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Matrix metalloproteinase 9 regulates cell death following pilocarpine-induced seizures in the developing brain
- Source :
- Neurobiology of Disease, Vol 48, Iss 3, Pp 339-347 (2012)
- Publication Year :
- 2012
- Publisher :
- Elsevier, 2012.
-
Abstract
- Matrix metalloproteinases (MMPs) are involved in tissue repair, cell death and morphogenesis. We investigated the role of the gelatinases MMP-2 and MMP-9 in the pathogenesis of neuronal death induced by prolonged seizures in the developing brain.Seven-day-old rats, MMP-9 knockout mice and transgenic rats overexpressing MMP-9 received intraperitoneal injections of pilocarpine, 250 mg/kg, to induce seizures. After 6–72 h pups were sacrificed, tissue from different brain regions was isolated and expression of MMP-9 mRNA and protein was analyzed by real-time PCR or Western blot. Additionally, brains were fixed and processed for TUNEL-staining, immunohistochemistry and in situ zymography.We found increased numbers of TUNEL-positive cells 24 h after pilocarpine-induced seizures, most pronounced in cortical areas and the dentate gyrus, and less pronounced in thalamus. At 6–24 h, MMP-9 mRNA levels showed significant elevation compared to sham-treated controls; this effect resolved by 48 h, whereas MMP-2 mRNA levels remained stable. Cortical gelatinolytic activity, monitored by in situ zymography, was enhanced following pilocarpine-induced seizures.The MMP inhibitor GM 6001 ameliorated cell death following pilocarpine-induced seizures in infant rats. MMP-9 knockout mice were less susceptible to seizure-induced brain injury. Transgenic rats overexpressing MMP-9 were equally susceptible to seizure-induced brain injury as wild type rats.Our results suggest a significant contribution of MMP-9 to cell death after pilocarpine-induced seizures in the developing brain. As indicated by Western blot analysis, MMP-9 activation may be linked to activation of the Erk/CREB-pathway. The findings implicate involvement of MMP-9 in the pathophysiology of brain injury following seizures in the developing brain.
Details
- Language :
- English
- ISSN :
- 1095953X
- Volume :
- 48
- Issue :
- 3
- Database :
- Directory of Open Access Journals
- Journal :
- Neurobiology of Disease
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.838162e721bb40009d7912674df836ba
- Document Type :
- article
- Full Text :
- https://doi.org/10.1016/j.nbd.2012.06.023