Neutrophil elastase inhibition reduces cerebral ischemic damage in the middle cerebral artery occlusion

• Published in: Brain research 2000-03, Vol.858 (1), p.55-60
• Main Authors: Shimakura, Akira, Kamanaka, Yoshihisa, Ikeda, Yasuhiko, Kondo, Kazunao, Suzuki, Yasuhiro, Umemura, Kazuo
• Format: Article
• Language: English
• Subjects: Animals; Antilymphocyte Serum - administration & dosage; Biological and medical sciences; Brain Edema - drug therapy; Brain Ischemia - drug therapy; Cell Count - drug effects; Cerebral Cortex - blood supply; Cerebral Cortex - drug effects; Cerebral Cortex - pathology; Corpus Striatum - blood supply; Corpus Striatum - drug effects; Corpus Striatum - pathology; Dose-Response Relationship, Drug; Edema; Elastase inhibitor; Glycine - administration & dosage; Glycine - analogs & derivatives; Glycine - therapeutic use; Infarction, Middle Cerebral Artery - chemically induced; Infarction, Middle Cerebral Artery - drug therapy; Infusions, Intravenous; Ischemic cerebral damage; Leukocyte Elastase - antagonists & inhibitors; Male; Medical sciences; Neurology; Neutrophil elastase; Neutrophils - cytology; Neutrophils - drug effects; Neutrophils - enzymology; Neutrophils - immunology; Rats; Rats, Wistar; Rose Bengal; Serine Proteinase Inhibitors - therapeutic use; Sulfonamides - administration & dosage; Sulfonamides - therapeutic use; Vascular diseases and vascular malformations of the nervous system
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/S0006-8993(99)02431-2

It has been reported that activated neutrophils are involved in the development of cerebral damage induced by ischemia. Activated neutrophils release a lot of mediators including toxic oxygen metabolites, elastase and cytokines which damage brain tissue. Therefore, we investigated roles of neutrophil elastase in the development of cerebral damage using an elastase inhibitor, ONO-5046. The rat middle cerebral artery (MCA) was occluded by a thrombus induced by photochemical reaction between green light and the photosensitizer dye, Rose Bengal. Photochemical reaction causes endothelial injury followed by formation of a platelet and fibrin-rich thrombus at the site of the irradiation. Photochemical reaction is routinely used in our laboratory to produce arterial occlusion in experimental animals. Twenty-four hours after the MCA occlusion, the size of cerebral damage was measured by histochemical technique. Water content in the brain was measured and neuronal deficits were examined 24 h after the MCA occlusion. ONO-5046 was administered at various doses as continuous infusion for 24 h, starting just after the MCA occlusion or from 3 h after. ONO-5046 at doses of 10 and 30 mg/kg/h significantly ( p