Chronic Intermittent Ethanol Exposure Induces Upregulation of Matrix Metalloproteinase-9 in the Rat Medial Prefrontal Cortex and Hippocampus.

Abstract

Matrix metalloproteinase-9 (MMP-9, Gelatinase B), an extracellular-acting Zn2+-dependent endopeptidase, are involved in brain pathologies including ischemia, glioma, and epilepsy. Recent studies suggested that MMP-9 plays an important role in neuronal plasticity, specifically in learning and memory. To determine whether and how MMP-9 plays role in alcohol-related behaviors, male Sprague-Dawley (SD) rats were subjected to chronic intermittent ethanol (CIE) exposure for 4weeks, following which we collected tissue samples from the hippocampus, medial prefrontal cortex (mPFC), and amygdala at different stages (acute and chronic exposure) during alcohol exposure. Real-time PCR and western blot assays were used to detect changes in the mRNA and protein expression of MMP-9. Our results indicated that both acute and chronic alcohol exposure induced up-regulation of MMP-9 mRNA levels in the hippocampus and mPFC, but not in the amygdala. Furthermore, acute and chronic alcohol exposure up regulated the expression of total MMP-9 and active MMP-9 in these two brain regions. Moreover, the increase of active MMP-9 expression was larger than those in total MMP-9 expression. Immunoprecipitation analyses identified potential MMP-9-interacting proteins, including Itgb1, Src, Eef1a2, tubulin, actin, and histone H2B. These results demonstrate that both acute and CIE exposure induced increases in MMP-9 expression in the mPFC and hippocampus, suggesting that MMP-9 plays a key role in chronic alcohol exposure and dependence.