Matrix metalloproteinase 9 regulates cell death following pilocarpine-induced seizures in the developing brain.

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.

Hoehna Y ，Uckermann O ，Luksch H ，Stefovska V ，Marzahn J ，Theil M ，Gorkiewicz T ，Gawlak M ，Wilczynski GM ，Kaczmarek L ，Ikonomidou C ... -  《-》

The role of matrix metalloproteinases in infant traumatic brain injury.

Sifringer M ，Stefovska V ，Zentner I ，Hansen B ，Stepulak A ，Knaute C ，Marzahn J ，Ikonomidou C ... -  《NEUROBIOLOGY OF DISEASE》

Matrix metalloproteinases 2 and 9 fail to influence drug-induced neuroapoptosis in developing rat brain.

Uckermann O ，Luksch H ，Stefovska V ，Hoehna Y ，Marzahn J ，Theil M ，Pesic M ，Górkiewicz T ，Gawlak M ，Wilczynski GM ，Kaczmarek L ，Ikonomidou C ... -  《-》

Matrix metalloproteinase inhibition facilitates cell death in intracerebral hemorrhage in mouse.

Grossetete M ，Rosenberg GA 《JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM》

Matrix metalloproteinase-9 (MMP-9) expression and extracellular signal-regulated kinase 1 and 2 (ERK1/2) activation in exercise-reduced neuronal apoptosis after stroke.

Exercise preconditioning has been shown to reduce neuronal damage in ischemic/reperfusion (I/R) injury. ERK1/2 signaling in injury has been thought to modulate neuroprotection. In this study, we investigated the effects of ERK1/2 activation on the expression and activity of MMP-9 and downstream neuronal apoptosis. Adult male Sprague-Dawley rats were subjected to 30min of exercise on a treadmill for 3 weeks. Stroke was induced by a 2-h middle cerebral artery (MCA) occlusion using an intraluminal filament. Apoptotic protein caspase-3 and neuronal apoptosis in cortex and striatum was determined by Western blot at 24h reperfusion and TUNEL staining at 48h reperfusion in 5 I/R injury groups: no treatment, MMP-9 inhibitor (doxycycline), pre-ischemic exercise, exercised animals undergone ERK1/2 inhibition (U0126), and dual inhibition of ERK1/2 and MMP-9 in exercised ischemic rats. Cerebral MMP-9 expression in ischemic rats with different treatment was determined at 6, 12 and 24h reperfusion by real-time PCR for mRNA, Western blot for protein and zymography for enzyme activity. Exercise preconditioning significantly (p<0.05) reduced apoptosis determined by caspase-3 and TUNEL. In non-exercised rats, doxycycline treatment had significant (p<0.05) reductions in apoptosis after I/R injury. The dual ERK1/2-MMP-9 inhibited exercised animals had significantly (p<0.05) reduced neuronal apoptosis that was similar to that seen in exercised ischemic rats. MMP-9 expression in I/R injury was significantly (p<0.05) reduced in the exercised animals as compared to non-exercised controls. When ERK1/2 was inhibited, the reduced MMP-9 expression was reversed to the level seen in the non-exercised controls. This study has suggested that exercise-induced neuroprotection in I/R injury may be mediated by MMP-9 and ERK1/2 expression, leading to a reduction in neuronal apoptosis.

Chaudhry K ，Rogers R ，Guo M ，Lai Q ，Goel G ，Liebelt B ，Ji X ，Curry A ，Carranza A ，Jimenez DF ，Ding Y ... -  《-》