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J Neural Transm (Vienna). 2018 Jun;125(6):899-912. doi: 10.1007/s00702-018-1839-7. Epub 2018 Jan 13.

Kynurenic acid and its derivatives are able to modulate the adhesion and locomotion of brain endothelial cells.

Author information

1
Department of Genetics, Cell- and Immunobiology, Semmelweis University, Nagyvárad tér 4, Budapest, 1089, Hungary.
2
MTA-SZTE Neuroscience Research Group, Semmelweis u. 6, Szeged, 6725, Hungary.
3
Institute of Pharmaceutical Chemistry, University of Szeged, Eötvös u. 6, Szeged, 6720, Hungary.
4
Stereochemistry Research Group of the Hungarian Academy of Sciences, Eötvös utca 6, Szeged, H-6720, Hungary.
5
Institute of Biophysics, Biological Research Centre of the Hungarian Academy of Sciences, Temesvári krt. 62, Szeged, 6726, Hungary.
6
Department of Physiology, Anatomy and Neuroscience, University of Szeged, Közép Fasor 52, Szeged, 6726, Hungary.
7
Department of Pharmacodynamics, Semmelweis University, Nagyvárad tér 4, Budapest, 1089, Hungary.
8
Department of Neurology, University of Szeged, Semmelweis u. 6, Szeged, 6725, Hungary.
9
Department of Genetics, Cell- and Immunobiology, Semmelweis University, Nagyvárad tér 4, Budapest, 1089, Hungary. kohlasz2@gmail.com.

Abstract

The neuroprotective actions of kynurenic acid (KYNA) and its derivatives in several neurodegenerative disorders [characterized by damage to the cerebral endothelium and to the blood-brain barrier (BBB)] are well established. Cell-extracellular matrix (ECM) adhesion is supposedly involved in recovery of impaired cerebral endothelium integrity (endothelial repair). The present work aimed to investigate the effects of KYNA and its synthetic derivatives on cellular behaviour (e.g. adhesion and locomotion) and on morphology of the GP8 rat brain endothelial cell line, modeling the BBB endothelium. The effects of KYNA and its derivatives on cell adhesion were measured using an impedance-based technique, the xCELLigence SP system. Holographic microscopy (Holomonitor M4) was used to analyse both chemokinetic responses and morphometry. The GP8 cells proved to be a suitable model cell line for investigating cell adhesion and the locomotion modulator effects of kynurenines. KYNA enhanced cell adhesion and spreading, and also decreased the migration/motility of GP8 cells at physiological concentrations (10-9 and 10-7 mol/L). The derivatives containing an amide side-chain at the C2 position (KYNA-A1 and A2) had lower adhesion inducer effects compared to KYNA. All synthetic analogues (except KYNA-A5) had a time-dependent inhibitory effect on GP8 cell adhesion at a supraphysiological concentration (10-3 mol/L). The immobilization promoting effect of KYNA and the adhesion inducer activity of its derivatives indicate that these compounds could contribute to maintaining or restoring the protective function of brain endothelium; they also suggest that cell-ECM adhesion and related cell responses (e.g. migration/motility) could be potential new targets of KYNA.

KEYWORDS:

Brain endothelial cell; Endothelial repair; Holographic microscopy; Impedimetry; Kynurenic acid; Kynurenic acid (PubChem CID: 3845); L-Kynurenine (Pubchem CID: 161166); Synthetic kynurenines

PMID:
29332257
DOI:
10.1007/s00702-018-1839-7

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