Matrix metalloproteinase-9 contributes to kindled seizure development in pentylenetetrazole-treated mice by converting pro-BDNF to mature BDNF in the hippocampus.

Abstract

Recurrent seizure activity has been shown to induce a variety of permanent structural changes in the brain. Matrix metalloproteinases (MMPs) function to promote neuronal plasticity, primarily through cleavage of extracellular matrix proteins. Here, we investigated the role of MMP-9 in the development of pentylenetetrazole (PTZ)-induced kindled seizure in mice. Repeated treatment with PTZ (40 mg/kg) produced kindled seizure, which was accompanied by enhanced MMP-9 activity and expression in the hippocampus. No change in MMP-9 activity was observed in the hippocampi of mice with generalized tonic seizure following single administration of PTZ (60 mg/kg). MMP-9 colocalized with the neuronal marker NeuN and the glial marker GFAP in the dentate gyrus of the kindled mouse hippocampus. Coadministration of diazepam or MK-801 with PTZ inhibited the development of kindling and the increased MMP-9 levels in the hippocampus. Marked suppression of kindled seizure progression in response to repeated PTZ treatment was observed in MMP-9((-/-)) mice compared with wild-type mice, an observation that was accompanied by decreased hippocampal levels of mature brain-derived neurotrophic factor. Microinjecting the BDNF scavenger TrkB-Fc into the right ventricle before each PTZ treatment significantly suppressed the development of kindling in wild-type mice, whereas no effect was observed in MMP-9((-/-)) mice. On the other hand, bilateral injections of pro-BDNF into the hippocampal dentate gyrus significantly enhanced kindling in wild-type mice but not MMP-9((-/-)) mice. These findings suggest that MMP-9 is involved in the progression of behavioral phenotypes in kindled mice because of conversion of pro-BDNF to mature BDNF in the hippocampus.

• Authors: Hiroyuki Mizoguchi, Junya Nakade, Masaki Tachibana, Daisuke Ibi, Eiichi Someya, Hiroyuki Koike, Hiroyuki Kamei, Toshitaka Nabeshima, Shigeyoshi Itohara, Kazuhiro Takuma, Makoto Sawada, Jun Sato, Kiyofumi Yamada
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 31 Issue 36 Pg. 12963-71 (Sep 07 2011) ISSN: 1529-2401 [Electronic] United States
• PMID: 21900575 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anticonvulsants
• Brain-Derived Neurotrophic Factor
• Convulsants
• Nerve Tissue Proteins
• Neuroprotective Agents
• Protein Precursors
• RNA, Messenger
• brain-derived neurotrophic factor precursor
• Dizocilpine Maleate
• Protein Kinases
• Receptor, trkB
• tropomyosin-related kinase-B, bovine
• Matrix Metalloproteinase 9
• Diazepam
• Pentylenetetrazole

Topics

• Animals
• Anticonvulsants (pharmacology)
• Blotting, Western
• Brain-Derived Neurotrophic Factor (administration & dosage, metabolism)
• Convulsants
• Diazepam (pharmacology)
• Dizocilpine Maleate (pharmacology)
• Electrophoresis, Polyacrylamide Gel
• Fear (psychology)
• Hippocampus (enzymology, metabolism)
• Kindling, Neurologic (physiology)
• Male
• Matrix Metalloproteinase 9 (metabolism, physiology)
• Memory (physiology)
• Mice
• Mice, Inbred ICR
• Mice, Knockout
• Microinjections
• Nerve Tissue Proteins (pharmacology)
• Neuroprotective Agents (pharmacology)
• Pentylenetetrazole
• Protein Kinases (pharmacology)
• Protein Precursors (administration & dosage, metabolism)
• RNA, Messenger (biosynthesis, genetics)
• Receptor, trkB (biosynthesis, genetics)
• Seizures (chemically induced, enzymology)