title: Neutrophil elastase inhibitor attenuates hippocampal neuronal damage after transient forebrain ischemia in rats.
abstract: Inflammatory responses have been known to contribute to the development of neuronal damage after brain ischemia in experimental animals. Also, neutrophil elastase activity in the plasma has been elevated in the patients with acute cerebral infarction. In order to clarify whether neutrophil elastase distributes into the brain parenchyma and exacerbates neuronal damage following ischemia, we examined the effects of specific neutrophil elastase inhibitor, ONO-5046, on hippocampal CA1 neuronal death in relation to neutrophil elastase activity in the plasma and its distribution in the brain and to caspase-3/7 activity. ONO-5046 (5 and 10 mg/kg) or saline (control group) was administrated after 8 min of forebrain ischemia in rats. Ratio of surviving neurons (median, [range]) in hippocampal CA1 seven days after ischemia was significantly higher in the ONO-5046 5 mg/kg (31% [12-57%]), and 10 mg/kg groups (69% [39-76%]) than in the control group (3.2% [0-10%]). Plasma neutrophil elastase activity in the ONO-5046 10 mg/kg group was significantly lower than in the control group (14 [11-25] vs. 41 [35-68] nmol/ml). Neutrophil elastase distributed in the extracellular space in the hippocampal CA1 neuronal layer in the control group, while, in the ONO-5046 10 mg/kg group, trace of neutrophil elastase was detected only in the endothelium. Caspase-3/7 activity was elevated after ischemia over 8 h in the control group, while, in the ONO-5046 10 mg/kg group, no elevation was observed. The results suggest that neutrophil elastase may contribute to neuronal death in hippocampal CA1 following forebrain ischemia and that neutrophil elastase inhibitor attenuates neuronal death.
authors.affiliation: Department of Anesthesiology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505 Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Matayoshi
authors.forename: Takao
authors.initials: T
authors.lastname: Hirata
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamashita
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Ishida
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Mizukami
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Gondo
authors.forename: Mishiya
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Takefumi
authors.initials: T
authors.lastname: Sakabe
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004727:Endothelium / Q000378:metabolism; D005110:Extracellular Space; D005998:Glycine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors / Q000097:blood; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000008:administration & dosage; D053491:Proteinase Inhibitory Proteins, Secretory / Q000008:administration & dosage* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D015424:Reperfusion; D013449:Sulfonamides / Q000008:administration & dosage* / Q000494:pharmacology; D013997:Time Factors
chemical_list: D018696:Neuroprotective Agents; D053491:Proteinase Inhibitory Proteins, Secretory; D013449:Sulfonamides; C069195:sivelestat; D019272:Leukocyte Elastase; C505410:Casp3 protein, rat; D053148:Caspase 3; D053179:Caspase 7; D005998:Glycine