DP-b99 modulates matrix metalloproteinase activity and neuronal plasticity

PLoS One. 2014 Jun 11;9(6):e99789. doi: 10.1371/journal.pone.0099789. eCollection 2014.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chelating Agents / pharmacology
  • Dendritic Spines / drug effects
  • Dendritic Spines / metabolism
  • Egtazic Acid / analogs & derivatives*
  • Egtazic Acid / pharmacology
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Kainic Acid
  • Male
  • Matrix Metalloproteinase 9 / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Neuronal Plasticity / drug effects*
  • Seizures / diet therapy
  • Seizures / metabolism

Substances

  • Chelating Agents
  • DP-b99
  • Egtazic Acid
  • Matrix Metalloproteinase 9
  • Kainic Acid

Grants and funding

This work has been supported by the 7FP EU grant Plasticise, ERANET NEURON grant TBI Epi, and grant no. N N301 665140 from National Science Centre Poland (IF). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.