title: PACAP suppresses dry eye signs by stimulating tear secretion.
abstract: Dry eye syndrome is caused by a reduction in the volume or quality of tears. Here, we show that pituitary adenylate cyclase-activating polypeptide (PACAP)-null mice develop dry eye-like symptoms such as corneal keratinization and tear reduction. PACAP immunoreactivity is co-localized with a neuronal marker, and PACAP receptor (PAC1-R) immunoreactivity is observed in mouse infraorbital lacrimal gland acinar cells. PACAP eye drops stimulate tear secretion and increase cAMP and phosphorylated (p)-protein kinase A levels in the infraorbital lacrimal glands that could be inhibited by pre-treatment with a PAC1-R antagonist or an adenylate cyclase inhibitor. Moreover, these eye drops suppress corneal keratinization in PACAP-null mice. PACAP eye drops increase aquaporin 5 (AQP5) levels in the membrane and pAQP5 levels in the infraorbital lacrimal glands. AQP5 siRNA treatment of the infraorbital lacrimal gland attenuates PACAP-induced tear secretion. Based on these results, PACAP might be clinically useful to treat dry eye disorder.
authors.affiliation: Laboratory of Regulatory Biology, Graduate School of Science and Engineering, University of Toyama, 3190-Gofuku, Toyama-shi, Toyama 930-8555, Japan.|Department of Anatomy, Showa University School of Medicine, Shinagawa-Ku, Tokyo 142-8555, Japan.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Nakamachi
authors.affiliation: Department of Anatomy, Showa University School of Medicine, Shinagawa-Ku, Tokyo 142-8555, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Ohtaki
authors.affiliation: Department of Anatomy, Showa University School of Medicine, Shinagawa-Ku, Tokyo 142-8555, Japan.
authors.forename: Tamotsu
authors.initials: T
authors.lastname: Seki
authors.affiliation: Department of Anatomy, Showa University School of Medicine, Shinagawa-Ku, Tokyo 142-8555, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Yofu
authors.affiliation: Department of Anatomy, Showa University School of Medicine, Shinagawa-Ku, Tokyo 142-8555, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Kagami
authors.affiliation: Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.|iPS Cell-based Research Project on Brain Neuropharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.|Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Hitoshi
authors.identifier: 0000-0001-6548-4016
authors.initials: H
authors.lastname: Hashimoto
authors.affiliation: Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Norihito
authors.identifier: 0000-0002-7850-9064
authors.initials: N
authors.lastname: Shintani
authors.affiliation: Hyogo University of Health Sciences, 1-3-6 Minatojima, Chuo-ku, Kobe, Hyogo 650-8530, Japan.
authors.forename: Akemichi
authors.initials: A
authors.lastname: Baba
authors.affiliation: Department of Analytical Biochemistry, Institute of Biochemistry and Medical Chemistry, Medical School, University of Pécs, Szigeti u 12, Pécs 7624, Hungary.|Imaging Center for Life and Material Sciences, University of Pécs, Szigeti u 12, Pécs 7624, Hungary.|János Szentágothai Research Center, University of Pécs, Szigeti u 12, Pécs 7624, Hungary.|PTE-MTA Human Reproduction Research Group, Szigeti u 12, Pécs 7624, Hungary.
authors.forename: Laszlo
authors.initials: L
authors.lastname: Mark
authors.affiliation: Department of Chemistry-BMC, Uppsala University, PO Box 599, Uppsala 751 24, Sweden.
authors.forename: Ingela
authors.identifier: 0000-0001-9040-3230
authors.initials: I
authors.lastname: Lanekoff
authors.affiliation: Department of Anatomy, MTA-PTE PACAP Lendulet Research Group, Centre for Neuroscience, University of Pécs, Szigeti u 12, Pécs 7624, Hungary.
authors.forename: Peter
authors.initials: P
authors.lastname: Kiss
authors.affiliation: Department of Anatomy, Showa University School of Medicine, Shinagawa-Ku, Tokyo 142-8555, Japan.|Department of Anatomy, MTA-PTE PACAP Lendulet Research Group, Centre for Neuroscience, University of Pécs, Szigeti u 12, Pécs 7624, Hungary.
authors.forename: Jozsef
authors.initials: J
authors.lastname: Farkas
authors.affiliation: Department of Anatomy, MTA-PTE PACAP Lendulet Research Group, Centre for Neuroscience, University of Pécs, Szigeti u 12, Pécs 7624, Hungary.
authors.forename: Dora
authors.initials: D
authors.lastname: Reglodi
authors.affiliation: Innovative Drug Discovery, Global Research Center for Innovative Life Science, Hoshi University, 4-41 Ebara 2-chome, Shinagawa-ku, Tokyo 142-8501, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Shioda
mesh_terms: D060433:Administration, Ophthalmic; D000818:Animals; D015352:Dry Eye Syndromes / Q000188:drug therapy* / Q000235:genetics; D005260:Female; D051379:Mice; D018345:Mice, Knockout; D009883:Ophthalmic Solutions; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D009883:Ophthalmic Solutions; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide