REAL

Compounds Blocking Methylglyoxal-induced Protein Modification and Brain Endothelial Injury

Tóth, Andrea and Tóth, András and Walter, Fruzsina and Kiss, Lóránd and Veszelka, Szilvia and Ózsvári, Béla and Puskás, László and Rákhely, Gábor and Deli, Mária Anna (2014) Compounds Blocking Methylglyoxal-induced Protein Modification and Brain Endothelial Injury. ARCHIVES OF MEDICAL RESEARCH, 45 (8). pp. 753-764. ISSN 0188-4409

[img] Text
TothAEArchMedRes.pdf
Restricted to Registered users only

Download (1MB)

Abstract

BACKGROUND AND AIMS: Elevated 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. METHODS: Methylglyoxal-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: beta-alanine, all-trans-retinoic acid, aminoguanidine, ascorbic acid, l-carnosine, GW-3333, indapamide, piracetam, gamma-tocopherol, U0126, verapamil. Barrier function of brain endothelial monolayers was characterized by resistance and permeability measurements and visualized by immunohistochemistry for beta-catenin. mRNA expression level of 60 selected blood-brain barrier-related genes in hCMEC/D3 cells was investigated by a custom Taqman gene array. RESULTS: Methylglyoxal 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 anti-glycation agent, U0126, a MAP/ERK kinase inhibitor and aminoguanidine attenuated methylglyoxal-induced damage in hCMEC/D3 cells. CONCLUSIONS: All-trans-retinoic acid and inhibition of the MAP/ERK signaling pathway may be protective in carbonyl stress induced brain endothelial damage.

Item Type: Article
Subjects: Q Science / természettudomány > QR Microbiology / mikrobiológia
R Medicine / orvostudomány > R1 Medicine (General) / orvostudomány általában
SWORD Depositor: MTMT SWORD
Depositing User: MTMT SWORD
Date Deposited: 30 Sep 2016 11:47
Last Modified: 30 Sep 2016 11:49
URI: http://real.mtak.hu/id/eprint/40630

Actions (login required)

Edit Item Edit Item