Matrix Metalloproteinases 2 and 9 Fail to Influence Drug-Induced Neuroapoptosis in Developing Rat Brain
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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.
KeywordsApoptosis Development Antiepileptic Sedative
Supported by BMBF Grant No. 01GZ0702.
- Ashai M, Wang X, Mori T, Sumii T, Jung J-C, Moskowitz AA, Fini E, Lo EH (2001) Effects of matrix metalloproteinase 9 gene knockout on proteolysis of blood-brain barrier and white matter components after cerebral ischemia. J Neurosci 21:7724–7732Google Scholar
- Hansen HH, Briem T, Dzietko M, Sifringer M, Voss A, Rzeski W, Zdzisinska B, Thor F, Heumann R, Stepulak A, Bittigau P, Ikonomidou C (2004) Mechanisms leading to disseminated apoptosis following NMDA receptor blockade in the developing rat brain. Neurobiol Dis 16(2):440–453PubMedCrossRefGoogle Scholar
- Morita-Fijimura Y, Fujimura M, Gasche Y, Copin J, Chan PH (1999) Overexpression of copper and zinc superoxide dismutase in transgenic mice prevents the induction and activation of matrix metalloproteinases after cold injury induced brain trauma. J Cereb Blood Flow Metab 20:130–138CrossRefGoogle Scholar
- Nagy V, Bozdagi O, Matynia A, Balcerzyk M, Balcerzyk M, Okulski P, Okulski P, Dzwonek J, Costa RM, Costa RM, Silva AJ, Kaczmarek L, Huntley GW (2006) Matrix metalloproteinase-9 is required for hippocampal late-phase long-term potentiation and memory. J Neurosci 15 26(7):1923–1934CrossRefGoogle Scholar
- Noble LJ, Donovan F, Igarashi T, Goussev S, Werb Z (2002) Matrix metalloproteinases limit functional recovery after spinal cord injury by modulation of early vascular events. J Neurosci 22:5726–5735Google Scholar
- Wilczynski GM, Konopoacki FA, Wilczek E, Lasiecka Z, Gorlewicz A, Michaluk P, Wawrzyniak M, Malinowska M, Okulski P, Kolodziej LR, Konopka W, Duniec K, Mioduszewska B, Nikolaev E, Walczak A, Owczarek D, Gorecki DC, Zuschratter W, Ottersen OP, Kaczmarek L (2008) Important role of matrix metalloproteinase-9 in epileptogenesis 10. J Cell Biol 180(5):1021–1035PubMedCrossRefGoogle Scholar