Endothelium-Mediated Action of Analogues of the Endogenous Neuropeptide Kyotorphin (Tyrosil-Arginine): Mechanistic Insights from Permeation and Effects on Microcirculation

• Type: Article in International Scientific Journal
• Date: 2016

Authors

Perazzo, J (Author) Other; Lopes Ferreira, M (Author) Other; Santos, SS (Author) Other; Serrano, I (Author) Other; Pinto, A (Author) Other; Lima, C (Author) Other; Bardaji, E (Author) Other; Isaura Tavares (Author) FMUP; Heras, M (Author) Other; Conceicao, K (Author) Other; Castanho, MARB (Author) Other

Journal

Title: Acs Chemical Neuroscience

Vol. 7

Pages: 1130-1140

ISSN: 1948-7193

Publisher: American Chemical Society

Indexing

ISI Web of Knowledge - 4 Citations

Scopus - 4 Citations

Other information

Authenticus ID: P-00K-SWT

DOI: 10.1021/acschemneuro.6b00099

Abstract (EN): Kyotorphin (KTP) is an endogenous peptide with analgesic properties when administered into the central nervous system (CNS). Its amidated form (L-Tyr-L-Arg-NH2; KTP-NH2) has improved analgesic efficacy after systemic administration, suggesting blood-brain barrier (BBB) crossing. KTP-NH2 also has anti-inflammatory action impacting on microcirculation. In this work, selected derivatives of KTP-NH2 were synthesized to improve lipophilicity and resistance to enzymatic degradation while introducing only minor changes in the chemical structure: N-terminal methylation and/or use of D amino acid residues. Intravital microscopy data show that KTP-NH2 having a D-Tyr residue, KTP-NH2-DL, efficiently decreases the number of leukocyte rolling in a murine model of inflammation induced by bacterial lipopolysaccharide (LPS): down to 46% after 30 min with 96 mu M KTP-NH2-DL. The same molecule has lower ability to permeate membranes (relative permeability of 0.38) and no significant activity in a behavioral test which evaluates thermal nociception (hot-plate test). On the contrary, methylated isomers at 96 mu M increase leukocyte rolling up to nearly 5-fold after 30 min, suggesting a proinflammatory activity. They have maximal ability to permeate membranes (relative permeability of 0.8) and induce long-lasting antinociception.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 11