title: Matrix metalloproteinases 2 and 9 fail to influence drug-induced neuroapoptosis in developing rat brain.
abstract: Matrix metalloproteinases (MMPs) play an essential role in tissue repair, cell death, and morphogenesis. The aim of the present study was to investigate potential involvement of selected MMPs in the pathogenesis of neuronal apoptosis induced by the NMDA antagonist MK-801 (dizocilpine) or the GABA(A) agonist phenobarbital in infant rats, transgenic rats overexpressing MMP-9 and MMP-9 knockout mice. Seven-day-old rats or knockout mice received intraperitoneal injections of MK-801, 1 mg/kg, or phenobarbital, 50 mg/kg. At different survival intervals following administration of the compounds (1-72 h), pups were sacrificed, tissue from different brain regions was isolated, and the expression and activity of MMP-2 and MMP-9 were analyzed by real-time PCR, western blot, and zymography. In addition, brains were fixed and processed for TUNEL staining. In all the brain regions analyzed, we found an increased number of TUNEL-positive cells 24 h after administration of MK-801. After treatment, we detected no significant increase in MMP-2 or MMP-9 mRNA expression in cortical areas. No changes in the MMP-9 protein expression or gelatinolytic activity of MMP-2 were observed in conjunction with MK-801 or phenobarbital-induced neuroapoptosis in any brain region analyzed. The extent of neurodegeneration induced by MK-801 or phenobarbital was not altered in MMP-9 transgenic rats and was increased in MMP-9 knockout mice compared to wild-type rats and mice. Treatment with the panmetalloproteinase inhibitor GM6001 did not confer protection against MK-801-induced apoptotic cell death in the developing rat brain. Our results suggest that activation of MMP-9 and MMP-2 does not contribute to pathogenesis of neuronal apoptosis caused by NMDA antagonists or GABA(A) agonists in the developing rat and mouse brain.
authors.affiliation: Department of Pediatric Neurology, Children's Hospital, Medical Faculty Carl Gustav Carus, Technical University Dresden, Fetscherstrasse 74, 01307 Dresden, Germany.
authors.forename: Ortrud
authors.initials: O
authors.lastname: Uckermann
authors.forename: Hella
authors.initials: H
authors.lastname: Luksch
authors.forename: Vanya
authors.initials: V
authors.lastname: Stefovska
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Hoehna
authors.forename: Jenny
authors.initials: J
authors.lastname: Marzahn
authors.forename: Marlen
authors.initials: M
authors.lastname: Theil
authors.forename: Mila
authors.initials: M
authors.lastname: Pesic
authors.forename: Tomasz
authors.initials: T
authors.lastname: Górkiewicz
authors.forename: Maciej
authors.initials: M
authors.lastname: Gawlak
authors.forename: Grzegorz M
authors.initials: GM
authors.lastname: Wilczynski
authors.forename: Leszek
authors.initials: L
authors.lastname: Kaczmarek
authors.forename: Chrysanthy
authors.initials: C
authors.lastname: Ikonomidou
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001921:Brain / Q000187:drug effects / Q000201:enzymology* / Q000254:growth & development; D016291:Dizocilpine Maleate / Q000633:toxicity*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism* / Q000502:physiology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology* / Q000187:drug effects* / Q000201:enzymology; D010634:Phenobarbital / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D016291:Dizocilpine Maleate; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D010634:Phenobarbital