The role of matrix metalloproteinases in infant traumatic brain injury.
Matrix metalloproteinases (MMPs) play an essential role in tissue repair, cell death and morphogenesis and may constitute therapeutic targets for acute brain injuries. In this study, we investigated the expression of 72 kDa and 92 kDa collagenases MMP-2 and MMP-9 at transcriptional, functional and protein expression level following traumatic brain injury in infant rats. Seven-day-old Wistar rats were subjected to head trauma using a weight drop device. Pups were sacrificed at defined time points (2-72 h) after trauma and brains were processed for molecular studies (semiquantitative and real-time PCR, Western blot, gelatin zymography) and histology. Trauma triggered widespread cell death in the cortex, basal ganglia and white matter. mRNA levels for MMP-2 and -9 were increased in the brain at 12-72 h after trauma. Protein expression of the analyzed MMPs and activity of MMP-2 were increased at 12 h and peaked at 24 h after trauma. Intraperitoneal injection of GM6001 (Ilomastat), an MMP inhibitor, 2 h after trauma, substantially attenuated traumatic brain injury in a dose-dependent manner. These findings causally link the MMPs to trauma-induced neuronal cell death in the immature rodent brain. MMPs might serve as useful targets for therapeutic approaches aimed at preserving neuronal function in the immature brain in the context of mechanical injury.
Sifringer
Marco
M
Department of Pediatric Neurology, Children's Hospital, Medical Faculty Carl Gustav Carus, Technical University Dresden, Fetscherstrasse 74, 01307 Dresden, Germany.
Stefovska
Vanya
V
Zentner
Ingo
I
Hansen
Berglind
B
Stepulak
Andrzej
A
Knaute
Christiane
C
Marzahn
Jenny
J
Ikonomidou
Chrysanthy
C
D000367:Age Factors; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000201:enzymology* / Q000254:growth & development / Q000473:pathology; D001930:Brain Injuries / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology*; D004151:Dipeptides / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D020287:In Situ Nick-End Labeling; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D009410:Nerve Degeneration / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D011480:Protease Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics / Q000378:metabolism
D004151:Dipeptides; D061965:Matrix Metalloproteinase Inhibitors; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D011480:Protease Inhibitors; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9