생쥐 Pilocarpine 모델에서 중첩경련으로 유발한 해마신경세포 사멸과 이끼섬유발아에 대한 MMP-9의 역할
The Role of MMP-9 on the Hippocampal Neuronal Cell Death and Mossy Fiber Sprouting due to Pilocarpine-Induced Status Epilepticus in Mice
주민경, 조양제, 조경주, 이두재, 김현우, 김현정, 김경환, 허경, 이병인,
소속 상세정보
주민경 ( Chu Min-Kyung )
한림대학교 의과대학 신경과학교실
조양제 ( Cho Yang-Je )
연세대학교 의과대학 신경과학교실
조경주 ( Cho Kyoung-Joo )
연세대학교 의과대학 신경과학교실
이두재 ( Lee Doo-Jae )
연세대학교 의과대학 신경과학교실
김현우 ( Kim Hyun-Woo )
연세대학교 의과대학 신경과학교실
김현정 ( Kim Hyun-Jeong )
연세대학교 의과대학 신경과학교실
김경환 ( Kim Gyung-Whan )
연세대학교 의과대학 신경과학교실
허경 ( Heo Kyoung )
연세대학교 의과대학 신경과학교실
이병인 ( Lee Byung-In )
연세대학교 의과대학 신경과학교실
KMID : 0877220050090020119
Abstract
Purpose: Matrix metalloproteinases (MMPs) have been known to participate in various pathologic situations by modulating extracellular matrix. Although MMP-9 upregulation has been reported in some experimental seizure models, the exact role of MMP-9 in hippocampal cell death during epileptogenesis and subsequent mossy fiber sprouting (MFS) is not clear. Here, we investigated the role of MMP-9 on hippocampal cell death and MFS after pilocarpine-induced status epilepticus (SE) in mice, using highly specific hydroxamic MMP-9 inhibitor.
Methods: SE was induced by intraperitoneal pilocarpine administration in adult male C57BL/6 mice. MMP-9 specific inhibitor was administered intracerebroventrically 3 h after pilocarpine-induced SE. Expression and activation of MMP-9 were assessed by zymography and Western blot analysis. TdT-mediated UTP-biotin nick end labeling (TUNEL) and caspase-3 activity assay were also performed. MFS was investigated using Timm staining.
Results: Increased expression and activation of MMP-9 after pilocarpine-induced SE were observed in zymography and Western blot analysis. MMP-9 specific inhibitor decreased MMP-9 activity in in situ zymography and hippocampal cell death in cresyl violet staining. DNA fragmentation and caspase-3 activity were also attenuated by MMP-9 specific inhibitor. Four months after pilocarpine-induced SE, MFS was evident in vehicle-treated mice; in contrast, MFS was barely observed in MMP-9 specific inhibitor-treated mice.
Conclusions: This study suggests MMP-9 is associated with hippocampal cell death and MFS after pilocarpine-induced SE. Furthermore, the findings that MMP-9 specific inhibitor ameliorates cell death and MFS offers the possibility of MMP-9 specific hydroxamic inhibitor as novel therapeutic strategy to reduce hippocampal damage and epileptogenesis.
키워드
Seizures;Gelatinase B;Apoptosis;Mossy fiber;hippocampal;Anthranilic hydroxamic acid
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