J Korean Epilepsy Soc.  2005 Dec;9(2):119-128.

The Role of MMP-9 on the Hippocampal Neuronal Cell Death and Mossy Fiber Sprouting due to Pilocarpine-Induced Status Epilepticus in Mice

• Chu MK
• Cho YJ
• Cho KJ
• Lee DJ
• Kim HW
• Kim HJ
• Kim GW
• Heo K
• Lee BI

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.

Keyword

Seizures; Gelatinase B; Apoptosis; Mossy fiber, hippocampal; Anthranilic hydroxamic acid

MeSH Terms

Adult
Animals
Apoptosis
Blotting, Western
Caspase 3
Cell Death*
DNA Fragmentation
Extracellular Matrix
Humans
Male
Matrix Metalloproteinase 9
Matrix Metalloproteinases
Mice*
Mossy Fibers, Hippocampal
Neurons*
Pilocarpine
Seizures
Status Epilepticus*
Up-Regulation
Viola
Caspase 3
Matrix Metalloproteinase 9
Matrix Metalloproteinases
Pilocarpine