title: Neuronal activity-dependent increase of net matrix metalloproteinase activity is associated with MMP-9 neurotoxicity after kainate.
abstract: Matrix metalloproteinases (MMPs) and the tissue inhibitors of MMPs (TIMPs) are emerging as important modulators of brain physiopathology. Dramatic changes in the expression of MMPs and TIMPs occur during excitotoxic/neuroinflammatory processes. However, only the measurement of net protease activity is relevant physiologically, and the functional consequences of MMP/TIMP ratio modifications in the brain remain elusive. In order to assess MMP activity and effects in brain tissue, we combined in vivo and organotypic culture models of kainate (KA)-induced excitotoxicity to provoke selective neuronal death and neuroinflammation in the hippocampus. Using in situ zymography, we show that KA-induced excitotoxic seizures in rats increase net MMP activity in hippocampal neurons 8 h after seizures, before their death, and that this increase is neuronal activity-dependent. Three days after KA, proteolytic activity increases in blood vessels and reactive glial cells of vulnerable areas, in relation with neuroinflammation. At 7 and 15 days, proteolysis remains high in blood vessels whereas it is reduced in glia. In organotypic hippocampal cultures, which lack blood cell-mediated inflammation and extrinsic connections, a broad-spectrum inhibitor of MMPs (MMPI), but also a selective MMP-9 inhibitor, protect hippocampal neurons against KA-induced excitotoxicity. Moreover, recombinant MMP-9, but not MMP-2, induces selective pyramidal cell death in these cultures and KA-induced neuronal activity exacerbates the neuronal death promoting effects of MMP-9. These data strongly implicate MMPs, and MMP-9 in particular, in both excitotoxic neuronal damage and subsequent neuroinflammatory processes, and suggest that selective MMPIs could be therapeutically relevant in related neurological disorders.
mesh_terms: D000818:Animals; D015703:Antigens, CD; D000951:Antigens, Neoplasm; D000954:Antigens, Surface; D030161:Avian Proteins; D051926:Basigin; D001798:Blood Proteins; D001808:Blood Vessels / Q000378:metabolism; D002452:Cell Count; D016923:Cell Death / Q000187:drug effects; D003975:Diazepam / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004660:Encephalitis / Q000201:enzymology*; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D018757:GABA Modulators / Q000494:pharmacology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D007608:Kainic Acid / Q000633:toxicity*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology; D009924:Organ Culture Techniques; D010618:Phenanthrolines / Q000494:pharmacology; D010663:Phenylmercury Compounds / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000139:chemically induced / Q000201:enzymology / Q000378:metabolism*; D013997:Time Factors; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000494:pharmacology
chemical_list: D015703:Antigens, CD; D000951:Antigens, Neoplasm; D000954:Antigens, Surface; D030161:Avian Proteins; D001798:Blood Proteins; C102624:Bsg protein, Gallus gallus; C079432:Bsg protein, rat; D018690:Excitatory Amino Acid Agonists; D018757:GABA Modulators; D005904:Glial Fibrillary Acidic Protein; D008562:Membrane Glycoproteins; D010618:Phenanthrolines; D010663:Phenylmercury Compounds; D011480:Protease Inhibitors; D019715:Tissue Inhibitor of Metalloproteinase-1; D051926:Basigin; C067422:4-aminophenylmercury chloride; D020782:Matrix Metalloproteinases; D020780:Matrix Metalloproteinase 9; D003975:Diazepam; D007608:Kainic Acid