Abstract

Mechanisms of selective neuronal death in the hippocampus after global cerebral ischemia remain to be clarified. Here, we explored a possible role for matrix metalloproteinases (MMPs) in this phenomenon. Although many studies have demonstrated detrimental roles for the gelatinase MMP-9 in focal cerebral ischemia, how dysregulated MMP proteolysis influences global cerebral ischemia is less well understood. In this study, CD-1 mice were subjected to transient global ischemia. Transient occlusions of common carotid arteries for periods between 20 and 40 min led to increasing hippocampal neuronal death after 3 d. Gel zymography showed elevations in gelatinase (MMP-2 and MMP-9) activity. In situ zymography showed that gelatinase activity was mostly colocalized with neuron-specific nuclear protein-stained pyramidal neurons. Mice treated with the broad-spectrum metalloproteinase inhibitor BB-94 (50 mg/kg, i.p.) showed reduced hippocampal gelatinase activity after transient global cerebral ischemia and suffered significantly reduced hippocampal neuronal damage compared with vehicle-treated controls (p < 0.01). Additionally, hippocampal gelatinase activity and neuronal damage after transient global ischemia were also significantly reduced in MMP-9 knock-out mice compared with wild-type mice (p < 0.05). These data indicate a potential deleterious role for MMP-9 in the pathogenesis of delayed neuronal damage in the hippocampus after global cerebral ischemia.