title: Physiological and Pathological Roles of 15-Deoxy-Δ12,14-Prostaglandin J2in 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-Δ12,14prostaglandin J2(15d-PGJ2). PGD2is non-enzymatically metabolized to PGJ2, Δ12-PGJ2, and 15d-PGJ2. In the central nervous system, 15d-PGJ2differentiates embryonic midbrain cells into dopaminergic neuronal cells via its nuclear peroxysome proliferator-activated receptor-γ (PPARγ). 15d-PGJ2exerts conflict actions: proinflammatory and anti-inflammatory activities. In the brain, 15d-PGJ2possesses 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-PGJ2but 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-PGJ2induces neuronal apoptosis via inactivating ubiquitin proteasome pathway and activating caspase cascade. Alternatively, 15d-PGJ2downregulates phosphoinositide 3-kinase (PI3K)-Akt pathway and suppresses neurite outgrowth. 15d-PGJ2possesses α,β-unsaturated ketone moiety in its cyclopentenone ring and acts an endogenous electrophile. By the Michael addition reaction, 15d-PGJ2is 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-PGJ2in 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-PGJ2in the central nervous system and neurological diseases.
authors.affiliation: Division of Physiology, Department of Pharmaceutical Health Care, Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, Himeji, Hyogo, Japan. yagami@himeji-du.ac.jp.
authors.forename: Tatsurou
authors.initials: T
authors.lastname: Yagami
authors.affiliation: Division of Physiology, Department of Pharmaceutical Health Care, Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, Himeji, Hyogo, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: Division of Physiology, Department of Pharmaceutical Health Care, Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, Himeji, Hyogo, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Koma
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002490:Central Nervous System / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D006801:Humans; D007155:Immunologic Factors / Q000502:physiology* / Q000633:toxicity*; D009422:Nervous System Diseases / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000502:physiology / Q000633:toxicity
chemical_list: C097240:15-deoxy-delta(12,14)-prostaglandin J2; D007155:Immunologic Factors; D015230:Prostaglandin D2
keywords: 15-Deoxy-Δ12,14 prostaglandin J2; Neuronal membrane targets; Peroxysome proliferator-activated receptor-γ; Phosphoinositide 3-kinase; Ubiquitin proteasome pathway