The role of matrix metalloproteinases in infant traumatic brain injury
Introduction
Traumatic brain injury (TBI) constitutes a major cause of morbidity and mortality in the industrialized world (Goldstein, 1990, Sosin et al., 1995, Thurman et al., 1999). Clinical studies suggest that age decidedly influences morbidity and mortality after head injury in children, with those under 4 years of age showing worst outcomes (Adelson and Kochanek, 1998, Koskiniemi et al., 1995). Differences in the mechanisms by which traumatic brain injury was sustained and the higher incidence of non-accidental closed head traumata in the very young (James, 1999, Kraus et al., 1987) may partly account for these findings. In addition, experimental studies suggest that the developing brain may be more prone to suffering irreversible neuronal loss following traumatic injury (Bittigau et al., 1999), but the mechanisms involved are only partly understood.
Matrix metalloproteinases (MMPs) are zinc-endopeptidases with multifactorial actions in central nervous system (CNS) physiology and pathology that are collectively able to degrade or modify components of the extracellular matrix (Nagase and Woessner, 1999). Target substrates include collagens, gelatin, fibronectin, laminin, elastin and proteoglycans. The biological activity of MMPs is strictly regulated via gene transcription, proenzyme activation, and dynamic inhibition by tissue inhibitors of metalloproteinases (TIMPs) (Yong, 2005, Vu et al., 1998). MMPs participate in important physiological processes including embryological remodeling, wound healing, angiogenesis, bone remodeling, ovulation, and implantation (Yong, 2005, Vu et al., 1998).
Experimental work has shown that overactivity of MMPs is involved in disease processes of the central nervous system (CNS), such as multiple sclerosis and Alzheimer’s disease (Yong, 2005, Lukashev and Werb, 1998, Yong et al., 1998). Evidence is also accumulating implicating involvement of MMPs in acute brain injury following stroke and trauma. MMP activity is upregulated after cerebral ischemia and edema (Morita-Fijimura et al., 1999), and MMPs are involved in stroke pathophysiology (Romanic et al., 1998, Rosenberg et al., 1996, Gasche et al., 1999, Heo et al., 1999). In stroke patients, MMP-9 biomarkers are correlated with clinical outcomes (Montaner et al., 2001, Montaner et al., 2003).
By degrading neurovascular matrix, MMPs promote injury of the blood–brain barrier, edema and hemorrhage (Asahi et al., 2001, Wang et al., 2003, Lo et al., 2003, Shigemori et al., 2006). By disrupting cell–matrix signaling and homeostasis, MMPs trigger neuronal and glial cell death (Lee and Lo, 2004, Gu et al., 2002).
In traumatic brain injury (TBI) models, it has been shown that activity of MMPs is increased after TBI (Wang et al., 2000) or spinal cord injury (Noble et al., 2002). Furthermore, MMP-9 knock-out mice showed fewer motor deficits and smaller contusion volumes compared with wild-type mice (Wang et al., 2000). In spinal cord injury, MMP-9 null mice exhibited significantly less disruption of the blood–spinal cord barrier, attenuation of neurotrophil infiltration and significantly better locomotor recovery (Noble et al., 2002). Hence, there is a movement towards the development of MMP inhibitors for the treatment of acute brain injuries.
In this study, we investigated the hypothesis that MMP-2 and MMP-9 may be involved in the pathophysiology of neuronal damage after traumatic injury in the developing brain. We tested this hypothesis by performing experiments using a weight drop model of traumatic brain injury in infant rats. Previously, we provided detailed description of the distribution pattern and time course of the neurodegenerative response to brain trauma in 7-day-old rats. We have performed detailed analysis of the delayed neurodegenerative response to trauma by electron microscopy, which has confirmed that neurons which degenerate in a disseminated and delayed fashion fulfil ultrastructural criteria for apoptosis (Bittigau et al., 1999). In addition, we have reported that marked activation of caspase-3 occurs in affected brain regions. This previously presented morphological and biochemical evidence represents the basis for our assumption that, in the study outlined here, we have been investigating mechanisms pertaining to apoptotic neurodegeneration following trauma to the developing rat brain. Our findings implicate involvement of MMP-2 and MMP-9 in the pathophysiology of TBI in the developing rat brain and suggest that MMPs may constitute useful therapeutic target to ameliorate cell loss following TBI in children.
Section snippets
Animal experiments
All animal experiments were performed in accordance with the guidelines of the Technical University in Dresden, Germany.
Trauma
Seven-day-old Wistar rat pups (Charles River, Sulzfeld, Germany), weighing 13–16 g, were anesthetized with halothane (induced with 4% and maintained with 1.5% in balanced room air) and subjected to head trauma as previously described (Bittigau et al., 1999, Pohl et al., 1999). Following fixation of the animals’ head, a skin incision was made to expose the skull. The trauma
Results
Rats subjected to sham surgery (n = 9) or trauma (n = 30) recovered within 10 min after anesthesia. At 24 h following percussion head trauma in 7-day-old rats, widespread cell death was detected by silver, TUNEL or FluoroJade staining in the frontal, parietal, cingulate and retrosplenial cortex, the thalamus, the dentate gyrus, the subiculum and the striatum (Fig. 1).
Discussion
Trauma triggers widespread and diffuse apoptosis in the immature rat brain in an age-dependent manner. Peak sensitivity is observed at 3 to 7 postnatal days. This vulnerable period corresponds to the brain growth spurt of rats and mice (Dobbing and Sands, 1979). Mainly affected brain regions are cerebral cortex, thalamus and caudate nucleus. The apoptotic nature of trauma-induced cell death has been previously confirmed by a combination of histological, immunohistochemical and molecular studies
Acknowledgment
Supported by DFG grant IK2/5-1.
References (54)
- et al.
Neuronal death in the hippocampus is promoted by plasmin-catalyzed degradation of laminin
Cell
(1997) - et al.
Plasminogen activators and matrix metalloproteinases, mediators of extracellular proteolysis in inflammatory demyelination of the central nervous system
J. Neuroimmunol.
(1999) - et al.
Pathways leading to apoptotic neurodegeneration following trauma to the developing brain
Neurobiol. Dis.
(2002) - et al.
Laminin antigens in rat CNS: distribution and changes upon brain injury
Neuron
(1989) - et al.
ECM signalling: orchestrating cell behavior and misbehavior
Trends Cell. Biol.
(1998) - et al.
Increased proteolytic activity of the granule neurons may contribute to neuronal death in the weaver mouse cerebellum
Dev. Biol.
(1995) - et al.
Matrix metalloproteinases: a minireview
J. Biol. Chem.
(1999) - et al.
The metalloproteinase matrilysin proteolytically generates active soluble Fas ligand and potentiates epithelial cell apoptosis
Curr. Biol.
(1999) - et al.
Fluoro-Jade: a novel fluorochrome for the sensitive and reliable histochemical localization of neuronal degeneration
Brain Res.
(1997) - et al.
MMP-9 is a key regulator of growth plate angiogenesis and apoptosis of hypertrophic chondrocytes
Cell
(1998)
Head injury in children
J. Child Neurol.
Effects of matrix metalloproteinase 9 gene knockout on the proteolysis of blood–brain barrier and white matter components after cerebral ischemia
J. Neurosci.
Expression of Fas and Fas ligand after experimental traumatic brain injury in the rat
J. Cereb. Blood Flow Metab.
Traumatic spinal cord injury induces nuclear factor kappa B activation
J. Neurosci.
Apoptotic neurodegeneration following trauma is markedly enhanced in the immature brain
Ann. Neurol.
Expression of endothelial adhesion molecules and recruitment of neutrophils after traumatic brain injury in rats
J. Leukocyte Biol.
Importance of posttraumatic hypothermia and hyperthermia on the inflammatory response after fluid percussion brain injury: biochemical and immunocytochemical studies
J. Cereb. Blood Flow Metab.
A controlled cortical impact model of traumatic brain injury in the rat
J. Neurosci. Methods
The brain growth spurt in various mammalian species
Early Hum. Dev.
Traumatic brain injury: a silent epidemic
Ann. Neurol.
Integrin signaling via the PI3-kinase-Akt pathway increases neuronal resistance to glutamate-induced apoptosis
J. Neurochem.
Early appearance of activated MMP-9 after focal cerebral ischemia in mice
J. Cereb. Blood Flow Metab.
S-nitrosylation of matrix metalloproteinases: signaling pathway to neuronal cell death
Science
Cortical spreading depression activates and upregulates MMP-9
J. Clin Invest.
Matrix metalloproteinases increase very early during experimental focal cerebral ischemia
J. Cereb. Blood Flow Metab.
Pediatric head injury: what is unique and different
Acta Neurochir., Suppl. (Wien)
Matrix metalloproteinases MMP-9 and MMP-7 are expressed in experimental autoimmune neuritis and the Guillain-Barré syndrome
Ann. Neurol.
Cited by (54)
Neuroinflammation, oxidative stress, and blood-brain barrier (BBB) disruption in acute Utah electrode array implants and the effect of deferoxamine as an iron chelator on acute foreign body response
2019, BiomaterialsCitation Excerpt :Matrix metalloproteinases (MMPs), specifically MMP2 and MMP9, were monitored at all of the above time-points (Fig. 4B). Both MMP2 and MMP9 are known for their role in the degradation of extracellular matrices and junction proteins of the BBB following an injury or foreign body response [89–91] Additionally, MMP2 is known for its delayed role in wound healing and angiogenesis [92,93]. There was a significant increase in MMP2 levels post-implant for both the controls and DFX-treated groups.
Pericyte ALK5/TIMP3 Axis Contributes to Endothelial Morphogenesis in the Developing Brain
2018, Developmental CellSelective small-molecule inhibitors as chemical tools to define the roles of matrix metalloproteinases in disease
2017, Biochimica et Biophysica Acta - Molecular Cell Research