Physiological and Pathological Roles of 15-Deoxy-Delta(12,14)-Prostaglandin J(2) in the Central Nervous System and Neurological Diseases

作者：Yagami Tatsurou^*; Yamamoto Yasuhiro; Koma Hiromi

来源：Molecular Neurobiology, 2018, 55(3): 2227-2248.

DOI：10.1007/s12035-017-0435-4

• 15-Deoxy-Delta(12,14) prostaglandin J(2)
• Neuronal membrane targets
• Peroxysome proliferator-activated receptor-gamma
• Phosphoinositide 3-kinase
• Ubiquitinproteasome pathway

Prostaglandins (PGs) are divided into conventional PGs, e.g., PGD(2), and cyclopentenone-type PGs, e.g., 15-deoxy-Delta(12,14) prostaglandin J(2) (15d-PGJ(2)). PGD(2) is non-enzymatically metabolized to PGJ(2), Delta(12)-PGJ(2), and 15d-PGJ(2). In the central nervous system, 15d-PGJ(2) differentiates embryonic midbrain cells into dopaminergic neuronal cells via its nuclear peroxysome proliferator-activated receptor-gamma (PPAR gamma). 15d-PGJ(2) exerts conflict actions: proinflammatory and anti-inflammatory activities. In the brain, 15d-PGJ(2) possesses opposite functions as a neuroprotectant at low concentrations and a neurotoxicant at high concentrations in the brain. PPAR gamma contributes to the neuroprotective effect of 15d-PGJ(2) 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-PGJ(2). 15d-PGJ(2) induces neuronal apoptosis via inactivating ubiquitin proteasome pathway and activating caspase cascade. Alternatively, 15d-PGJ(2) downregulates phosphoinositide 3-kinase (PI3K)-Akt pathway and suppresses neurite outgrowth. 15d-PGJ(2) possesses alpha,beta-unsaturated ketone moiety in its cyclopentenone ring and acts an endogenous electrophile. By the Michael addition reaction, 15d-PGJ(2) is covalently bound to cellular nucleophiles, such as free cysteine residues of proteins that regulate intracellular signaling pathways. There are specific binding sites of [H-3]15d-PGJ(2) 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-PGJ(2). In the present review, we provide evidences for pathophysiological roles of 15d-PGJ(2) in the central nervous system and neurological diseases.

• 出版日期2018-3