PACAP suppresses dry eye signs by stimulating tear secretion

Tomoya Nakamachi; Hirokazu Ohtaki; Tamotsu Seki; Sachiko Yofu; Nobuyuki Kagami; Hitoshi Hashimoto; Norihito Shintani; Akemichi Baba; Laszlo Mark; Ingela Lanekoff; Peter Kiss; Jozsef Farkas; Dora Reglodi; Seiji Shioda

doi:10.1038/ncomms12034

PACAP suppresses dry eye signs by stimulating tear secretion

Nat Commun. 2016 Jun 27:7:12034. doi: 10.1038/ncomms12034.

Authors

Tomoya Nakamachi^{1

2}, Hirokazu Ohtaki², Tamotsu Seki², Sachiko Yofu², Nobuyuki Kagami², Hitoshi Hashimoto^{3

4

5}, Norihito Shintani³, Akemichi Baba⁶, Laszlo Mark^{7

8

9

10}, Ingela Lanekoff¹¹, Peter Kiss¹², Jozsef Farkas^{2

12}, Dora Reglodi¹², Seiji Shioda¹³

Affiliations

¹ Laboratory of Regulatory Biology, Graduate School of Science and Engineering, University of Toyama, 3190-Gofuku, Toyama-shi, Toyama 930-8555, Japan.
² Department of Anatomy, Showa University School of Medicine, Shinagawa-Ku, Tokyo 142-8555, Japan.
³ Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
⁴ 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.
⁵ 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.
⁶ Hyogo University of Health Sciences, 1-3-6 Minatojima, Chuo-ku, Kobe, Hyogo 650-8530, Japan.
⁷ Department of Analytical Biochemistry, Institute of Biochemistry and Medical Chemistry, Medical School, University of Pécs, Szigeti u 12, Pécs 7624, Hungary.
⁸ Imaging Center for Life and Material Sciences, University of Pécs, Szigeti u 12, Pécs 7624, Hungary.
⁹ János Szentágothai Research Center, University of Pécs, Szigeti u 12, Pécs 7624, Hungary.
¹⁰ PTE-MTA Human Reproduction Research Group, Szigeti u 12, Pécs 7624, Hungary.
¹¹ Department of Chemistry-BMC, Uppsala University, PO Box 599, Uppsala 751 24, Sweden.
¹² Department of Anatomy, MTA-PTE PACAP Lendulet Research Group, Centre for Neuroscience, University of Pécs, Szigeti u 12, Pécs 7624, Hungary.
¹³ Innovative Drug Discovery, Global Research Center for Innovative Life Science, Hoshi University, 4-41 Ebara 2-chome, Shinagawa-ku, Tokyo 142-8501, Japan.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Administration, Ophthalmic
Animals
Dry Eye Syndromes / drug therapy*
Dry Eye Syndromes / genetics
Female
Mice
Mice, Knockout
Ophthalmic Solutions
Pituitary Adenylate Cyclase-Activating Polypeptide / administration & dosage
Pituitary Adenylate Cyclase-Activating Polypeptide / pharmacology*

Substances

Ophthalmic Solutions
Pituitary Adenylate Cyclase-Activating Polypeptide