Yoshihiro Urade
Tsukuba University, Japan
Title: Pathophysiological roles of the prostaglandin D2 system in the central and peripheral nervous system
Biography
Biography: Yoshihiro Urade
Abstract
Prostaglandin (PG) D2 is a major prostanoid produced in the CNS of various mammals including humans and acts as an endogeneous sleep-promoting substance and an infl ammatory lipid mediator. PGD2 is produced by two distinct synthases, i.e., lipocalin-type PGD synthase (L-PGDS) and hematopoietic PGD synthase (H-PGDS), and stimulates two distinct G-proteincoupled receptors, Gs-coupled DP1 receptor and Gi-coupled DP2 (CRTH-2/GPR-44) receptor. (1) In the CNS, L-PGDS is dominantly expressed in the leptomeninges, choroid plexus and oligodendrocytes, and secreted into the cerebrospinal fluid (CSF) as beta-trace protein, a major human CSF protein, whereas H-PGDS is localized in microglia and mast cells. DP1 receptor is localized in subpopulation of cells within the leptoneninges and glial limitance and upregulated in hypertrophied astrocytes in various neuro-infl ammatory circumstances. DP2 receptor is expressed in various infl ammatory cells including activated microglia and invaded macrophages aft er brain damages. By using gene-knockout mice and pharmacological blockades with enzyme inhibitors or receptor antagonists, we revealed that the L-PGDS/DP1 receptor system is involved in the regulation of sleep; (2) the L-PGDS/DP2 system, in myelination of Schwann cells; (3) the H-PGDS/DP1 system, in the suppression of epilepsy; (4) and the H-PGDS/DP2 system, in the chemotaxis of infl ammatory cells during neuroinfl ammation. We reported that L-PGDS/beta-trace protein secreted into the human CSF is upregulated aft er subarachnoid hemorrhage and acts as a scavenger for biliverdin, a harmful heme-degrading product.(5) We recently found that L-PGDS/beta-trace protein binds PGD2 at a high affi nity with Kd value in a submicromoler range and also covalently binds PGJ2 derivatives, nonenzymic dehydration products of PGD2. Th ese results are useful to develop new drugs targeting the PGD2 system and diagnostic kits for various neuroinfl ammatory and neuroimmunological diseases.