Neuroprotective effect of adenoviral-mediated gene transfer of TIMP-1 and -2 in ischemic brain injury

Magnoni, Sandra; Baker, Andrew H.; Thomson, Sophie R.; Jordan, Graeme R; George, Simon J.; McColl, Barry W.; McCulloch, James; Horsburgh, Karen

doi:10.1038/sj.gt.3302894

Cited by 40 publications

(36 citation statements)

References 22 publications

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“…viously showed that infusion of recombinant TIMP-1 was effective in a rat model of trauma-induced neuropathic pain (Kawasaki et al, 2008). Other groups showed that viral delivery of TIMP-1 or TIMP-2 were neuroprotective in rat models of focal cerebral ischemia Magnoni et al, 2007). Furthermore, TIMP-1-deficient knockout mice were found to be more vulnerable to cerebral ischemia (Fujimoto et al, 2008).…”

Section: Discussionmentioning

confidence: 97%

Neuroprotective Effects of Overexpressing Tissue Inhibitor of Metalloproteinase TIMP-1

Tejima

Guo

Murata

et al. 2009

Journal of Neurotrauma

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Accumulating data suggest that matrix metalloproteinases (MMPs) may be important mediators in the pathophysiology of acute brain injury after trauma or stroke. Here, we test the hypothesis that the endogenous tissue inhibitor of metalloproteinase (TIMP-1) is neuroprotective in vitro and in vivo. For in vitro studies, primary cortical neuronal cultures were subjected to hypoxia and reoxygenation. Treatment with recombinant TIMP-1 protein significantly decreased neuronal death. In vivo studies in models of brain trauma and stroke supported these cell culture results. After controlled cortical impact, 24-h MMP-9 levels were significantly reduced in transgenic mice overexpressing TIMP-1 compared to wild-type mice. And at 7 days post-trauma, brain lesion volumes were also significantly decreased by TIMP-1 overexpression as well. In a model of transient 2-h focal cerebral ischemia, MMP-9 levels were lower in TIMP-1 transgenic mice compared with wild-types. Correspondingly, blood-brain barrier leakage was ameliorated by TIMP-1 overexpression, and 24-h infarction volumes were also reduced. Taken together, these cell culture and in vivo data provide initial proof-of-principle that TIMP-1 is neuroprotective against traumatic and ischemic brain injury in mice.

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Section: Discussionmentioning

confidence: 97%

Neuroprotective Effects of Overexpressing Tissue Inhibitor of Metalloproteinase TIMP-1

Tejima

Guo

Murata

et al. 2009

Journal of Neurotrauma

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“…MMP inhibition provides neuroprotection against HI in the developing brain (21). A neuroprotective role for TIMP-1 in excitotoxic damage and ischemia has been previously proposed (10,11,22). In addition, TIMP-1 levels have recently been shown to be correlated with stroke outcome in adult humans (23).…”

Section: Mmp-9/timp-1 In Perinatal Brain Injurymentioning

confidence: 97%

“…MMP-9 also has long-term beneficial effects on neurovascular remodeling and behavioral recovery after stroke in adult rats (8,9). In the adult rat central nervous system, elevated TIMP-1 expression levels may play a neuroprotective role after kainate-induced excitotoxic seizures (10), and gene transfer of TIMP-1 and 2 protects against global cerebral ischemia in mice (11,12). The fact that MMPs and TIMPs are secreted proteins that can easily be measured in bodily fluids including peripheral blood (13) highlights their potential as biomarkers for brain injury.…”

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confidence: 99%

Increased MMP-9 and TIMP-1 in mouse neonatal brain and plasma and in human neonatal plasma after hypoxia–ischemia: a potential marker of neonatal encephalopathy

et al. 2011

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ArticlesTranslational Investigation nature publishing group INTRODUCTION:To implement neuroprotective strategies in newborns, sensitive and specific biomarkers are needed for identifying those who are at risk for brain damage. We evaluated the effectiveness of matrix metalloproteinases (MMPs) and their naturally occurring tissue inhibitors of metalloproteinases (TIMPs) in predicting neonatal encephalopathy (Ne) damage in newborns. RESULTS: Plasma MMP-9 and TIMP-1 levels were upregulated as early as 1 h after the hI insult but not did not show such elevations after other types of injury (ibotenate-induced excitotoxicity, hypoxia, lipopolysaccharide-induced inflammation), and brain levels reflected this increase soon thereafter. We confirmed these results by carrying out plasma MMP-9 and TIMP-1 measurements in human newborns with Ne. In these infants, protein levels of MMP-9 and TIMP-1 were found to be elevated during a short window up to 6 h after birth. DISCUSSION: This feature is particularly useful in identifying newborns in need of neuroprotection. a second peak observed 72 h after birth is possibly related to the second phase of energy failure after a hI insult. Our data, although preliminary, support the use of MMP-9 and TIMP-1 as early biomarkers for the presence and extent of perinatal brain injury in human term newborns. METHODS: We first used a mouse model of neonatal hI injury to explore mechanistic aspects such as the time course of these markers after the hypoxia-ischemia event, and the correlation between the levels of these candidate markers in brain and plasma.T he major perinatal brain lesions associated with cerebral palsy and cognitive impairment are periventricular white matter damage and cortical-subcortical lesions, observed mainly in preterm and term infants, respectively (1,2). A crucial step for the implementation of neuroprotective therapies is the rapid detection of neonates at risk. Despite this urgent need, no appropriate and easily detectable biomarkers for perinatal injury are currently available.Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are involved in multiple processes during development and in adulthood (3-5), including perinatal hypoxia-ischemia (HI) and white matter damage in human neonates. Recent studies in adult MMP-9 knockout mice have demonstrated the key role played by this metalloproteinase in the pathophysiology of traumatic and hypoxic-ischemic (HI) brain injury (6). Concordantly, MMP-9 has been shown to have deleterious effects in the immature brain after HI injury (7). Several of these studies demonstrated a significant increase in MMP-9 expression in the central nervous system within the first 24 h after the insult. MMP-9 also has long-term beneficial effects on neurovascular remodeling and behavioral recovery after stroke in adult rats (8,9). In the adult rat central nervous system, elevated TIMP-1 expression levels may play a neuroprotective role after kainate-induced excitotoxic seizures (10), and gene transfer of TIMP-...

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“…Adenovirus-mediated gene transfer of TIMP-1 and TIMP-2 were neuroprotective in global ischemia (Magnoni et al, 2007). Additionally, transplantation of autologous bone marrow cells overexpressing TIMP-1 and TIMP-2 reduced focal ischemic damage and promoted functional recovery with enhanced neurogenesis and angiogenesis .…”

Section: Introductionmentioning

confidence: 96%

Tissue Inhibitor of Metalloproteinases Protect Blood—Brain Barrier Disruption in Focal Cerebral Ischemia

Fujimoto

Takagi

Aoki

et al. 2008

J Cereb Blood Flow Metab

136

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Enhanced matrix metalloproteinases (MMPs) can cause vasogenic edema and hemorrhagic transformation after cerebral ischemia, and affect the extent of ischemic injury. We hypothesized that the endogenous MMP inhibitors, tissue inhibitor of MMPs (TIMPs), were essential to protect against blood-brain barrier (BBB) disruption after ischemia by regulating the activities of MMPs. We confirmed the transition of MMP-2 and MMP-9, and the TIMPs family after 30 mins of middle cerebral artery occlusion, and elucidated the function of TIMP-1 and TIMP-2 in focal ischemia, using TIMP-1 À/À and TIMP-2 À/À mice. TIMP-1 mRNA expression was gradually increased until 24 h after reperfusion. In TIMP-1 À/À mice, MMP-9 protein expression and gelatinolytic activity were significantly more augmented after cerebral ischemia than those in WT mice, and were accompanied by exacerbated BBB disruption, neuronal apoptosis, and ischemic injury. In contrast, TIMP-2 gene deletion mice exhibited no significant difference in MMP expressions and the degree of ischemic injury despite an increased Evans blue leakage. These results suggest that TIMP-1 inhibits MMP-9 activity and can play a neuroprotective role in cerebral ischemia.

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Neuroprotective effect of adenoviral-mediated gene transfer of TIMP-1 and -2 in ischemic brain injury

Cited by 40 publications

References 22 publications

Neuroprotective Effects of Overexpressing Tissue Inhibitor of Metalloproteinase TIMP-1

Neuroprotective Effects of Overexpressing Tissue Inhibitor of Metalloproteinase TIMP-1

Increased MMP-9 and TIMP-1 in mouse neonatal brain and plasma and in human neonatal plasma after hypoxia–ischemia: a potential marker of neonatal encephalopathy

Tissue Inhibitor of Metalloproteinases Protect Blood—Brain Barrier Disruption in Focal Cerebral Ischemia

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