Safety, efficacy, and molecular mechanism of claudin-1-specific peptides to enhance blood–nerve–barrier permeability

摘要: Abstract The blood–nerve barrier consists of the perineurium and endoneurial vessels. perineurial is composed a basal membrane layer cells sealed by tight junction proteins preventing e.g. application analgesics for selective regional pain control. One barrier-sealing in claudin-1. Therefore, claudin-1-peptidomimetics (C1C2), derived from first extracellular loop (ECL1) on claudin-1 was developed. In this study, we further evaluated expression Wistar rats characterized specificity, vivo applicability, mechanism action as well biocompatibility C1C2. perineurium, claudin-19, tricellulin ZO-1, but no claudin-2, 3, 8 -11 were expressed. C1C2 specifically bound to ECL1 fluorescent 5,6-carboxytetramethylrhodamine-C1C2 rapidly internalized. Opening with reduced mRNA protein increased small macromolecule permeability into peripheral nerve. Application facilitated analgesia using μ-opioid receptor agonists like DAMGO or morphine without motor impairment naive hind paw inflammation. contrast control peptide C2C2 claudin-2 did neither open nor opioid-mediated analgesia. delivery tolerated caused morphological functional nerve damage. effects could be reversed interference wnt-signal-transduction pathway, homeobox transcription factor cdx2, glycogen-synthase-kinase-3 inhibitor. summary, describe composition pathway employing deliver hydrophilic substances