title: Expression and detrimental role of hematopoietic prostaglandin D synthase in spinal cord contusion injury.
abstract: Prostaglandin D(2) (PGD(2) ) is a potent inflammatory mediator, which is implicated in both the initiation and resolution of inflammation in peripheral non-neural tissues. Its role in the central nervous system has not been fully elucidated. Spinal cord injury (SCI) is associated with an acute inflammatory response, which contributes to secondary tissue damage that worsens functional loss. We show here, with the use of hematopoietic prostaglandin D synthase (HPGDS) deficient mice and a HPGDS selective inhibitor (HQL-79), that PGD(2) plays a detrimental role after SCI. We also show that HPGDS is expressed in macrophages in the injured mouse spinal cord and contributes to the increase in PGD(2) in the contused spinal cord. HPGDS(-/-) mice also show reduced secondary tissue damage and reduced expression of the proinflammatory chemokine CXCL10 as well as an increase in IL-6 and TGFβ-1 expression in the injured spinal cord. This was accompanied by a reduction in the expression of the microglia/macrophage activation marker Mac-2 and an increase in the antioxidant metallothionein III. Importantly, HPGDS deficient mice exhibit significantly better locomotor recovery after spinal cord contusion injury than wild-type (Wt) mice. In addition, systemically administered HPGDS inhibitor (HQL-79) also enhanced locomotor recovery after SCI in Wt mice. These data suggest that PGD(2) generated via HPGDS has detrimental effects after SCI and that blocking the activity of this enzyme can be beneficial.
authors.affiliation: Center for Research in Neuroscience, Research Institute, McGill University Health Center, Montreal, Quebec, Canada H3G 1A4.
authors.forename: Adriana
authors.initials: A
authors.lastname: Redensek
authors.forename: Khizr I
authors.initials: KI
authors.lastname: Rathore
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Berard
authors.forename: Rubèn
authors.initials: R
authors.lastname: López-Vales
authors.forename: Leigh Anne
authors.initials: LA
authors.lastname: Swayne
authors.forename: Steffany A L
authors.initials: SA
authors.lastname: Bennett
authors.forename: Ikuko
authors.initials: I
authors.lastname: Mohri
authors.forename: Masako
authors.initials: M
authors.lastname: Taniike
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Urade
authors.forename: Samuel
authors.initials: S
authors.lastname: David
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D005260:Female; D037502:Galectin 3 / Q000235:genetics / Q000378:metabolism; D007124:Immunoenzyme Techniques; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D019746:Intramolecular Oxidoreductases; D007535:Isomerases / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D000090023:Metallothionein 3; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D013119:Spinal Cord Injuries / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology
chemical_list: C116322:4-benzhydryloxy-1-(3-(1H-tetrazol-5-yl-)-propyl)piperidine; D037502:Galectin 3; D015850:Interleukin-6; D000090023:Metallothionein 3; D009419:Nerve Tissue Proteins; D010880:Piperidines; D007535:Isomerases; D019746:Intramolecular Oxidoreductases; C545516:HPGDS protein, mouse