Neuroprotective Effects of Overexpressing Tissue Inhibitor of Metalloproteinase TIMP-1

Tejima, Emiri; Guo, Shuzhen; Murata, Yoshinori; Arai, Ken; Lok, Josephine; Leyen, Klaus van; Rosell, Anna; Wang, Xiaoying; Lo, Eng H.

doi:10.1089/neu.2009.0959

Cited by 101 publications

(64 citation statements)

References 48 publications

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“…In vitro and in vivo models of brain trauma and stroke suggest that TIMP1 is neuroprotective and that overexpression of TIMP1 prevents the BBB leakage and reduces neuronal cell death. 50 Downregulation of TIMP1 was observed in HIV-infected macrophages and vascular endothelial cells. 51 In our previous studies, among different dysregulated genes, TIMP1 was one of the highly downregulated synaptic plasticity genes in HIV-infected neuronal cells.…”

Section: Discussionmentioning

confidence: 98%

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Development of TIMP1 magnetic nanoformulation for regulation of synaptic plasticity in HIV-1 infection

Atluri¹,

Jayant²,

Pilakka-Kanthikeel³

et al. 2016

IJN

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Although the introduction of antiretroviral therapy has reduced the prevalence of severe forms of neurocognitive disorders, human immunodeficiency virus (HIV)-1-associated neurocognitive disorders were observed in 50% of HIV-infected patients globally. The blood–brain barrier is known to be impermeable to most of antiretroviral drugs. Successful delivery of antiretroviral drugs into the brain may induce an inflammatory response, which may further induce neurotoxicity. Therefore, alternate options to antiretroviral drugs for decreasing the HIV infection and neurotoxicity may help in reducing neurocognitive impairments observed in HIV-infected patients. In this study, we explored the role of magnetic nanoparticle (MNP)-bound tissue inhibitor of metalloproteinase-1 (TIMP1) protein in reducing HIV infection levels, oxidative stress, and recovering spine density in HIV-infected SK-N-MC neuroblastoma cells. We did not observe any neuronal cytotoxicity with either the free TIMP1 or MNP-bound TIMP1 used in our study. We observed significantly reduced HIV infection in both solution phase and in MNP-bound TIMP1-exposed neuronal cells. Furthermore, we also observed significantly reduced reactive oxygen species production in both the test groups compared to the neuronal cells infected with HIV alone. To observe the effect of both soluble-phase TIMP1 and MNP-bound TIMP1 on spine density in HIV-infected neuronal cells, confocal microscopy was used. We observed significant recovery of spine density in both the test groups when compared to the cells infected with HIV alone, indicting the neuroprotective effect of TIMP1. Therefore, our results suggest that the MNP-bound TIMP1 delivery method across the blood–brain barrier can be used for reducing HIV infectivity in brain tissue and neuronal toxicity in HIV-infected patients.

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Section: Discussionmentioning

confidence: 98%

“…[53][54][55] TIMP1 has been reported to have neuroprotective effects equivalent to that of brain-derived neurotropic factor. 50 Therefore, supplementing TIMP1 may …”

Section: Discussionmentioning

confidence: 99%

Development of TIMP1 magnetic nanoformulation for regulation of synaptic plasticity in HIV-1 infection

Atluri¹,

Jayant²,

Pilakka-Kanthikeel³

et al. 2016

IJN

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“…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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“…Indeed, we have shown that overexpression of TIMP-1 results in suppression of the MMP-3 activity increase and provides cell protection in CATH.a cells exposed to BFA. Protective roles of TIMP-1 have previously been reported in other systems (35)(36)(37)(38)(39)(40).…”

Section: Discussionmentioning

confidence: 68%

Matrix Metalloproteinase-3 Is Increased and Participates in Neuronal Apoptotic Signaling Downstream of Caspase-12 during Endoplasmic Reticulum Stress

Kim

Shin

Choi

et al. 2010

Journal of Biological Chemistry

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Although endoplasmic reticulum (ER) stress-induced apoptosis has been associated with pathogenesis of neurodegenerative diseases, the cellular components involved have not been well delineated. The present study shows that matrix metalloproteinase (MMP)-3 plays a role in the ER stress-induced apoptosis. ER stress induced by brefeldin A (BFA) or tunicamycin (TM) increases gene expression of MMP-3, selectively among various MMP subtypes, and the active form of MMP-3 (actMMP-3) in the brain-derived CATH.a cells. Pharmacological inhibition of enzyme activity, small interference RNA-mediated gene knockdown, and gene knock-out of MMP-3 all provide protection against ER stress. MMP-3 acts downstream of caspase-12, because both pharmacological inhibition and gene knockdown of caspase-12 attenuate the actMMP-3 increase, but inhibition and knock-out of MMP-3 do not alter caspase-12. Furthermore, independently of the increase in the protein level, the catalytic activity of MMP-3 enzyme can be increased via lowering of its endogenous inhibitor protein TIMP-1. Caspase-12 causes liberation of MMP-3 enzyme activity by degrading TIMP-1 that is already bound to actMMP-3. TIMP-1 is decreased in response to ER stress, and TIMP-1 overexpression leads to cell protection and a decrease in MMP-3 activity. Taken together, actMMP-3 protein level and catalytic activity are increased following caspase-12 activation during ER stress, and this in turn plays a role in the downstream apoptotic signaling in neuronal cells. MMP-3 and TIMP-1 may therefore serve as cellular targets for therapy against neurodegenerative diseases. The endoplasmic reticulum (ER)2 is the organelle responsible for proper synthesis and folding of proteins as well as maintenance of intracellular calcium homeostasis. Various cellular stresses cause disruption of normal ER functions, leading to ER stress, and excessive and prolonged ER stress leads to accumulation of misfolded and/or unfolded proteins, and ultimately apoptosis (1).Neurons are particularly vulnerable to ER stress, and ample evidence exists in the literature that links ER stress with neurodegeneration (2-4). Therefore, identification of cellular components and elucidation of the sequence of events following ER stress in neuronal cells would be of great importance in understanding the mechanism of neurodegeneration. The molecular connection between the ER stress response and apoptotic signaling, however, is not clearly understood. Although caspase-12, residing outside of ER membrane, has been shown to be specifically involved in the apoptotic signaling that results from ER stress (5, 6), the exact mechanism by which this occurs has not been elucidated and immediate downstream targets of caspase-12 remain to be identified.Matrix metalloproteinase (MMP)-3 belongs to a family of MMP enzymes known to participate in degradation of components of the extracellular matrix. MMP-3 has been associated with pathogenesis of a number of diseases such as Alzheimer disease, Parkinson disease, stroke, brain trauma, neuroinfl...

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Neuroprotective Effects of Overexpressing Tissue Inhibitor of Metalloproteinase TIMP-1

Cited by 101 publications

References 48 publications

Development of TIMP1 magnetic nanoformulation for regulation of synaptic plasticity in HIV-1 infection

Development of TIMP1 magnetic nanoformulation for regulation of synaptic plasticity in HIV-1 infection

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

Matrix Metalloproteinase-3 Is Increased and Participates in Neuronal Apoptotic Signaling Downstream of Caspase-12 during Endoplasmic Reticulum Stress

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