title: A peptidomimetic tight junction modulator to improve regional analgesia.
abstract: The paracellular flux of solutes through tissue barriers is limited by transmembrane tight junction proteins. Within the family of tight junction proteins, claudin-1 seems to be a key protein for tightness formation and integrity. In the peripheral nervous system, the nerve fibers are surrounded with a barrier formed by the perineurium which expresses claudin-1. To enhance the access of hydrophilic pharmaceutical agents via the paracellular route, a claudin-1 specific modulator was developed. For this purpose, we designed and investigated the claudin-1 derived peptide C1C2. It transiently increased the paracellular permeability for ions and high and low molecular weight compounds through a cellular barrier model. Structural studies revealed a β-sheet potential for the functionality of the peptide. Perineurial injection of C1C2 in rats facilitated the effect of hydrophilic antinociceptive agents and raised mechanical nociceptive thresholds. The mechanism is related to the internalization of C1C2 and to a vesicle-like distribution within the cells. The peptide mainly colocalized with intracellular claudin-1. C1C2 decreased membrane-localized claudin-1 of cells in culture and in vivo in the perineurium of rats after perineurial injection. In conclusion, a novel tool was developed to improve the delivery of pharmaceutical agents through the perineurial barrier by transient modulation of claudin-1.
authors.affiliation: Leibniz Institut für Molekulare Pharmakologie, Robert-Rössle-Strasse 10, 13125, Berlin-Buch, Germany.
authors.forename: Denise
authors.initials: D
authors.lastname: Zwanziger
authors.forename: Dagmar
authors.initials: D
authors.lastname: Hackel
authors.forename: Christian
authors.initials: C
authors.lastname: Staat
authors.forename: Alexander
authors.initials: A
authors.lastname: Böcker
authors.forename: Alexander
authors.initials: A
authors.lastname: Brack
authors.forename: Michael
authors.initials: M
authors.lastname: Beyermann
authors.forename: Heike
authors.initials: H
authors.lastname: Rittner
authors.forename: Ingolf E
authors.initials: IE
authors.lastname: Blasig
mesh_terms: D000698:Analgesia / Q000379:methods*; D000818:Animals; D015153:Blotting, Western; D018938:Caco-2 Cells; D002460:Cell Line; D002942:Circular Dichroism; D062445:Claudin-1 / Q000737:chemistry; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D018613:Microscopy, Confocal; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D057786:Peptidomimetics / Q000737:chemistry* / Q000378:metabolism*; D010525:Peripheral Nerves / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012584:Sciatic Nerve / Q000187:drug effects / Q000378:metabolism; D019108:Tight Junctions / Q000378:metabolism*
chemical_list: D062445:Claudin-1; D010455:Peptides; D057786:Peptidomimetics