Multiple roles of matrix metalloproteinases in the developing brain

Abstract

Matrix metalloproteinases (MMPs) are a large family of zinc-dependent endoproteases with multiple roles in extracellular matrix remodelling and modulation of signalling pathways. In the central nervous system, they play various beneficial roles in a lot of physiological processes related mainly to the embryonic development and tissue repair - morphogenesis, cell proliferation, migration, differentiation, angiogenesis, synaptogenesis and others. MMPs are also involved in many pathological processes such as brain trauma, inflammation, neurodegeneration, tumor invasion, epilepsy, multiple sclerosis etc., in which they have well-expressed varying detrimental effects. We used two experimental models in the developing rodent brain, i.e., unilateral traumatic cortical lesion and pharmacological administration of MK-801 (dizocilpine), an antagonist of NMDA glutamate receptors, or phenobarbital, agonist of GABAA receptors. Molecular, biochemical and immunohistochemical methods were applied to investigate the complex beneficial and detrimental effects of MMP-2/-9 in these specific pathological conditions. Our findings suggest that focal trauma to the immature rodent brain leads to an increased synthesis and expression of MMP-2/-9 within various brain regions. Their increased activity contribute to developmental neuroapoptosis in a time dependent fashion. The metalloproteinase inhibitor GM6001 (Ilomastat) ameliorates neurodegeneration following brain trauma in a significant and dose-dependent manner. MMP-2 and MMP-9 are not pathogenetically involved in apoptotic neuronal death induced by NMDA antagonists or GABAA agonists. Inhibition of MMP expression may be a useful therapeutic approach for preventing secondary damage following acute trauma to the developing brain.