Author: Andrea E. Tóth ; Béla Ózsvári ; Szilvia Veszelka ; Shinya Dohgu ; Fruzsina R. Walter ; Markus M. Heimesaat ; András Tóth ; Mária A. Deli ; Yasufumi Kataoka ; Gábor Rákhely ; László G. Puskás ; Lóránd Kiss

BACKGROUND AND AIMSElevated levels of reactive carbonyl species such as methylglyoxal triggers carbonyl stress and activates a series of inflammatory responses leading to accelerated vascular damage. Carbonyl stress is implicated in conditions and diseases like aging, diabetes mellitus, Alzheimer's disease and cardiovascular diseases. Our aim was to examine the effects of methylglyoxal on human hCMEC/D3 brain endothelial cells and search for protective molecules to prevent endothelial damage.METHODSMethylglyoxal-induced modification of albumin was tested in a cell-free assay. Endothelial cell viability was monitored by impedance measurement in real-time. The following compounds were tested in cell-free and viability assays: β-alanine, all-trans-retinoic acid, aminoguanidine, ascorbic acid, L-carnosine, GW-3333, indapamide, piracetam, γ-tocopherol, U0126, verapamil. Barrier function of brain endothelial monolayers was characterized by permeability measurements and visualized by immunohistochemistry for β-catenin. mRNA expression level of 60 selected blood-brain barrier-related genes in hCMEC/D3 cells was investigated by a custom Taqman gene array.RESULTSMethylglyoxal treatment significantly elevated protein modification, exerted toxicity, reduced barrier integrity, increased permeability for markers FITC-dextran and albumin and caused higher production of reactive oxygen species in hCMEC/D3 endothelial cells. Changes in the mRNA expression of 30 genes coding tight junction proteins, transporters and enzymes were observed in methylglyoxal-treated hCMEC/D3 cells. From the tested 11 compounds only all-trans-retinoic acid, an antioxidant and antiglycation agent, U0126, a MAP/ERK kinase inhibitor and aminoguanidine attenuated methylglyoxal-induced damage in hCMEC/D3 cells.CONCLUSIONSAll-trans-retinoic acid and inhibition of the MAP/ERK signaling pathway may be protective in carbonyl stress induced brain endothelial damage.

01 Jul 2003·Drug Metabolism and DispositionQ2 · MEDICINE

CYP3A INDUCTION BY N-HYDROXYFORMAMIDE TUMOR NECROSIS FACTOR-α CONVERTING ENZYME/MATRIX METALLOPROTEINASE INHIBITORS: USE OF A PREGNANE X RECEPTOR ACTIVATION ASSAY AND PRIMARY HEPATOCYTE CULTURE FOR ASSESSING INDUCTION POTENTIAL IN HUMANS

Q2 · MEDICINE

Article

Author: Darryl L. McDougald ; Zhiyang Zhao ; Robert C. Andrews ; Kathy Mellon-Kusibab ; Debie J. Hoivik ; Michael D. Gaul ; Steven Novick ; Linda Moore ; Edward L. LeCluyse ; Summer Jolley ; Geraldine Hamilton ; J. David Becherer ; Ron Laethem ; Elizabeth J. Beaudet ; Jurgen Lehmann ; Steven Kliewer ; Timothy K. Tippin ; Thomas A. Brodie

A series of N-hydroxyformamide tumor necrosis factor-alpha converting enzyme (TACE)/matrix metalloprotease (MMP) inhibitors were evaluated for their potential to induce human cytochrome P450 3A (CYP3A). Two in vitro assays were used: 1) a cell-based reporter gene assay for activation of the pregnane X receptor (PXR), and 2) a primary "sandwich" culture of human hepatocytes. Approximately 50 TACE/MMP inhibitors were evaluated in the human PXR assay. A range of PXR activation was observed, 0 to 150% of the activation of the known human CYP3A inducer rifampicin. Three TACE/MMP inhibitors were evaluated in rat and human hepatocytes. Significantly higher PXR activation/CYP3A induction was observed in PXR/hepatocyte models, respectively, for (2R,3S) 3-(formyl-hydroxyamino)-2-(2-methyl-1-propyl)-4-methylpentanoic acid [(1S,2S)-2-methyl-1-(2-pyridylcarbamoyl)-1-butyl]amide (GW3333) compared with (2R,3S)-6,6,6-trifluoro-3-[formyl(hydroxy)amino]-2-isobutyl-N-[(1S,2R)-2-methoxy-1-[(1,3-thiazol-2-ylamino)carbonyl]propyl]hexanamide (GW6495) and (2R)-N-[(1S)-2,2-dimethyl-1-[(methylamino)carbonyl]-propyl]-2-[(1S)-1-[formyl(hydroxy)amino]ethyl]-5-phenylpentanamide (GI4023). The CYP3A induction level achieved with GW3333 at a concentration of approximately 10 microM in human hepatocytes was comparable to that achieved with rifampicin at a concentration of 10 microM. The extent of rodent CYP3A induction caused by GW3333 was confirmed in vivo after daily oral administration for 14 days to rats. In conclusion, GW3333 is a potential inducer of CYP3A expression in vivo in humans, but other N-hydroxyformamides are less likely to induce CYP3A.

01 Jul 2002·Expert Opinion on Investigational DrugsQ2 · MEDICINE

TACE inhibition: a new approach to treating inflammation

Q2 · MEDICINE

Article

Author: Doggrell, Sheila A

Clinical trials showing the benefits of reducing the effects of TNF- alpha in rheumatoid arthritis have highlighted the key role of the cytokine TNF- alpha in this inflammatory condition. A new approach to reducing the effects of TNF- alpha is to decrease its synthesis by inhibiting TNF- alpha converting enzyme with GW3333. In rat models of arthritis, GW3333 has some beneficial effects. Further longer-term studies of GW3333 in animal models are required to determine whether its benefit is maintained. TACE inhibition may represent a new approach to treating inflammation.

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Indication	Highest Phase	Country/Location	Organization	Date
Rheumatoid Arthritis	Preclinical	US	GSK Plc	-

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