Matrix metalloproteinase-9 (MMP-9) in human intractable epilepsy caused by focal cortical dysplasia

Abstract

Focal cortical dysplasia (FCD) is a developmental brain disorder characterized by localized abnormalities of cortical layering and neuronal morphology. It is associated with pharmacologically intractable forms of epilepsy in both children and adults. The mechanisms that underlie FCD-associated seizures and lead to the progression of the disease are unclear. Matrix metalloproteinases (MMPs) are enzymes that are able to influence neuronal function through extracellular proteolysis in various normal and pathological conditions. The results of experiments that have used rodent models showed that extracellular MMP-9 can play an important role in epileptogenesis. However, no studies have shown that MMP-9 is involved in the pathogenesis of human epilepsy. The aim of the present study was to determine whether MMP-9 plays a role in intractable epilepsy. Using an unbiased antibody microarray approach, we found that up regulation of MMP-9 is prominent and consistent in FCD tissue derived from epilepsy surgery, regardless of the patient's age. Additionally, an up regulation of MMP-1, -2, -8, -10, and -13 was found but was either less pronounced or limited only to adult cases. In the dysplastic cortex, immunohistochemistry revealed that the highest MMP-9 immuno reactivity occurred in the cytoplasm of abnormal neurons and balloon cells. The neuronal over expression of MMP-9 also occurred in sclerotic hippocampi that were excised together with the dysplastic cortex, but sclerotic hippocampi were free of dysplastic features. In both locations, MMP-9 was also found in reactive astrocytes, albeit to a lesser extent. At the subcellular level, increased MMP-9 immunoreactivity was prominently upregulated at synapses. Thus, although upregulation of the enzyme in FCD is not causally linked to the developmental malformation, it may be a result of ongoing abnormal synaptic plasticity. The present findings support the hypothesis of the pathogenic role of MMP-9 in human epilepsy and may stimulate discussions about whether MMPs could be novel therapeutic targets for intractable epilepsy.