title: Sodium caprate-induced increases in intestinal permeability and epithelial damage are prevented by misoprostol.
abstract: Epithelial damage caused by intestinal permeation enhancers is a source of debate concerning safety. The medium chain fatty acid, sodium caprate (C10), causes reversible membrane perturbation at high dose levels required for efficacy in vivo, so the aim was to model it in vitro. Exposure of Caco-2 monolayers to 8.5mM C10 for 60min followed by incubation in fresh buffer led to (i) recovery in epithelial permeability (i.e. transepithelial electrical resistance (TEER) and apparent permeability coefficient (Papp) of [(14)C]-mannitol), (ii) recovery of cell viability parameters (monolayer morphology, plasma membrane potential, mitochondrial membrane potential, and intracellular calcium) and (iii) reduction in mRNA expression associated with inflammation (IL-8). Pre-incubation of monolayers with a mucosal prostaglandin cytoprotectant was attempted in order to further decipher the mechanism of C10. Misoprostol (100nM), inhibited C10-induced changes in monolayer parameters, an effect that was partially attenuated by the EP1 receptor antagonist, SC51322. In rat isolated intestinal tissue mucosae and in situ loop instillations, C10-induced respective increases in the [(14)C]-mannitol Papp and the AUC of FITC-dextran 4000 (FD-4) were similarly inhibited by misoprostol, with accompanying morphological damage spared. These data support a temporary membrane perturbation effect of C10, which is linked to its capacity to mainly increase paracellular flux, but which can be prevented by pre-exposure to misoprostol.
authors.affiliation: School of Veterinary Medicine and Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland. Electronic address: david.brayden@ucd.ie.
authors.forename: David J
authors.initials: DJ
authors.lastname: Brayden
authors.affiliation: School of Veterinary Medicine and Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Sam
authors.initials: S
authors.lastname: Maher
authors.affiliation: School of Veterinary Medicine and Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Bojlul
authors.initials: B
authors.lastname: Bahar
authors.affiliation: School of Veterinary Medicine and Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Edwin
authors.initials: E
authors.lastname: Walsh
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D002470:Cell Survival / Q000187:drug effects; D003106:Colon / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D019610:Cytoprotection; D003652:Decanoic Acids / Q000633:toxicity*; D003911:Dextrans / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D017097:Electric Impedance; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D066298:In Vitro Techniques; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D007408:Intestinal Absorption / Q000187:drug effects*; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008353:Mannitol / Q000378:metabolism; D016595:Misoprostol / Q000494:pharmacology*; D010539:Permeability; D020011:Protective Agents / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D013997:Time Factors
chemical_list: C508606:CXCL8 protein, human; D003652:Decanoic Acids; D003911:Dextrans; D016209:Interleukin-8; D020011:Protective Agents; D012333:RNA, Messenger; C015219:fluorescein isothiocyanate dextran; D016595:Misoprostol; D008353:Mannitol; C031071:decanoic acid; D016650:Fluorescein-5-isothiocyanate
keywords: Caco-2 monolayers; Cytotoxicity assays; Intestinal permeation enhancers; Medium chain fatty acids; Oral peptide delivery; Sodium caprate