Reversal of experimental autoimmune encephalomyelitis with a hydroxamate inhibitor of matrix metalloproteases.

Gijbels, Koenraad; Galardy, Richard E.; Steinman, Lawrence

doi:10.1172/jci117578

Cited by 325 publications

(210 citation statements)

References 20 publications

Supporting

Mentioning

201

Contrasting

Unclassified

Order By: Relevance

“…Elevated levels of MMP-9 are found around the time of onset of symptoms and the MMP inhibitor, GM6001, blocked the BBB injury and improved the clinical condition (Gijbels et al, 1994). Other studies, using different synthetic MMP inhibitors, have shown similar results (Hewson et al, 1995;Liedtke et al, 1998).…”

Section: Mmps In Neuroinflammation In the Absence Of Hypoxiamentioning

confidence: 99%

“…TIMP-2 blocked the MMP-2-induced BBB opening in MMPinduced injury in the brain (Rosenberg et al, 1992). Damage to the BBB was blocked, and symptomatic improvement occurred in experimental allergic encephalomyelitis (EAE) with hydroxymate treatment (Gijbels et al, 1994;Hewson et al, 1995;Clements et al, 1997). BB-94 blocked the BBB opening after intracerebral injection of TNF-␣, and BB-1101 was effective in LPS-induced BBB injury MunBryce and Rosenberg,1998a).…”

Section: Synthetic Mmp Inhibitorsmentioning

confidence: 99%

See 1 more Smart Citation

Matrix metalloproteinases in neuroinflammation

Rosenberg

2002

Glia

781

667

View full text Add to dashboard Cite

Matrix metalloproteinases (MMPs) are a gene family of neutral proteases that are important in normal development, wound healing, and a wide variety of pathological processes, including the spread of metastatic cancer cells, arthritic destruction of joints, atherosclerosis, and neuroinflammation. In the central nervous system (CNS), MMPs have been shown to degrade components of the basal lamina, leading to disruption of the blood-brain barrier (BBB), and to contribute to the neuroinflammatory response in many neurological diseases. Brain cells express both constitutive and inducible MMPs in response to cellular stress. MMPs are tightly regulated to avoid unwanted proteolysis. Secreted as inactive enzymes, the MMPs require activation by other proteases and free radicals. The MMPs are part of a larger class of metalloproteinases (MPs), which includes the recently discovered ADAMs (a disintegrin and metalloproteinase domain) and ADAMTS (a disintegrin and metalloproteinase thrombospondin) families. MPs have complex roles at the cell surface and within the extracellular matrix. At the cell surface, they act as sheddases, releasing growth factors, death receptors, and death-inducing ligands, making them important in cell survival and death. Tissue inhibitors of metalloproteinases (TIMPs) are endogenous inhibitors that regulate the activity of the MMPs. Synthetic inhibitors have been developed for the treatment of arthritis and cancer. These hydroxymate-based compounds have been shown to reduce injury in experimental allergic encephalomyelitis (EAE), experimental allergic neuritis (EAN), cerebral ischemia, intracerebral hemorrhage, and viral and bacterial infections. MPs have both beneficial and detrimental roles; understanding their expression in various CNS insults will allow for the use of MMP inhibitors in the treatment of neurological disorders. GLIA 39: 279 -291, 2002.

show abstract

Section: Mmps In Neuroinflammation In the Absence Of Hypoxiamentioning

confidence: 99%

Section: Synthetic Mmp Inhibitorsmentioning

confidence: 99%

Matrix metalloproteinases in neuroinflammation

Rosenberg

2002

Glia

781

667

View full text Add to dashboard Cite

show abstract

“…Interestingly, the expression of various MMPs is increased in MS [10,31] and EAE [8]. Inhibitors of MMP also block the development of EAE [4,17,22]. The effects of PPAR-γ agonists on MMP expression in the CNS have not been thoroughly investigated.…”

Section: Ppar-γ: Effects On Peripheral Leukocytesmentioning

confidence: 99%

Hormone regulation of microglial cell activation: relevance to multiple sclerosis

Drew

Storer

et al. 2005

Brain Research Reviews

View full text Add to dashboard Cite

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of proteins. The role of PPARs in regulating the transcription of genes involved in glucose and lipid metabolism has been extensively characterized. Interestingly, PPARs have also been demonstrated to mediate inflammatory responses.Microglia participate in pathology associated with multiple sclerosis (MS). Upon activation, microglia produce molecules including NO and TNF-α that can be toxic to CNS cells including myelin-producing oligodendrocytes and neurons, which are compromised in the course of MS.Previously, we and others demonstrated that PPAR-γ agonists including 15d-PGJ 2 are effective in the treatment of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. PPAR-γ modulation of EAE may occur, at least in part, by inhibition of microglial cell activation. Here, we indicate that 15d-PGJ 2 is a more potent inhibitor of microglial activation than thiazolidinediones, which are currently used to treat diabetes. Furthermore, 15d-PGJ 2 acts cooperatively with 9-cis retinoic acid, the ligand for the retinoid X receptor (RXR), in inhibiting microglial cell activation. This suggests that 15d-PGJ 2 and 9-cis RA inhibit cell activation through the formation of PPAR-γ/ RXR heterodimers. Interestingly, PGA 2 , which like 15d-PGJ 2 is a cyclopentenone prostaglandin, but which unlike 15d-PGJ 2 does not bind PPAR-γ, is a potent inhibitor of microglial cell activation. Collectively, these studies suggest that 15d-PGJ 2 inhibits microglial cell activation by PPAR-γ-dependent as well as PPAR-γ-independent mechanisms. The studies further suggest that the PPAR-γ agonist 15d-PGJ 2 in combination with retinoids may be effective in the treatment of MS.

show abstract

“…Severe EAE in MMP-2 null mice is believed to be due to the elevated MMP-9 levels seen in these animals (Esparza et al, 2004). Conversely, young MMP-9 null mutant mice are resistant to EAE (Dubois et al, 1999) and it is possible to partially suppress EAE using MMP inhibitors (Gijbels et al, 1994;Hewson et al, 1995;Nygardas et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Cleavage of myelin associated glycoprotein by matrix metalloproteinases

Milward

Kim

Szklarczyk

et al. 2008

Journal of Neuroimmunology

View full text Add to dashboard Cite

Derivative myelin associated glycoprotein (dMAG) results from proteolysis of transmembrane MAG and can inhibit axonal growth. We have tested the ability of certain matrix metalloproteinases Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access

show abstract

Reversal of experimental autoimmune encephalomyelitis with a hydroxamate inhibitor of matrix metalloproteases.

Abstract: Gelatinases, belonging to the matrix metalloproteases, con-

Cited by 325 publications

References 20 publications

Matrix metalloproteinases in neuroinflammation

Matrix metalloproteinases in neuroinflammation

Hormone regulation of microglial cell activation: relevance to multiple sclerosis

Cleavage of myelin associated glycoprotein by matrix metalloproteinases

Contact Info

Product

Resources

About