title: DP-b99 modulates matrix metalloproteinase activity and neuronal plasticity.
abstract: DP-b99 is a membrane-activated chelator of zinc and calcium ions, recently proposed as a therapeutic agent. Matrix metalloproteinases (MMPs) are zinc-dependent extracellularly operating proteases that might contribute to synaptic plasticity, learning and memory under physiological conditions. In excessive amounts these enzymes contribute to a number of neuronal pathologies ranging from the stroke to neurodegeneration and epileptogenesis. In the present study, we report that DP-b99 delays onset and severity of PTZ-induced seizures in mice, as well as displays neuroprotective effect on kainate excitotoxicity in hippocampal organotypic slices and furthermore blocks morphological reorganization of the dendritic spines evoked by a major neuronal MMP, MMP-9. Taken together, our findings suggest that DP-b99 may inhibit neuronal plasticity driven by MMPs, in particular MMP-9, and thus may be considered as a therapeutic agent under conditions of aberrant plasticity, such as those subserving epileptogenesis.
authors.affiliation: Department of Neurophysiology, The Nencki Institute of Experimental Biology, Warsaw, Poland.
authors.forename: Marine
authors.initials: M
authors.lastname: Yeghiazaryan
authors.affiliation: Department of Molecular and Cellular Neurobiology, The Nencki Institute of Experimental Biology, Warsaw, Poland.
authors.forename: Izabela
authors.initials: I
authors.lastname: Rutkowska-Wlodarczyk
authors.affiliation: Department of Neurophysiology, The Nencki Institute of Experimental Biology, Warsaw, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Konopka
authors.affiliation: Department of Neurophysiology, The Nencki Institute of Experimental Biology, Warsaw, Poland.
authors.forename: Grzegorz M
authors.initials: GM
authors.lastname: Wilczyński
authors.affiliation: D-Pharm Ltd, Kiryat Weizmann Science Park, Rehovot, Israel.
authors.forename: Armenuhi
authors.initials: A
authors.lastname: Melikyan
authors.affiliation: Department of Neurobiology, Weizmann Institute, Rehovot, Israel.
authors.forename: Eduard
authors.initials: E
authors.lastname: Korkotian
authors.affiliation: Department of Molecular and Cellular Neurobiology, The Nencki Institute of Experimental Biology, Warsaw, Poland.
authors.forename: Leszek
authors.initials: L
authors.lastname: Kaczmarek
authors.affiliation: Department of Molecular and Cellular Neurobiology, The Nencki Institute of Experimental Biology, Warsaw, Poland.
authors.forename: Izabela
authors.initials: I
authors.lastname: Figiel
mesh_terms: D000818:Animals; D002614:Chelating Agents / Q000494:pharmacology; D049229:Dendritic Spines / Q000187:drug effects / Q000378:metabolism; D004533:Egtazic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007608:Kainic Acid; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009473:Neuronal Plasticity / Q000187:drug effects*; D012640:Seizures / Q000178:diet therapy / Q000378:metabolism
chemical_list: D002614:Chelating Agents; C428064:DP-b99; D004533:Egtazic Acid; D020780:Matrix Metalloproteinase 9; D007608:Kainic Acid