzymes, respiratory chain enzymes, molecular chaperones, adaptor proteins and cytoskeletons are identified as membrane targets for 15d-PGJ₂. In the present review, we provide evidences for pathophysiological roles of 15d-PGJ₂ in the central nervous system and neurological diseases.

Keywords: 15-Deoxy-Δ12,14 prostaglandin J2; Neuronal membrane targets; Peroxysome proliferator-activated receptor-γ; Phosphoinositide 3-kinase; Ubiquitin proteasome pathway.