The role of MMP-9 in integrin-mediated hippocampal cell death after pilocarpine-induced status epilepticus.
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.
Kim
Gyung W
GW
Department of Neurology and Brain Korea 21 Project for Medical Science, College of Medicine, Yonsei University, 134, Sinchon-dong, Seodaemun-gu, Seoul 120-752, Republic of Korea.
Kim
Hyun-Jeong
HJ
Cho
Kyoung-Joo
KJ
Kim
Hyun-Woo
HW
Cho
Yang-Je
YJ
Lee
Byung I
BI
D000704:Analysis of Variance; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology*; D020287:In Situ Nick-End Labeling / Q000379:methods; D019012:Integrin beta1 / Q000276:immunology / Q000378:metabolism*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D011419:Propidium; D015398:Signal Transduction / Q000187:drug effects; D013223:Statistics as Topic; D013226:Status Epilepticus / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology*; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects
D000906:Antibodies; D004791:Enzyme Inhibitors; D019012:Integrin beta1; D061965:Matrix Metalloproteinase Inhibitors; D011419:Propidium; D053148:Caspase 3; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D010751:Phosphopyruvate Hydratase