title: 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: Futuristic Environmental Simulation Center, Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601, Japan.
authors: Hiroyuki
authors: H
authors: Mizoguchi
authors: Junya
authors: J
authors: Nakade
authors: Masaki
authors: M
authors: Tachibana
authors: Daisuke
authors: D
authors: Ibi
authors: Eiichi
authors: E
authors: Someya
authors: Hiroyuki
authors: H
authors: Koike
authors: Hiroyuki
authors: H
authors: Kamei
authors: Toshitaka
authors: T
authors: Nabeshima
authors: Shigeyoshi
authors: S
authors: Itohara
authors: Kazuhiro
authors: K
authors: Takuma
authors: Makoto
authors: M
authors: Sawada
authors: Jun
authors: J
authors: Sato
authors: Kiyofumi
authors: K
authors: Yamada
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D015153:Blotting, Western; D019208:Brain-Derived Neurotrophic Factor / Q000008:administration & dosage / Q000378:metabolism*; D003292:Convulsants; D003975:Diazepam / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004591:Electrophoresis, Polyacrylamide Gel; D005239:Fear / Q000523:psychology; D006624:Hippocampus / Q000201:enzymology / Q000378:metabolism*; D007696:Kindling, Neurologic / Q000502:physiology*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism / Q000502:physiology*; D008568:Memory / Q000502:physiology; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D008845:Microinjections; D009419:Nerve Tissue Proteins / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000494:pharmacology; D010433:Pentylenetetrazole; D011494:Protein Kinases / Q000494:pharmacology; D011498:Protein Precursors / Q000008:administration & dosage / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020813:Receptor, trkB / Q000096:biosynthesis / Q000235:genetics; D012640:Seizures / Q000139:chemically induced / Q000201:enzymology*
chemical_list: D000927:Anticonvulsants; D019208:Brain-Derived Neurotrophic Factor; D003292:Convulsants; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D011498:Protein Precursors; D012333:RNA, Messenger; C426674:brain-derived neurotrophic factor precursor; D016291:Dizocilpine Maleate; D011494:Protein Kinases; D020813:Receptor, trkB; C530988:tropomyosin-related kinase-B, bovine; D020780:Matrix Metalloproteinase 9; D003975:Diazepam; D010433:Pentylenetetrazole