Author(s): Perazzo, Juliana ; Ferreira, Mónica Lopes ; Santos, Sónia Sá ; Serrano, Isa ; Pinto, Antónia ; Lima, Carla ; Bardaji, Eduard ; Tavares, Isaura ; Heras, Montserrat ; Conceição, Katia ; Castanho, Miguel A. R. B.
Date: 2016
Persistent ID: http://hdl.handle.net/10451/32812
Origin: Repositório da Universidade de Lisboa
Subject(s): Kyotophin; Analgesia; Microcirculation; Permeability; Pain, blood-brain barrier
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 μM 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 μM 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.
