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Neurotoxicity Research

, Volume 19, Issue 4, pp 638–648 | Cite as

Matrix Metalloproteinases 2 and 9 Fail to Influence Drug-Induced Neuroapoptosis in Developing Rat Brain

  • Ortrud Uckermann
  • Hella Luksch
  • Vanya Stefovska
  • Yvonne Hoehna
  • Jenny Marzahn
  • Marlen Theil
  • Mila Pesic
  • Tomasz Górkiewicz
  • Maciej Gawlak
  • Grzegorz M. Wilczynski
  • Leszek Kaczmarek
  • Chrysanthy Ikonomidou
Article

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 GABAA 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 GABAA agonists in the developing rat and mouse brain.

Keywords

Apoptosis Development Antiepileptic Sedative 

Notes

Acknowledgments

Supported by BMBF Grant No. 01GZ0702.

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Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Ortrud Uckermann
    • 1
  • Hella Luksch
    • 1
  • Vanya Stefovska
    • 1
    • 2
  • Yvonne Hoehna
    • 1
  • Jenny Marzahn
    • 1
  • Marlen Theil
    • 1
  • Mila Pesic
    • 1
  • Tomasz Górkiewicz
    • 3
    • 4
  • Maciej Gawlak
    • 5
  • Grzegorz M. Wilczynski
    • 5
  • Leszek Kaczmarek
    • 3
  • Chrysanthy Ikonomidou
    • 6
  1. 1.Department of Pediatric Neurology, Children’s Hospital, Medical Faculty Carl Gustav CarusTechnical University DresdenDresdenGermany
  2. 2.Department of Anatomy, Histology and EmbryologyVarna Medical UniversityVarnaBulgaria
  3. 3.Department of Molecular and Cellular NeurologyNencki Institute of Experimental BiologyWarsawPoland
  4. 4.Department of BiophysicsWarsaw University of Life Sciences SGGWWarsawPoland
  5. 5.Department of NeurophysiologyNencki Institute of Experimental BiologyWarsawPoland
  6. 6.Waisman Center and Department of NeurologyUniversity of WisconsinMadisonUSA

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