title: Role of matrix metalloproteinases in delayed neuronal damage after transient global cerebral ischemia.
abstract: Mechanisms of selective neuronal death in the hippocampus after global cerebral ischemia remain to be clarified. Here, we explored a possible role for matrix metalloproteinases (MMPs) in this phenomenon. Although many studies have demonstrated detrimental roles for the gelatinase MMP-9 in focal cerebral ischemia, how dysregulated MMP proteolysis influences global cerebral ischemia is less well understood. In this study, CD-1 mice were subjected to transient global ischemia. Transient occlusions of common carotid arteries for periods between 20 and 40 min led to increasing hippocampal neuronal death after 3 d. Gel zymography showed elevations in gelatinase (MMP-2 and MMP-9) activity. In situ zymography showed that gelatinase activity was mostly colocalized with neuron-specific nuclear protein-stained pyramidal neurons. Mice treated with the broad-spectrum metalloproteinase inhibitor BB-94 (50 mg/kg, i.p.) showed reduced hippocampal gelatinase activity after transient global cerebral ischemia and suffered significantly reduced hippocampal neuronal damage compared with vehicle-treated controls (p < 0.01). Additionally, hippocampal gelatinase activity and neuronal damage after transient global ischemia were also significantly reduced in MMP-9 knock-out mice compared with wild-type mice (p < 0.05). These data indicate a potential deleterious role for MMP-9 in the pathogenesis of delayed neuronal damage in the hippocampus after global cerebral ischemia.
authors.affiliation: Neuroprotection Research Laboratory, Department of Neurology, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.
authors.forename: Seong-Ryong
authors.initials: SR
authors.lastname: Lee
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Tsuji
authors.forename: Sun-Ryung
authors.initials: SR
authors.lastname: Lee
authors.forename: Eng H
authors.initials: EH
authors.lastname: Lo
mesh_terms: D000818:Animals; D004151:Dipeptides / Q000494:pharmacology; D004195:Disease Models, Animal; D018450:Disease Progression; D006624:Hippocampus / Q000201:enzymology / Q000473:pathology; D007150:Immunohistochemistry; D002546:Ischemic Attack, Transient / Q000201:enzymology* / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000201:enzymology* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology
chemical_list: D004151:Dipeptides; D061965:Matrix Metalloproteinase Inhibitors; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D018696:Neuroprotective Agents; D011480:Protease Inhibitors; D013876:Thiophenes; D010649:Phenylalanine; C080985:batimastat; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9