Analysis of Variance ; Animals ; Antibodies/pharmacology ; Caspase 3/metabolism ; Cell Death/drug effects ; Cell Death/physiology ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/pharmacology ; Hippocampus/drug effects ; Hippocampus/metabolism* ; Hippocampus/physiopathology* ; In Situ Nick-End Labeling/methods ; Integrin beta1/immunology ; Integrin beta1/metabolism* ; Male ; Matrix Metalloproteinase 2/metabolism ; Matrix Metalloproteinase 9/metabolism* ; Matrix Metalloproteinase Inhibitors ; Mice ; Mice, Inbred C57BL ; Phosphopyruvate Hydratase/metabolism ; Propidium ; Signal Transduction/drug effects ; Statistics as Topic ; Status Epilepticus/chemically induced ; Status Epilepticus/drug therapy ; Status Epilepticus/pathology* ; Time Factors ; Up-Regulation/drug effects
Keywords
Matrix metalloproteinase ; Integrins ; Pilocarpine ; Status epilepticus
Abstract
Recent studies demonstrate that matrix metalloproteinase-9 (MMP-9) is closely involved in the pathogenesis of epilepsy. This study investigated the role of MMP-9 in hippocampal cell death after pilocarpine-induced status epilepticus (SE). We showed that MMP-9 expression and activity significantly increased and beta1-integrin levels decreased on day 3 after SE. beta1-integrin degradation was also observed in hippocampal ex vivo extracts incubated with recombinant active MMP-9. Treatment with a selective MMP-9 inhibitor attenuated MMP-9 up-regulation, beta1-integrin degradation, the reduction of ILK activity and Akt phosphorylation, and subsequent hippocampal damage after SE. However, co-treatment with anti-beta1-integrin antibody almost completely blocked the protective effects of the MMP-9 inhibitor on both integrin-mediated survival signaling and hippocampal cell death. Our study demonstrates that MMP-9 induces apoptotic hippocampal cell death by interrupting integrin-mediated survival signaling after SE and suggests that MMP-9 may be a promising target for a neuroprotective approach to preventing seizure-induced hippocampal damage