title: Blood-brain barrier transport of short proline-rich antimicrobial peptides.
abstract: Infections by antibiotic-resistant bacteria are becoming a great risk for human health, leading to an urgent need for new efficient antibacterial therapies. The short, proline-rich antimicrobial peptides from insects gained a lot of interest as a potential antibacterial treatment, having a low toxicity profile and being mainly active against Gram-negative bacteria. To know whether these antimicrobial peptides can be used for the treatment of cerebral infections, the blood-brain barrier transport characteristics of these peptides were investigated. This study describes the results of the in vivo blood-brain barrier experiments in mice, as well as the in vitro metabolic stability in mouse plasma and brain of apidaecin Api137, oncocin, drosocin and drosocin Pro5Hyp. The four investigated peptides showed a significant influx into the brain with a K(in) ranging between 0.37 and 0.86 µL/g x min and brain distribution volumes of 19.6 to 25.8 µL/g. Only for drosocin, a significant efflux was determined, with a k(out) of 0.22 min(-1). After entering the brain, oncocin was for approximately 80% trapped in the endothelial cells, while the other peptides reached the brain parenchyma for about 70%. All peptides were stable in plasma and brain during the experiments, with estimated metabolic half-lives ranging between 47 min and 637 min. We conclude that the investigated short, proline-rich antimicrobial peptides show an influx into the brain, which make them a promising antibacterial treatment of cerebral infections.
authors.forename: Sofie
authors.initials: S
authors.lastname: Stalmans
authors.forename: Evelien
authors.initials: E
authors.lastname: Wynendaele
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bracke
authors.forename: Daniel
authors.initials: D
authors.lastname: Knappe
authors.forename: Ralf
authors.initials: R
authors.lastname: Hoffmann
authors.forename: Kathelijne
authors.initials: K
authors.lastname: Peremans
authors.forename: Ingeborgh
authors.initials: I
authors.lastname: Polis
authors.forename: Christian
authors.initials: C
authors.lastname: Burvenich
authors.affiliation: Drug Quality and Registration (DruQuaR) group, Faculty of Pharmaceutical Sciences, Ghent University, Harelbekestraat 72, B-9000 Ghent, Belgium. Bart.DeSpiegeleer@UGent.be.
authors.forename: Bart
authors.initials: B
authors.lastname: De Spiegeleer
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000890:Anti-Infective Agents / Q000097:blood / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D023181:Antimicrobial Cationic Peptides / Q000097:blood / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D006020:Glycopeptides / Q000097:blood / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D006801:Humans; D019476:Insect Proteins; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data
chemical_list: D000890:Anti-Infective Agents; D023181:Antimicrobial Cationic Peptides; D006020:Glycopeptides; D019476:Insect Proteins; C551620:oncocin; C061361:apidaecin; C082117:drosocin