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-Δ12,14 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,ß-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.