MMP-12, a Promising Therapeutic Target for Neurological Diseases

Chelluboina, Bharath; Nalamolu, Koteswara Rao; Klopfenstein, Jeffrey D.; Pinson, David M.; Wang, David Z.; Vemuganti, Raghu; Veeravalli, Krishna Kumar

doi:10.1007/s12035-017-0418-5

Cited by 40 publications

(42 citation statements)

References 49 publications

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“…It is possible that the dramatic upregulation of MMP-12 (172-fold increase) that we observe in aged spinal cord can contribute to increased apoptosis in α-MN. Also, MMP-12 knockdown mice exhibit decreased apoptosis and increased myelin basic protein (MBP) levels in ischemic brain (Chelluboina et al 2015b;Chelluboina et al 2018). Interestingly, MBP is one of MMP-12 substrates, and the main source of MMP-12 is microglia, which undergo proliferation and activation in aged spinal cord, as we demonstrated in our study.…”

Section: Discussionsupporting

confidence: 74%

Molecular changes associated with spinal cord aging

et al. 2020

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Age-related muscle weakness and loss of muscle mass (sarcopenia) is a universal problem in the elderly. Our previous studies indicate that alpha motor neurons (α-MNs) play a critical role in this process. The goal of the current study is to uncover changes in the aging spinal cord that contribute to loss of innervation and the downstream degenerative processes that occur in skeletal muscle. The number of α-MNs is decreased in the spinal cord of wildtype mice during aging, beginning in middle age and reaching a 41% loss by 27 months of age. There is evidence for age-related loss of myelin and mild inflammation, including astrocyte and microglia activation and an increase in levels of sICAM-1. We identified changes in metabolites consistent with compromised neuronal viability, such as reduced levels of N-acetyl-aspartate. Cleaved caspase-3 is more abundant in spinal cord from old mice, suggesting that apoptosis contributes to neuronal loss. RNA-seq analysis revealed changes in the expression of a number of genes in spinal cord from old mice, in particular genes encoding extracellular matrix components (ECM) and a 172-fold increase in MMP-12 expression. Furthermore, blood-spinal cord barrier (BSCB) permeability is increased in old mice, which may contribute to alterations in spinal cord homeostasis and exacerbate neuronal distress. Together, these data show for the first time that the spinal cord undergoes significant changes during aging, including progressive α-MNs loss that is associated with low-grade inflammation, apoptosis, changes in ECM, myelination, and vascular permeability.

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Section: Discussionsupporting

confidence: 74%

Molecular changes associated with spinal cord aging

et al. 2020

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“…MMP-12, also known as macrophage metalloelastase or macrophage elastase, is able to degrade a wide variety of extracellular matrix components, such as laminin, type IV collagen, fibronectin, chondroitin sulfate, and vitronectin [2,3]. By degrading basal membrane components, MMP-12 permits the entry of macrophages and other immune cells into injured tissues during inflammation [2].…”

Section: Introductionmentioning

confidence: 99%

“…In the case of the central nervous system (CNS), MMP-12 might be responsible for blood–brain barrier (BBB) disruption occurring in several neurological diseases/disorders characterized by inflammatory processes, such as spinal cord injury [4], multiple sclerosis [5], and ischemic or hemorrhagic strokes [6,7]. Therefore, clinical research on specific MMP-12 inhibitors has become a major therapeutic interest [3]. …”

Section: Introductionmentioning

confidence: 99%

A Hydroxypyrone-Based Inhibitor of Metalloproteinase-12 Displays Neuroprotective Properties in Both Status Epilepticus and Optic Nerve Crush Animal Models

Vinet

Costa

Salinas‐Navarro

et al. 2018

IJMS

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Recently, we showed that matrix metalloproteinase-12 (MMP-12) is highly expressed in microglia and myeloid infiltrates, which are presumably involved in blood–brain barrier (BBB) leakage and subsequent neuronal cell death that follows status epilepticus (SE). Here, we assessed the effects of a hydroxypyrone-based inhibitor selective for MMP-12 in the pilocarpine-induced SE rat model to determine hippocampal cell survival. In the hippocampus of rats treated with pilocarpine, intra-hippocampal injections of the MMP-12 inhibitor protected Cornu Ammonis 3 (CA3) and hilus of dentate gyrus neurons against cell death and limited the development of the ischemic-like lesion that typically develops in the CA3 stratum lacunosum-moleculare of the hippocampus. Furthermore, we showed that MMP-12 inhibition limited immunoglobulin G and albumin extravasation after SE, suggesting a reduction in BBB leakage. Finally, to rule out any possible involvement of seizure modulation in the neuroprotective effects of MMP-12 inhibition, neuroprotection was also observed in the retina of treated animals after optic nerve crush. Overall, these results support the hypothesis that MMP-12 inhibition can directly counteract neuronal cell death and that the specific hydroxypyrone-based inhibitor used in this study could be a potential therapeutic agent against neurological diseases/disorders characterized by an important inflammatory response and/or neuronal cell loss.

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“…Moreover, it is the biggest reason for serious long-term disability. Several studies suggests that elevated matrix metalloproteinases (MMPs) play a detrimental role in various types of CNS pathology, including ischemic stroke [1][2][3]. Our recent studies demonstrated the predominant upregulation of MMP-12 and its pathological role in acute brain damage after ischemic stroke [4,5].…”

Section: Introductionmentioning

confidence: 81%

Mesenchymal Stem Cell Treatment Prevents Post-Stroke Dysregulation of Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases

Chelluboina

Nalamolu

Mendez

et al. 2017

Cell Physiol Biochem

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Background/Aims: Stem cell treatment is one of the potential treatment options for ischemic stroke. We recently demonstrated a protective effect of human umbilical cord blood-derived mesenchymal stem cells (HUCB-MSCs) in a rat model of ischemic stroke. The treatment attenuated apoptosis and prevented DNA damage. A collection of published studies, including several from our laboratory, indicated the induction and detrimental role for several matrix metalloproteinases (MMPs) in post-stroke brain injury. We hypothesized that the HUCB-MSCs treatment after focal cerebral ischemia prevents the dysregulation of MMPs and induces the expression of endogenous tissue inhibitors of metalloproteinases (TIMPs) to neutralize the elevated activity of MMPs. Methods: To test our hypothesis, we administered HUCBMSCs (0.25 million cells/animal and 1 million cells/animal) intravenously via tail vein to male Sprague-Dawley rats that were subjected to a transient (two-hour) right middle cerebral artery occlusion (MCAO) and one-day reperfusion. Ischemic brain tissues obtained from various groups of rats seven days after reperfusion were subjected to real-time PCR, immunoblot, and immunofluorescence analysis. Results: HUCB-MSCs treatment prevented the induction of MMPs, which were upregulated in ischemia-induced rats that received no treatment. HUCBMSCs treatment also prevented the induction of TIMPs expression. The extent of prevention of MMPs and TIMPs induction by HUCB-MSCs treatment is similar at both the doses tested. Conclusion: Prevention of stroke-induced MMPs upregulation after HUCB-MSCs treatment is not mediated through TIMPs upregulation.

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MMP-12, a Promising Therapeutic Target for Neurological Diseases

Cited by 40 publications

References 49 publications

Molecular changes associated with spinal cord aging

Molecular changes associated with spinal cord aging

A Hydroxypyrone-Based Inhibitor of Metalloproteinase-12 Displays Neuroprotective Properties in Both Status Epilepticus and Optic Nerve Crush Animal Models

Mesenchymal Stem Cell Treatment Prevents Post-Stroke Dysregulation of Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases

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