title: Electric stimulus opens intercellular spaces in skin.
abstract: Iontophoresis is a technology for transdermal delivery of ionic small medicines by faint electricity. Since iontophoresis can noninvasively deliver charged molecules into the skin, this technology could be a useful administration method that may enhance patient comfort. Previously, we succeeded in the transdermal penetration of positively charged liposomes (diameters: 200-400 nm) encapsulating insulin by iontophoresis (Kajimoto, K., Yamamoto, M., Watanabe, M., Kigasawa, K., Kanamura, K., Harashima, H., and Kogure, K. (2011) Int. J. Pharm. 403, 57-65). However, the mechanism by which these liposomes penetrated the skin was difficult to define based on general knowledge of principles such as electro-repulsion and electro-osmosis. In the present study, we confirmed that rigid nanoparticles could penetrate into the epidermis by iontophoresis. We further found that levels of the gap junction protein connexin 43 protein significantly decreased after faint electric stimulus (ES) treatment, although occludin, CLD-4, and ZO-1 levels were unchanged. Moreover, connexin 43 phosphorylation and filamentous actin depolymerization in vivo and in vitro were observed when permeation of charged liposomes through intercellular spaces was induced by ES. Ca(2+) inflow into cells was promoted by ES with charged liposomes, while a protein kinase C inhibitor prevented ES-induced permeation of macromolecules. Consequently, we demonstrate that ES treatment with charged liposomes induced dissociation of intercellular junctions via cell signaling pathways. These findings suggest that ES could be used to regulate skin physiology.
authors: From the Department of Biophysical Chemistry, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan.
authors: Susumu
authors: S
authors: Hama
authors: Yuki
authors: Y
authors: Kimura
authors: Aya
authors: A
authors: Mikami
authors: Kanako
authors: K
authors: Shiota
authors: Mao
authors: M
authors: Toyoda
authors: Atsushi
authors: A
authors: Tamura
authors: Yukio
authors: Y
authors: Nagasaki
authors: Kiyoshi
authors: K
authors: Kanamura
authors: Kazuaki
authors: K
authors: Kajimoto
authors: Kentaro
authors: K
authors: Kogure
mesh_terms: D000818:Animals; D018031:Connexin 43 / Q000378:metabolism; D004817:Epidermis / Q000378:metabolism*; D007365:Intercellular Junctions; D007478:Iontophoresis / Q000379:methods*; D008081:Liposomes / Q000494:pharmacology; D008297:Male; D053758:Nanoparticles; D062793:Occludin / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012879:Skin Physiological Phenomena; D062826:Zonula Occludens-1 Protein / Q000378:metabolism
chemical_list: D018031:Connexin 43; C580592:Gja1 protein, rat; D008081:Liposomes; D062793:Occludin; C568987:Ocln protein, rat; C569044:Tjp1 protein, rat; D062826:Zonula Occludens-1 Protein
keywords: Actin; Calcium; Cell Junctions; Cell Signaling; Connexin; Electric Stimulus; Iontophoresis; Transdermal Delivery