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      PACAP suppresses dry eye signs by stimulating tear secretion

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          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.


          Dry eye disease is a complex condition with limited treatments. Here the authors show that mice lacking a multi-functional peptide PACAP develop dry eye-like signs that can be topically treated with PACAP peptide that stimulates tearing in mice, suggesting a possible therapy in humans with dry eyes.

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          Most cited references 41

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          Isolation of a novel 38 residue-hypothalamic polypeptide which stimulates adenylate cyclase in pituitary cells.

          A novel neuropeptide which stimulates adenylate cyclase in rat anterior pituitary cell cultures was isolated from ovine hypothalamic tissues. Its amino acid sequence was revealed as: His-Ser-Asp-Gly-Ile-Phe-Thr-Asp-Ser-Tyr-Ser-Arg-Tyr-Arg-Lys-Gln- Met-Ala- Val-Lys-Lys-Tyr-Leu-Ala-Ala-Val-Leu-Gly-Lys-Arg-Tyr-Lys-Gln-Arg-Val-Lys-Asn-Lys - NH2. The N-terminal sequence shows 68% homology with vasoactive intestinal polypeptide (VIP) but its adenylate cyclase stimulating activity was at least 1000 times greater than that of VIP. It increased release of growth hormone (GH), prolactin (PRL), corticotropin (ACTH) and luteinizing hormone (LH) from superfused rat pituitary cells at as small a dose as 10(-10)M (GH, PRL, ACTH) or 10(-9)M (LH). Whether these hypophysiotropic effects are the primary actions of the peptide or what physiological action in the pituitary is linked with the stimulation of adenylate cyclase by this peptide remains to be determined.
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            Neural regulation of lacrimal gland secretory processes: relevance in dry eye diseases.

             Darlene Dartt (2009)
            The lacrimal gland is the major contributor to the aqueous layer of the tear film which consists of water, electrolytes and proteins. The amount and composition of this layer is critical for the health, maintenance, and protection of the cells of the cornea and conjunctiva (the ocular surface). Small changes in the concentration of tear electrolytes have been correlated with dry eye syndrome. While the mechanisms of secretion of water, electrolytes and proteins from the lacrimal gland differ, all three are under tight neural control. This allows for a rapid response to meet the needs of the cells of the ocular surface in response to environmental conditions. The neural response consists of the activation of the afferent sensory nerves in the cornea and conjunctiva to stimulate efferent parasympathetic and sympathetic nerves that innervate the lacrimal gland. Neurotransmitters are released from the stimulated parasympathetic and sympathetic nerves that cause secretion of water, electrolytes, and proteins from the lacrimal gland and onto the ocular surface. This review focuses on the neural regulation of lacrimal gland secretion under normal and dry eye conditions.
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              The pathology of dry eye: the interaction between the ocular surface and lacrimal glands.

              Most dry-eye symptoms result from an abnormal, nonlubricative ocular surface that increases shear forces under the eyelids and diminishes the ability of the ocular surface to respond to environmental challenges. This ocular-surface dysfunction may result from immunocompromise due to systemic autoimmune disease or may occur locally from a decrease in systemic androgen support to the lacrimal gland as seen in aging, most frequently in the menopausal female. Components of the ocular surface (cornea, conjunctiva, accessory lacrimal glands, and meibomian glands), the main lacrimal gland, and interconnecting innervation act as a functional unit. When one portion is compromised, normal lacrimal support of the ocular surface is impaired. Resulting immune-based inflammation can lead to lacrimal gland and neural dysfunction. This progression yields the OS symptoms associated with dry eye. Restoration of lacrimal function involves resolution of lymphocytic activation and inflammation. This has been demonstrated in the MRL/lpr mouse using systemic androgens or cyclosporine and in the dry-eye dog using topical cyclosporine. The efficacy of cyclosporine may be due to its immunomodulatory and antiinflammatory (phosphatase inhibitory capability) functions on the ocular surface, resulting in a normalization of nerve traffic. Although the etiologies of dry eye are varied, common to all ocular-surface disease is an underlying cytokine/receptor-mediated inflammatory process. By treating this process, it may be possible to normalize the ocular surface/lacrimal neural reflex and facilitate ocular surface healing.

                Author and article information

                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group
                27 June 2016
                : 7
                [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
                Author notes
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