Protective role of hematopoietic prostaglandin D synthase in transient focal cerebral ischemia in mice.
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.
Liu
M
M
Research Institute for Disease of Old Age, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
Eguchi
N
N
Yamasaki
Y
Y
Urade
Y
Y
Hattori
N
N
Urabe
T
T
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D015415:Biomarkers / Q000378:metabolism; D016026:Bone Marrow Transplantation / Q000379:methods; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004660:Encephalitis / Q000188:drug therapy* / Q000503:physiopathology / Q000517:prevention & control; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D049452:Green Fluorescent Proteins / Q000235:genetics; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy* / Q000503:physiopathology / Q000517:prevention & control; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000503:physiopathology / Q000517:prevention & control; D007535:Isomerases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054834:Lipocalins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000503:physiopathology / Q000517:prevention & control; D018183:Transplantation Chimera
C116322:4-benzhydryloxy-1-(3-(1H-tetrazol-5-yl-)-propyl)piperidine; D000893:Anti-Inflammatory Agents; D015415:Biomarkers; D004791:Enzyme Inhibitors; D054834:Lipocalins; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D010880:Piperidines; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D052247:Nitric Oxide Synthase Type II; D007535:Isomerases; D019746:Intramolecular Oxidoreductases; C545516:HPGDS protein, mouse; C022466:prostaglandin R2 D-isomerase