Protective role of hematopoietic prostaglandin D synthase in transient focal cerebral ischemia in mice.

Abstract

Cerebral ischemia/reperfusion injury is characterized by the development of inflammatory response, in which vascular macrophages and endogenous microglia are involved. Recent studies showed marked induction of hematopoietic prostaglandin D synthase (HPGDS) after ischemic/reperfusion injury and its localization in microglia, but the molecular mechanism(s) of HPGDS actions in cerebral ischemia is not clear. To clarify the role of HPGDS in cerebral ischemia, C57BL/6 mice and bone marrow chimera mice with cerebral ischemia/reperfusion injury were treated with (4-benzhydryloxy-(1) {3-(1H-tetrazol-5-yl)-propyl}piperidine (HQL-79), a specific inhibitor of HPGDS. The bone marrow chimera mice exhibit expression of enhanced green fluorescent protein (EGFP) in bone marrow/blood-derived monocytes/macrophages. Mice were subjected to ischemia/reperfusion and either treated with HQL-79 (n=44) or vehicle (n=44). Brain sections prepared at 72 h and 7 days after reperfusion were analyzed for neuronal nuclei (NeuN), HPGDS, ionized calcium-binding adapter molecule 1 (Iba1), inducible NO synthase (iNOS), nitrotyrosine, nuclear factor kappa B (NF-kB) and cyclooxygenase-2 (COX-2). The mortality rate (80%) and infarct size were larger in HQL-79- than vehicle-treated mice (58.7+/-8.5 versus 45.2+/-4.9 mm(3); mean+/-SEM, P<0.0001) at 7 days after reperfusion. HQL-79 reduced NeuN expression in the transition area and Iba1 expression (P<0.0001) in the ischemic peri- and penumbra area, but increased COX-2 (P<0.05) and NF-kB expression (P<0.05) in ischemic penumbra and increased formation of nitrotyrosine (P<0.0001) and iNOS (P<0.0001) in the ischemic core area at 72 h and 7 days after reperfusion. In EGFP chimera mice, HQL-79 increased the migration of Iba1/EGFP-positive bone marrow-derived monocytes/macrophages, and simultaneously upregulated iNOS expression in the ischemic core area (P<0.0001), but increased intrinsic microglia/macrophages in ischemic peri-area and penumbra (P<0.0001) at 72 h and 7 days after reperfusion, suggesting involvement of monocytes/macrophages in HQL-79-induced expansion of ischemic injury. Our results demonstrated that the neuroprotective effects of HPGDS in our model are mediated by suppression of activation and infiltration of inflammatory cells.

• Authors: M Liu, N Eguchi, Y Yamasaki, Y Urade, N Hattori, T Urabe
• Journal: Neuroscience (Neuroscience) Vol. 163 Issue 1 Pg. 296-307 (Sep 29 2009) ISSN: 1873-7544 [Electronic] United States
• PMID: 19531375 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 4-benzhydryloxy-1-(3-(1H-tetrazol-5-yl-)-propyl)piperidine
• Anti-Inflammatory Agents
• Biomarkers
• Enzyme Inhibitors
• Lipocalins
• Nerve Tissue Proteins
• Neuroprotective Agents
• Piperidines
• enhanced green fluorescent protein
• Green Fluorescent Proteins
• Nitric Oxide Synthase Type II
• Isomerases
• Intramolecular Oxidoreductases
• HPGDS protein, mouse
• prostaglandin R2 D-isomerase

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology, therapeutic use)
• Biomarkers (metabolism)
• Bone Marrow Transplantation (methods)
• Brain (drug effects, enzymology, physiopathology)
• Chemotaxis, Leukocyte (drug effects, physiology)
• Disease Models, Animal
• Encephalitis (drug therapy, physiopathology, prevention & control)
• Enzyme Inhibitors (pharmacology, therapeutic use)
• Green Fluorescent Proteins (genetics)
• Hypoxia-Ischemia, Brain (drug therapy, physiopathology, prevention & control)
• Intramolecular Oxidoreductases (antagonists & inhibitors, metabolism)
• Ischemic Attack, Transient (drug therapy, physiopathology, prevention & control)
• Isomerases (antagonists & inhibitors, metabolism)
• Lipocalins (antagonists & inhibitors, metabolism)
• Macrophages (drug effects, physiology)
• Male
• Mice
• Mice, Inbred C57BL
• Microglia (drug effects, physiology)
• Nerve Tissue Proteins (metabolism)
• Neuroprotective Agents (pharmacology, therapeutic use)
• Nitric Oxide Synthase Type II (metabolism)
• Piperidines (pharmacology, therapeutic use)
• Reperfusion Injury (drug therapy, physiopathology, prevention & control)
• Transplantation Chimera