Kim Gyung W, Kim Hyun-Jeong, Cho Kyoung-Joo, Kim Hyun-Woo, Cho Yang-Je, Lee Byung I
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.
Neurobiol Dis. 2009 Oct;36(1):169-80. doi: 10.1016/j.nbd.2009.07.008. Epub 2009 Jul 23.
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.
最近的研究表明，基质金属蛋白酶-9（MMP-9）与癫痫的发病机制密切相关。本研究调查了MMP-9在毛果芸香碱诱导的癫痫持续状态（SE）后海马细胞死亡中的作用。我们发现，SE后第3天，MMP-9的表达和活性显著增加，而β1整合素水平降低。在用重组活性MMP-9孵育的海马体外提取物中也观察到了β1整合素的降解。用选择性MMP-9抑制剂治疗可减轻MMP-9的上调、β1整合素的降解、ILK活性和Akt磷酸化的降低以及SE后随后的海马损伤。然而，与抗β1整合素抗体联合治疗几乎完全阻断了MMP-9抑制剂对整合素介导的生存信号和海马细胞死亡的保护作用。我们的研究表明，MMP-9通过中断SE后整合素介导的生存信号诱导海马细胞凋亡性死亡，并表明MMP-9可能是预防癫痫发作诱导的海马损伤的神经保护方法的一个有前景的靶点。
