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
|