title: A putative antipruritic mechanism of the phosphodiesterase-4 inhibitor E6005 by attenuating capsaicin-induced depolarization of C-fibre nerves.
abstract: E6005, a potent, selective phosphodiesterase (PDE) 4 inhibitor, has been developed as a novel topical agent of atopic dermatitis (AD). It has been shown to inhibit itching in patients with AD as well in mouse models. To study the mechanism underlying the anti-pruritic effect of E6005, we examined its effect on the activation of dorsal root ganglion (DRG) neurons associated with the itch sensation. Depolarization of DRG neurons by a transient receptor potential vanilloid 1 (TRPV 1) activator, capsaicin was attenuated by E6005 as well as by a 3',5'-cyclic adenosine monophosphate (cAMP) elevator, forskolin. E6005 elevated intracellular levels of cAMP in DRG cells. Taken together, these results suggest that E6005 suppresses TRPV1-mediated C-fibre depolarization through elevation of cAMP levels, thereby exerting an anti-pruritic effect. Thus, E6005 shows the potential to be a new agent for managing pruritus in various skin disorders, including AD.
authors.affiliation: Tsukuba Research Laboratories, Eisai Co. Ltd., Ibaraki, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Wakita
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Ohkuro
authors.forename: Naoto
authors.initials: N
authors.lastname: Ishii
authors.forename: Ieharu
authors.initials: I
authors.lastname: Hishinuma
authors.forename: Manabu
authors.initials: M
authors.lastname: Shirato
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D000982:Antipruritics / Q000494:pharmacology*; D002211:Capsaicin / Q000037:antagonists & inhibitors; D000242:Cyclic AMP / Q000378:metabolism; D005727:Ganglia, Spinal; D008297:Male; D009412:Nerve Fibers / Q000187:drug effects* / Q000502:physiology; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology*; D010795:Phthalic Acids / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D050916:TRPV Cation Channels / Q000378:metabolism
chemical_list: D000982:Antipruritics; D058988:Phosphodiesterase 4 Inhibitors; D010795:Phthalic Acids; D011799:Quinazolines; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; C583128:methyl 4-(((3-(6,7-dimethoxy-2-(methylamino)quinazolin-4-yl)phenyl)amino)carbonyl)benzoate; D000242:Cyclic AMP; D002211:Capsaicin
keywords: C-fibre nerve; antipruritic effect; cAMP; phosphodiesterase 4