title: Matrix metalloproteinase-7 regulates cleavage of pro-nerve growth factor and is neuroprotective following kainic acid-induced seizures.
abstract: The neurotrophin nerve growth factor (NGF) regulates neuronal growth, differentiation, and survival during development. However, the precursor of NGF, proNGF, is a potent apoptotic ligand for the p75 neurotrophin receptor (p75(NTR))-sortilin complex. The mechanisms that regulate cleavage of proNGF, therefore, are critical determinants of whether this factor promotes neuronal survival or death. In this study, we demonstrate that, following kainic acid-induced seizures, the proNGF processing enzyme matrix metalloproteinase 7 (MMP-7) and its inhibitor TIMP-1 (tissue inhibitor of matrix metalloproteinase 1) are regulated in a manner that prevents proneurotrophin cleavage and leads to increased proNGF in the extracellular milieu. Furthermore, we demonstrate both in vitro and in vivo that exogenous MMP-7 enhances proNGF cleavage and provides neuroprotection following kainic acid treatment. These data demonstrate that increased extracellular proNGF levels following seizures are stabilized by altered MMP-7 enzymatic activity, leading to increased neuronal death via activation of p75(NTR).
authors.affiliation: Department of Biological Sciences, Center for Molecular and Behavioral Neuroscience, Rutgers University, Newark, New Jersey 07102, USA.
authors.forename: Audrey P
authors.initials: AP
authors.lastname: Le
authors.forename: Wilma J
authors.initials: WJ
authors.lastname: Friedman
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D004827:Epilepsy / Q000139:chemically induced / Q000150:complications / Q000503:physiopathology*; D007608:Kainic Acid / Q000633:toxicity; D008297:Male; D020783:Matrix Metalloproteinase 7 / Q000502:physiology*; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000209:etiology / Q000517:prevention & control; D009414:Nerve Growth Factors / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000378:metabolism*; D009924:Organ Culture Techniques; D011498:Protein Precursors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D011498:Protein Precursors; C514218:pro-nerve growth factor, rat; D020783:Matrix Metalloproteinase 7; D007608:Kainic Acid