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Pituitary Adenylate Cyclase Activating Polypeptide — PACAP pp 501–527Cite as

Protective Effects of PACAP in the Retina

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Part of the book series: Current Topics in Neurotoxicity ((Current Topics Neurotoxicity,volume 11))

Abstract

Pituitary adenylate cyclase activating polypeptide (PACAP) is a widespread neuropeptide that is well known for its general cytoprotective effects in different neuronal injuries, such as traumatic brain and spinal cord injury, models of neurodegenerative diseases, and cerebral ischemia. PACAP and its receptors also occur in the retina. In this review, we summarize the retinoprotective effects of PACAP. In vitro, PACAP is protective against glutamate, thapsigargin, anisomycin, oxidative stress, UV light, high glucose, inflammation, and anoxia. Both the neural retina and the pigment epithelial cells can be protected by PACAP in various experimental paradigms. In vivo, the protective effects of intravitreal PACAP treatment have been shown in the following models in rats and mice: excitotoxic injury induced by glutamate, N-methyl-d-aspartate (NMDA) or kainate, ischemic injury induced by carotid artery ligation and high intraocular pressure, degeneration caused by UV-A light, optic nerve transection, and streptozotocin-induced diabetic retinopathy as well as retinopathy of prematurity. Molecular biological methods have revealed that PACAP activates anti-apoptotic, while inhibits pro-apoptotic signaling pathways, and it also stimulates an anti-inflammatory environment in the retina. Altogether, PACAP is suggested to be a potential therapeutic retinoprotective agent in various retinal diseases.

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Abbreviations

6-OHDA:

6-hydroxydopamine

AIF:

Apoptosis inducing factor

AMPA receptor:

α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor

Bad:

Bcl-2-associated death promoter

Bax:

Bcl-2-associated X protein

BBB:

Blood–brain barrier

BCCAO:

Bilateral common carotid artery occlusion

Bcl-2:

B-cell lymphoma 2

Bcl-xl:

B-cell lymphoma-extra large

cAMP/PKA/CREB:

Cyclic AMP/protein-kinase A/cAMP response element-binding protein

CIAP-1:

Cellular inhibitor of apoptosis protein-1

CINC:

Cytokine-induced neutrophil chemoattractant

CNS:

Central nervous system

CNTF:

Ciliary neurotrophic factor

CtBP2:

C-terminal binding protein 2

DR:

Diabetic retinopathy

eNOS:

Endothelial nitric oxide synthase

ERG:

Electroretinography

ERK:

Extracellular signal-regulated kinase

Fas TNFR:

Fas tumor necrosis factor receptor

FITC:

Fluorescein isothiocyanate

GCL:

Ganglion cell layer

GFAP:

Glial fibrillary acidic protein

HIF1α, 2α, 3α:

Hypoxia-inducible factor 1-alpha, 2-alpha, 3-alpha

HO-1:

Heme oxygenase-1

HSP-27:

Heat shock protein-27

IL-1β:

Interleukin-1 beta

INL:

Inner nuclear layer

IP3:

Inositol trisphosphate

IPL:

Inner plexiform layer

JNK:

c-Jun N-terminal kinase

LPS:

Lipopolysaccharide

MAPK:

Mitogen-activated protein kinase

MIP-1:

Macrophage inflammatory protein 1

MSG:

Monosodium glutamate

NBL:

Neuroblast layer

NF-kB:

Nuclear factor-kB

NFL:

Nerve fiber layer

NMDA:

N-methyl-d-aspartate

NPY:

Neuropeptide Y

OLM-ILM:

Outer limiting membrane-inner limiting membrane

ONL:

Outer nuclear layer

OPL:

Outer plexiform layer

Ops:

Oscillatory potentials

PAC1:

PACAP receptor 1

PACAP:

Pituitary adenylate cyclase activating polypeptide

PACAP KO:

PACAP knockout

PKCα:

Protein kinase C alpha

PLC gamma-1:

Phospholipase C gamma-1

RANTES:

Regulated on activation normal T cell expressed and secreted

RGCs:

Retinal ganglion cells

ROP:

Retinopathy of prematurity

ROS:

Reactive oxygen species

RPE:

Retinal pigment epithelial

RSK1/2:

Ribosomal s6 kinase 1, 2

sICAM:

Soluble intercellular adhesion molecule

STAT4:

Signal transducer and activator of transcription 4

TGF-β:

Transforming growth factor beta

TH:

Tyrosine hydroxylase

TIMP-1:

Tissue inhibitor metallopeptidase inhibitor-1

Trail R2 DR5:

TRAIL receptor 2—death receptor 5

TUNEL:

Terminal deoxynucleotidyl transferase dUTP nick end labeling

UV-A, B:

Ultraviolet A, ultraviolet B

VEGF:

Vascular endothelial growth factor

VGAT:

Vesicular GABA transporter

VGLUT1:

Vesicular glutamate transporter 1

VIP:

Vasoactive intestinal peptide

VPAC1:

Vasoactive intestinal peptide (VIP) receptor type 1

VPAC2:

Vasoactive intestinal peptide (VIP) receptor type 2

ZO-1:

Zona occludens protein 1

References

  1. Arimura A. PACAP: the road to discovery. Peptides. 2007;28:1617–9.

    Article  CAS  PubMed  Google Scholar 

  2. Miyata A, Arimura A, Dahl RR, Minamino N, Uehara A, Jiang L, et al. Isolation of a novel 38 residue-hypothalamic polypeptide which stimulates adenylate cyclase in pituitary cells. Biochem Biophys Res Commun. 1989;164:567–74.

    Article  CAS  PubMed  Google Scholar 

  3. Arimura A, Shioda S. Pituitary adenylate cyclase polypeptide (PACAP) and its receptors: neuroendocrine and endocrine interactions. Front Neuroendocrinol. 1995;16:53–8.

    Article  CAS  PubMed  Google Scholar 

  4. Vaudry D, Falluel-Morel A, Bourgault S, Basille M, Burel D, Wurtz O, et al. Pituitary adenylate cyclase activating polypeptide and its receptors: 20 years after the discovery. Pharmacol Rev. 2009;61:283–357.

    Article  CAS  PubMed  Google Scholar 

  5. Ohtaki H, Nakamachi T, Dohi K, Shioda S. Role of PACAP in ischemic neural death. J Mol Neurosci. 2008;36:16–25.

    Article  CAS  PubMed  Google Scholar 

  6. Reglodi D, Kiss P, Lubics A, Tamas A. Review of the protective effects of PACAP in models of neurodegenerative diseases in vitro and in vivo. Curr Pharm Des. 2011;17:962–72.

    Article  CAS  PubMed  Google Scholar 

  7. Reglodi D, Renaud J, Tamas A, Tizabi Y, Socias B, Del-Bel E, et al. Novel tactics for neuroprotection in Parkinson’s disease: role of antibiotics, polyphenols and neuropeptides. Prog Neurobiol. doi: 10.1016/j.pneurobio.2015.10.004. Accessed 2 Nov 2015.

    Google Scholar 

  8. Shioda S, Ohtaki H, Nakamachi T, Dohi K, Watanabe J, Nakajo S, et al. Pleiotropic functions of PACAP in the CNS: neuroprotection and neurodevelopment. Ann N Y Acad Sci. 2006;1070:550–60.

    Article  CAS  PubMed  Google Scholar 

  9. Shioda S, Nakamachi T. PACAP as a neuroprotective factor in ischemic neuronal injuries. Peptides. 2015;72:202–7.

    Article  CAS  PubMed  Google Scholar 

  10. Somogyvari-Vigh A, Reglodi D. Pituitary adenylate cyclase activating polypeptide: a potential neuroprotective peptide. Rev Curr Pharm Des. 2004;10:2861–89.

    Article  CAS  Google Scholar 

  11. Waschek JA. Multiple actions of pituitary adenylyl cyclase activating peptide in nervous system development and regeneration. Dev Neurosci. 2002;24:14–23.

    Article  CAS  PubMed  Google Scholar 

  12. Atlasz T, Szabadfi K, Kiss P, Racz B, Gallyas F, Tamas A, et al. Pituitary adenylate cyclase activating polypeptide in the retina: focus on the retinoprotective effects. Ann N Y Acad Sci. 2010;1200:128–39.

    Article  CAS  PubMed  Google Scholar 

  13. Atlasz T, Szabadfi K, Kiss P, Tamas A, Toth G, Reglodi D, et al. Evaluation of the protective effects of PACAP with cell-specific markers in ischemia-induced retinal degeneration. Brain Res Bull. 2010;81:497–504.

    Article  CAS  PubMed  Google Scholar 

  14. Nemeth A, Szabadfi K, Fulop B, Reglodi D, Kiss P, Farkas J, et al. Examination of calcium-binding protein expression in the inner ear of wild type, heterozygous and homozygous pituitary adenylate cyclase activating polypeptide (PACAP)-knockout mice in kanamycin-induced ototoxicity. Neurotox Res. 2014;25:57–67.

    Article  CAS  PubMed  Google Scholar 

  15. Nakamachi T, Matkovits A, Seki T, Shioda S. Distribution and protective function of pituitary adenylate cyclase-activating polypeptide in the retina. Front Endocrinol (Lausanne). 2012;3:145.

    CAS  Google Scholar 

  16. D’Agata V, Cavallaro S. Functional and molecular expression of PACAP/VIP receptors in the rat retina. Mol Brain Res. 1998;54:161–4.

    Article  PubMed  Google Scholar 

  17. Hannibal J, Fahrenkrug J. Target areas innervated by PACAP-immunoreactive retinal ganglion cells. Cell Tissue Res. 2004;316:99–113.

    Article  CAS  PubMed  Google Scholar 

  18. Izumi S, Seki T, Shioda S, Zhou CJ, Arimura A, Koide R. Ultrastructural localization of PACAP immunoreactivity in the rat retina. Ann NY Acad Sci. 2000;921:317–20.

    Article  CAS  PubMed  Google Scholar 

  19. Kubrusly RC, da Cunha MC, Reis RA, Soares H, Ventura AL, Kurtenbach E, et al. Expression of functional receptors and transmitter enzymes in cultured Muller cells. Brain Res. 2005;1038:141–9.

    Article  CAS  PubMed  Google Scholar 

  20. Seki T, Shioda S, Izumi S, Arimura A, Koide R. Electron microscopic observation of pituitary adenylate cyclase activating polypeptide (PACAP)-containing neurons in the rat retina. Peptides. 2000;21:109–13.

    Article  CAS  PubMed  Google Scholar 

  21. Mathis U, Schaeffel F. Glucagon-related peptides in the mouse retina and the effects of deprivation of form vision. Graefe’s Arch Clin Exp Ophthalmol. 2007;245:267–75.

    Article  CAS  Google Scholar 

  22. Grone BP, Zhao S, Chen CC, Fernald RD. Localization and diurnal expression of melanopsin, vertebrate ancient opsin, and pituitary adenylate cyclase activating peptide mRNA in a teleost retina. J Biol Rhythms. 2007;22:558–61.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Reglodi D, Somogyvari-Vigh A, Vigh J, Li M, Lengvari I, Arimura A. Pituitary adenylate cyclase activating polypeptide is highly abundant in the nervous system of anoxia-tolerant turtle, Pseudemys scripta elegans. Peptides. 2001;22:873–8.

    Article  CAS  PubMed  Google Scholar 

  24. Jozsa R, Somogyvari-Vigh A, Reglodi D, Hollosy T, Arimura A. Distribution and daily variations of PACAP in the chicken brain. Peptides. 2001;22:1371–7.

    Article  CAS  PubMed  Google Scholar 

  25. Sakamoto K, Liu C, Kasamatsu M, Pozdeyev NV, Iuvone PM, Tosini G. Dopamine regulates melanopsin mRNA expression in intrinsically photosensitive retinal ganglion cells. Eur J Neurosci. 2005;22:3129–36.

    Article  PubMed  Google Scholar 

  26. Wan J, Zheng H, Hu BY, Xiao HL, She ZJ, Chen ZL, et al. Acute photoreceptor degeneration down-regulates melanopsin expression in adult rat retina. Neurosci Lett. 2006;400:48–52.

    Article  CAS  PubMed  Google Scholar 

  27. Perez de Sevilla Muller L, Sargoy A, Rodriguez AR, Brecha NC. Melanopsin ganglion cells are the most resistant retinal ganglion cell type to axonal injury in the rat retina. PLoS One. 2014;9:e93274.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Hannibal J, Kankipati L, Strang CE, Peterson BB, Dacey D, Gamlin PD. Central projections of intrinsically photosensitive retinal ganglion cells in the macaque monkey. J Comp Neurol. 2014;522:2231–48.

    Article  CAS  PubMed  Google Scholar 

  29. La Morgia C, Ross-Cisneros FN, Hannibal J, Montagna P, Sadun AA, Carelli V. Melanopsin-expressing retinal ganglion cells: implications for human diseases. Vision Res. 2011;51:296–302.

    Article  PubMed  CAS  Google Scholar 

  30. Langel JL, Smale L, Esquiva G, Hannibal J. Central melanopsin projections in the diurnal rodent. Arvicanthis niloticus. Front Neuroanat. 2015;9:93.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Delwig A, Majumdar S, Ahern K, LaVail MM, Edwards R, Hnaski TS, et al. Glutamatergic neurotransmission from melanopsin retinal ganglion cells is required for neonatal photoaversion but not adult pupillary light reflex. PLoS One. 2013;8:e83974.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Purrier N, Engeland WC, Kofuji P. Mice deficient of glutamatergic signaling from intrinsically photosensitive retinal ganglion cells exhibit abnormal circadian photoentrainment. PLoS One. 2014;9:e111449.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Vereczki V, Koves K, Csaki A, Grosz K, Hoffman GE, Fiskum G. Distribution of hypothalamic, hippocampal and other limbic peptidergic neuronal cell bodies giving rise to retinopetal fibers: anterograde and retrograde tracing and neuropeptide immunohistochemical studies. Neuroscience. 2006;140:1089–100.

    Article  CAS  PubMed  Google Scholar 

  34. Bagnoli P, Dal Monte M, Casini G. Expression of neuropeptides and their receptors in the developing retina of mammals. Histol Histopathol. 2003;18:1219–42.

    CAS  PubMed  Google Scholar 

  35. Borba JC, Henze IP, Silveira MS, Kubrusly RC, Gardino PF, de Mello MC, et al. Pituitary adenylate cyclase activating polypeptide (PACAP) can act as a determinant of the tyrosine hydroxylase phenotype of dopaminergic cells during retina development. Dev Brain Res. 2005;156:193–201.

    Article  CAS  Google Scholar 

  36. Mathieu M, Girosi L, Vallarino M, Tagliafierro G. PACAP in developing sensory and peripheral organs of the zebrafish, Danio rerio. Eur J Histochem. 2005;49:167–78.

    CAS  PubMed  Google Scholar 

  37. Mathieu M, Ciarlo M, Trucco N, Griffero F, Damonte G, Salis A, et al. Pituitary adenylate cyclase activating polypeptide in the brain, spinal cord and sensory organs of the zebrafish, Danio rerio, during development. Brain Res Dev Brain Res. 2004;151:169–85.

    Article  CAS  PubMed  Google Scholar 

  38. Skoglosa Y, Takei N, Lindholm D. Distribution of pituitary adenylate cyclase activating polypeptide mRNA in the developing rat brain. Mol Brain Res. 1999;65:1–13.

    Article  CAS  PubMed  Google Scholar 

  39. Nilsson SF, De Neef P, Robberecht P, Christophe J. Characterization of ocular receptors for pituitary adenylate cyclase activating polypeptide (PACAP) and their coupling to adenylate cyclase. Exp Eye Res. 1994;58:459–67.

    Article  CAS  PubMed  Google Scholar 

  40. Silveira MS, Costa MR, Bozza M, Linden R. Pituitary adenylate cyclase activating polypeptide prevents induced cell death in retinal tissue through activation of cyclic AMP-dependent protein kinase. J Biol Chem. 2002;277:16075–80.

    Article  CAS  PubMed  Google Scholar 

  41. Seki T, Shioda S, Ogino D, Nakai Y, Arimura A, Koide R. Distribution and ultrastructural localization of a receptor for pituitary adenylate cyclase activating polypeptide and its mRNA in the rat retina. Neurosci Lett. 1997;238:127–30.

    Article  CAS  PubMed  Google Scholar 

  42. Seki T, Izumi S, Shioda S, Zhou CJ, Arimura A, Koide R. Gene expression for PACAP receptor mRNA in the rat retina by in situ hybridization and in situ RT-PCR. Ann N Y Acad Sci. 2000;921:366–9.

    Article  CAS  PubMed  Google Scholar 

  43. Seki T, Nakatani M, Taki C, Shinohara Y, Ozawa M, Nishimura S, et al. Neuroprotective effects of PACAP against kainic acid-induced neurotoxicity in rat retina. Ann N Y Acad Sci. 2006;1070:531–4.

    Article  CAS  PubMed  Google Scholar 

  44. Njaine B, Martins RA, Santiago MF, Linden R, Silveira MS. Pituitary adenylyl cyclase-activating polypeptide controls the proliferation of retinal progenitor cells through downregulation of cyclin D1. Eur J Neurosci. 2010;32:311–21.

    Article  PubMed  Google Scholar 

  45. Denes V, Czotter N, Lakk M, Berta G, Gabriel R. PAC1-expressing structures of neural retina alter their PAC1 isoform splicing during postnatal development. Cell Tissue Res. 2014;355:279–88.

    Article  CAS  PubMed  Google Scholar 

  46. Lakk M, Szabo B, Volgyi B, Gabriel R, Denes V. Development-related splicing regulates pituitary adenylate cyclase-activating polypeptide (PACAP) receptors in the retina. Invest Ophthalmol Vis Sci. 2012;53:7825–32.

    Article  PubMed  CAS  Google Scholar 

  47. Njaine B, Rocha-Martins M, Vieira-Vieira CH, De-Melo LD, Linden R, Braas K, et al. Pleiotropic functions of pituitary adenylyl cyclase-activating polypeptide on retinal ontogenesis: involvement of KLF4 in the control of progenitor cell proliferation. J Mol Neurosci. 2014;54:430–42.

    Article  CAS  PubMed  Google Scholar 

  48. Shoge K, Mishima HK, Saitoh T, Ishihara K, Tamura Y, Shiomi H, et al. Protective effects of vasoactive intestinal peptide against delayed glutamate neurotoxicity in cultured retina. Brain Res. 1998;809:127–36.

    Article  CAS  PubMed  Google Scholar 

  49. Shoge K, Mishima HK, Saitoh T, Ishihara K, Tamura Y, Shiomi H, et al. Attenuation by PACAP of glutamate-induced neurotoxicity in cultured retinal neurons. Brain Res. 1999;839:66–73.

    Article  CAS  PubMed  Google Scholar 

  50. Rabl K, Reglodi D, Banvolgyi T, Somogyvari-Vigh A, Lengvari I, Gabriel R, et al. PACAP inhibits anoxia-induced changes in physiological responses in horizontal cells in the turtle retina. Regul Pept. 2002;109:71–4.

    Article  CAS  PubMed  Google Scholar 

  51. Zhang XY, Hayasaka S, Chi ZL, Cui HS, Hayasaka Y. Effect of pituitary adenylate cyclase-activating polypeptide (PACAP) on IL-6, IL-8, and MCP-1 expression in human retinal pigment epithelial cell line. Curr Eye Res. 2005;30:1105–11.

    Article  CAS  PubMed  Google Scholar 

  52. Mester L, Kovacs K, Racz B, Solti I, Atlasz T, Szabadfi K, et al. Pituitary adenylate cyclase-activating polypeptide is protective against oxidative stress in human retinal pigment epithelial cells. J Mol Neurosci. 2011;43:35–43.

    Article  CAS  PubMed  Google Scholar 

  53. Fabian E, Reglodi D, Mester L, Szabo A, Szabadfi K, Tamas A, et al. Effects of PACAP on intracellular signaling pathways in human retinal pigment epithelial cells exposed to oxidative stress. J Mol Neurosci. 2012;48:493–500.

    Article  CAS  PubMed  Google Scholar 

  54. Ko JA, Hirata J, Yamane K, Sonoda KH, Kiuchi Y. Up-regulation of semaphorin 4A expression in human retinal pigment epithelial cells by PACAP released from cocultured neural cells. Cell Biochem Funct. 2015;33:29–36.

    Article  CAS  PubMed  Google Scholar 

  55. Scuderi S, D’Amico AG, Castorina A, Imbesi R, Carnazza ML, D’Agata V. Ameliorative effect of PACAP and VIP against increased permeability in a model of outer blood retinal barrier dysfunction. Peptides. 2013;39:119–24.

    Article  CAS  PubMed  Google Scholar 

  56. Wilhelm I, Fazakas C, Tamas A, Toth G, Reglodi D, Krizbai IA. PACAP enhances barrier properties of cerebral microvessels. J Mol Neurosci. 2014;54:469–76.

    Article  CAS  PubMed  Google Scholar 

  57. Szabadfi K, Atlasz T, Horvath G, Kiss P, Hamza L, Farkas J, et al. Early postnatal enriched environment decreases retinal degeneration induced by monosodium glutamate treatment. Brain Res. 2009;1259:107–12.

    Article  CAS  PubMed  Google Scholar 

  58. Babai N, Atlasz T, Tamas A, Reglodi D, Toth G, Kiss P, et al. Search for the optimal monosodium glutamate treatment schedule to study the neuroprotective effects of PACAP in the retina. Ann N Y Acad Sci. 2006;1070:149–55.

    Article  CAS  PubMed  Google Scholar 

  59. Babai N, Atlasz T, Tamas A, Reglodi D, Kiss P, Gabriel R. Degree of damage compensation by various PACAP treatments in monosodium glutamate-induced retina degeneration. Neurotox Res. 2005;8:227–33.

    Article  CAS  PubMed  Google Scholar 

  60. Atlasz T, Szabadfi K, Reglodi D, Kiss P, Tamas A, Toth G, et al. Effects of pituitary adenylate cyclase activating polypeptide (PACAP1-38) and its fragments on retinal degeneration induced by neonatal MSG treatment. Ann N Y Acad Sci. 2009;1163:348–52.

    Article  CAS  PubMed  Google Scholar 

  61. Tamas A, Gabriel R, Racz B, Denes V, Kiss P, Lubics A, et al. Effects of pituitary adenylate cyclase activating polypeptide in retinal degeneration induced by monosodium-glutamate. Neurosci Lett. 2004;372:110–3.

    Article  CAS  PubMed  Google Scholar 

  62. Kiss P, Tamas A, Lubics A, Lengvari I, Szalai M, Hauser D, et al. Effects of systemic PACAP treatment in monosodium glutamate-induced behavioral changes and retinal degeneration. Ann N Y Acad Sci. 2006;1070:365–70.

    Article  CAS  PubMed  Google Scholar 

  63. Kiss P, Atlasz T, Szabadfi K, Horvath G, Griecs M, Farkas J, et al. Comparison between PACAP- and enriched environment-induced retinal protection in MSG-treated newborn rats. Neurosci Lett. 2011;487:400–5.

    Article  CAS  PubMed  Google Scholar 

  64. Atlasz T, Szabadfi K, Kiss P, Babai N, Koszegi Z, Tamas A, et al. PACAP-mediated neuroprotection of neurochemically identified cell types in MSG-induced retinal regeneration. J Mol Neurosci. 2008;36:97–104.

    Article  CAS  PubMed  Google Scholar 

  65. Racz B, Tamas A, Kiss P, Toth G, Gasz B, Borsiczky B, et al. Involvement of ERK and CREB signaling pathways in the protective effect of PACAP in monosodium glutamate-induced retinal lesion. Ann N Y Acad Sci. 2006;1070:507–11.

    Article  CAS  PubMed  Google Scholar 

  66. Racz B, Gallyas Jr F, Kiss P, Toth G, Hegyi O, Gasz B, et al. The neuroprotective effects of PACAP in monosodium glutamate-induced retinal lesion involves inhibition of proapoptotic signaling pathways. Regul Pept. 2006;137:20–6.

    Article  CAS  PubMed  Google Scholar 

  67. Racz B, Gallyas Jr F, Kiss P, Tamas A, Lubics A, Lengvari I, et al. Effects of pituitary adenylate cyclase activating polypeptide (PACAP) on the PKA-Bad-14-3-3 signaling pathway in glutamate-induced retinal injury in neonatal rats. Neurotox Res. 2007;12:95–104.

    Article  CAS  PubMed  Google Scholar 

  68. Lakk M, Denes V, Gabriel R. Pituitary adenylate cyclase-activating polypeptide receptors signal via phospholipase C pathway to block apoptosis in newborn rat retina. Neurochem Res. 2015;40:1402–9.

    Article  CAS  PubMed  Google Scholar 

  69. Atlasz T, Balogh M, Werling D, Zhang Y, Reglodi D, Bloomfield S, et al. Pituitary adenylate cyclase-activating polypeptide (PACAP) prevents monosodium glutamate (MSG) induced functional disturbances in the mouse retina. Presented at 9th FENS Forum of Neuroscience July 5–9, 2014, Milan, Italy.

    Google Scholar 

  70. Zhang D, Sucher NJ, Lipton SA. Co-expression of AMPA/kainate receptor-operated channels with high and low Ca2+ permeability in single rat retinal ganglion cells. Neuroscience. 1995;67:177–88.

    Article  CAS  PubMed  Google Scholar 

  71. Atlasz T, Koszegi Z, Babai N, Tamas A, Reglodi D, Kovacs P, et al. Microiontophoretically applied PACAP blocks excitatory effects of kainic acid in vivo. Ann N Y Acad Sci. 2006;1070:143–8.

    Article  CAS  PubMed  Google Scholar 

  72. Teuchner B, Dimmer A, Humpel C, Amberger A, Fischer-Colbrie R, Nemeth J, et al. VIP, PACAP-38, BDNF and ADNP in NMDA-induced excitotoxicity in the rat retina. Acta Ophthalmol. 2011;89:670–5.

    Article  CAS  PubMed  Google Scholar 

  73. Cheng H, Ding Y, Yu R, Chen J, Wu C. Neuroprotection of a novel cyclopeptide C*HSDGIC* from the cyclization of PACAP (1-5) in cellular and rodent models of retinal ganglion cell apoptosis. PLoS One. 2014;9, e108090.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Wada Y, Nakamachi T, Endo K, Seki T, Ohtaki H, Tsuchikawa D, et al. PACAP attenuates NMDA-induced retinal damage in association wit modulation of the microglia/macrophage status into an acquired deactivation subtype. J Mol Neurosci. 2013;51:493–502.

    Article  CAS  PubMed  Google Scholar 

  75. Varga B, Szabadfi K, Kiss P, Fabian E, Tamas A, Griecs M, et al. PACAP improves functional outcome in excitotoxic retinal lesion: an electroretinographic study. J Mol Neurosci. 2011;43:44–50.

    Article  CAS  PubMed  Google Scholar 

  76. Atlasz T, Babai N, Kiss P, Reglodi D, Tamas A, Szabadfi K, et al. Pituitary adenylate cyclase activating polypeptide is protective in bilateral carotid occlusion-induced retinal lesion in rats. Gen Comp Endocrinol. 2007;153:108–14.

    Article  CAS  PubMed  Google Scholar 

  77. Mester L, Szabo A, Atlasz T, Szabadfi K, Reglodi D, Kiss P, et al. Protection against chronic hypoperfusion-induced retinal neurodegeneration by PARP inhibition via activation of PI3-kinase Akt pathway and suppression of JNK and p38 MAP kinases. Neurotox Res. 2009;16:68–76.

    Article  CAS  PubMed  Google Scholar 

  78. Szabadfi K, Mester L, Reglodi D, Kiss P, Babai N, Racz B, et al. Novel neuroprotective strategies in ischemic retinal lesions. Int J Mol Sci. 2010;11:544–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Seki T, Itoh H, Nakamachi T, Endo K, Wada Y, Nakamura K, et al. Suppression of rat retinal ganglion cell death by PACAP following transient ischemia induced by high intraocular pressure. J Mol Neurosci. 2011;43:30–4.

    Article  CAS  PubMed  Google Scholar 

  80. Szabadfi K, Danyadi B, Kiss P, Tamas A, Fabian E, Gabriel R, et al. Protective effects of vasoactive intestinal peptide (VIP) in ischemic retinal degeneration. J Mol Neurosci. 2012;48:501–7.

    Article  CAS  PubMed  Google Scholar 

  81. Werling D, Reglodi D, Kiss P, Toth G, Szabadfi K, Tamas A, et al. Investigation of PACAP fragments and related peptides in chronic retinal hypoperfusion. J Ophthalmol. 2014:563812.

    Google Scholar 

  82. Werling D, Kvarik T, Varga R, Nagy N, Mayer F, Vaczy A, et al. Investigating the retinoprotective effects of PACAP eye-drop in ischemic retinopathy. Presented at 12th International Symposium on VIP, PACAP and Related Peptides, September 21–26, 2015, Cappadocia, Turkey.

    Google Scholar 

  83. Szabo A, Danyadi B, Bognar E, Szabadfi K, Fabian E, Kiss P, et al. Effect of PACAP on MAP kinases, Akt and cytokine expressions in rat retinal hypoperfusion. Neurosci Lett. 2012;523:93–8.

    Article  CAS  PubMed  Google Scholar 

  84. Danyadi B, Szabadfi K, Reglodi D, Mihalik A, Danyadi T, Kovacs Zs, et al. PACAP application improves functional outcome of chronic retinal ischemic injury in rats—evidence from electroretinographic measurements. J Mol Neurosci. 2014;54:293–9.

    Article  CAS  PubMed  Google Scholar 

  85. D’Alessandro A, Cervia D, Catalani E, Gevi F, Zolla L, Casini G. Protective effects of the neuropeptides PACAP, substance P and the somatostatin analogue octreotide in retinal ischemia: a metabolomic analysis. Mol Biosyst. 2014;10:1290–304.

    Article  PubMed  CAS  Google Scholar 

  86. Cervia D, Casini G. The neuropeptide systems and their potential role in the treatment of mammalian retinal ischemia: a developing story. Curr Neuropharmacol. 2013;11:95–101.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Quigley HA, Nickells RW, Kerrigan LA, Pease ME, Thibault DJ, Zack DJ. Retinal ganglion cell death in experimental glaucoma and after axotomy occurs by apoptosis. Invest Ophthalmol Vis Sci. 1995;36:774–86.

    CAS  PubMed  Google Scholar 

  88. Seki T, Itoh H, Nakamachi T, Shioda S. Suppression of ganglion cell death by PACAP following optic nerve transection in the rat. J Mol Neurosci. 2008;36:57–60.

    Article  CAS  PubMed  Google Scholar 

  89. Atlasz T, Szabadfi K, Kiss P, Marton Z, Griecs M, Hamza L, et al. Effects of PACAP in UV-A radiation-induced retinal degeneration models in rats. J Mol Neurosci. 2011;43:51–7.

    Article  CAS  PubMed  Google Scholar 

  90. Atlasz T, Szabadfi K, Molnar A, Kiss P, Reglodi D, Marton ZS, et al. PACAP protects rat retina from UV-A radiation-induced degeneration. Presented at the Satellite Symposium of the 9th International Symposium on VIP, PACAP and Related Peptides, October 2–3, 2009, Yakushima, Japan.

    Google Scholar 

  91. Ding Y, Cheng H, Yu R, Tang C, Liu X, Chen J. Effects of cyclopeptide C*HSDGIC* from the cyclization of PACAP (1-5) on the proliferation and UVB-induced apoptosis of the retinal ganglion cell line RGC-5. Peptides. 2012;36:280–5.

    Article  CAS  PubMed  Google Scholar 

  92. Szabadfi K, Atlasz T, Kiss P, Reglodi D, Szabo A, Kovacs K, et al. Protective effects of the neuropeptide PACAP in diabetic retinopathy. Cell Tissue Res. 2012;348:37–46.

    Article  CAS  PubMed  Google Scholar 

  93. Szabadfi K, Szabo A, Kiss P, Reglodi D, Setalo Jr G, Kovacs K, et al. PACAP promotes neuron survival in early experimental diabetic retinopathy. Neurochem Int. 2014;64:84–91.

    Article  CAS  PubMed  Google Scholar 

  94. Szabadfi K, Reglodi D, Szabo A, Szalontai B, Valasek A, Setalo Gy Jr et al. Pituitary adenylate cyclase activating polypeptide, a potential therapeutic agent for diabetic retinopathy in rats: focus on the vertical information processing pathway. Neurotox Res. 2016;29:432–46.

    Google Scholar 

  95. D’Amico AG, Maugeri G, Reitano R, Bucolo C, Saccone S, Drago F, et al. PACAP modulates expression of hypoxia-inducible factors in streptozotocin-induced diabetic rat retina. J Mol Neurosci. 2015;57:501–9.

    Article  PubMed  CAS  Google Scholar 

  96. Gabriel R. Neuropeptides and diabetic retinopathy. Br J Clin Pharmacol. 2013;75:1189–201.

    Article  CAS  PubMed  Google Scholar 

  97. Marzagalli R, Scuderi S, Drago F, Waschek JA, Castorina A. Emerging role of PACAP as a new potential therapeutic target in major diabetes complications. Int J Endocrinol. 2015;2015:160928.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Szabadfi K, Pinter E, Reglodi D, Gabriel R. Neuropeptides, trophic factors, and other substances providing morphofunctional and metabolic protection in experimental models of diabetic retinopathy. Int Rev Cell Mol Biol. 2014;311:1–121.

    Article  CAS  PubMed  Google Scholar 

  99. Banki E, Degrell P, Kiss P, Kovacs K, Kemeny A, Csanaky K, et al. Effect of PACAP treatment on kidney morphology and cytokine expression in rat diabetic nephropathy. Peptides. 2013;42C:125–30.

    Article  CAS  Google Scholar 

  100. Banki E, Kovacs K, Nagy D, Juhasz T, Degrell P, Csanaky K, et al. Molecular mechanisms underlying the nephroprotective effects of PACAP in diabetes. J Mol Neurosci. 2014;54:300–9.

    Article  CAS  PubMed  Google Scholar 

  101. Ola MS, Ahmed MM, Ahmad R, Abuohashish HM, Al-Rejaie SS, Alhomida AS. Neuroprotective effects of rutin in streptozotocin-induced diabetic rat retina. J Mol Neurosci. 2015;56:440–8.

    Article  CAS  PubMed  Google Scholar 

  102. Scuderi S, D’Amico AG, Federico C, Saccone S, Magro G, Bucolo C, et al. Different retinal expression patterns of IL-1α, IL-1β, and their receptors in a rat model of type 1 STZ-induced diabetes. J Mol Neurosci. 2015;56:431–9.

    Article  CAS  PubMed  Google Scholar 

  103. Kvarik T, Mammel B, Reglodi D, Kovacs K, Werling D, Bede B, Vaczy A, Fabian E, Toth G, Kiss P, Tamas A, Ertl T, Gyarmati J, Atlasz T. PACAP is protective in a rat model of retinopathy of prematurity. J Mol Neurosci 2016 in press. DOI:10.1007/s12031-016-0797-5.

    Google Scholar 

  104. Szabadfi K, Kiss P, Reglodi D, Tamas A, Hashimoto H, Helyes ZS, et al. Neurochemical differences between wild type and PACAP KO mice in adult and aging retina. Presented at the 8th FENS Forum of Neuroscience, July 14–18, 2012, Barcelona, Spain.

    Google Scholar 

  105. Reglodi D, Kiss P, Szabadfi K, Atlasz T, Gabriel R, Horvath G, et al. PACAP is an endogenous protective factor—insights from PACAP deficient mice. J Mol Neurosci. 2012;48:482–92.

    Article  CAS  PubMed  Google Scholar 

  106. Szabadfi K, Atlasz T, Kiss P, Danyadi B, Tamas A, Helyes ZS, et al. Mice deficient in pituitary adenylate cyclase activating polypeptide (PACAP) are more susceptible to retinal ischemic injury in vivo. Neurotox Res. 2012;21:41–8.

    Article  CAS  PubMed  Google Scholar 

  107. Endo K, Nakamachi T, Seki T, Kagami N, Wada Y, Nakamura K, et al. Neuroprotective effect of PACAP against NMDA-induced retinal damage in the mouse. J Mol Neurosci. 2011;43:22–9.

    Article  CAS  PubMed  Google Scholar 

  108. Atlasz T, Váczy A, Kovács K, Lőkös E, Kvárik T, Werling D, et al. The protective role of the endogenous PACAP in LPS-induced inflammation in the retina. Presented at 12th International Symposium on VIP, PACAP and Related Peptides, September 21–26, 2015, Cappadocia, Turkey.

    Google Scholar 

  109. Engelund A, Fahrenkrug J, Harrison A, Luuk H, Hannibal J. Altered pupillary light reflex in PACAP receptor-1 deficient mice. Brain Res. 2012;1453:17–25.

    Article  CAS  PubMed  Google Scholar 

  110. Lang B, Zhao L, McKie L, Forrester JV, McCaig CD, Jackson IJ, et al. GABAergic amacrine cells and visual function are reduced in PAC1 transgenic mice. Neuropharmacology. 2010;58:215–25.

    Article  CAS  PubMed  Google Scholar 

  111. Brubel R, Boronkai A, Reglodi D, Racz B, Nemeth J, Kiss P, et al. Changes in the expression of pituitary adenylate cyclase activating polypeptide (PACAP) in the human placenta during pregnancy and its effects on survival of JAR choriocarcinoma cells. J Mol Neurosci. 2010;42:450–8.

    Article  CAS  PubMed  Google Scholar 

  112. Juhasz T, Helgadottir SL, Reglodi D, Tamas A, Zakany R. Signalisation of VIP and PACAP in chondrogenesis and osteogenesis. Peptides. 2015;66:51–7.

    Article  CAS  PubMed  Google Scholar 

  113. Saghy E, Payrits M, Helyes ZS, Reglodi D, Banki E, Toth G, et al. Stimulatory effect of pituitary adenylate-cyclase activating polypeptide 6-38, M65 and vasoactive intestinal polypeptide 6-28 on trigeminal sensory neurons. Neuroscience. 2015;308:144–56.

    Article  CAS  PubMed  Google Scholar 

  114. Olianas MC, Ennas MG, Lampis G, Onali P. Presence of pituitary adenylate cyclase-activating polypeptide receptors in Y-79 human retinoblastoma cells. J Neurochem. 1996;67:1803–9.

    Google Scholar 

  115. Wojcieszak J, Zawilska JB. PACAP38 and PACAP6-38 exert cytotoxic activity against human retinoblastoma Y79 cells. J Mol Neurosci. 2014;54:463–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This study was supported by OTKA K104984, 119759 Arimura Foundation, TAMOP 4.2.4.A/2-11-1-2012-0001 “National Excellence Program,” MTA-PTE “Lendulet” Program, Bolyai Scholarship of the Hungarian Academy of Sciences, PTE AOK KA Research Grant, National Brain Research Programme KTIA_13_NAP-A-III/5 and New National Excellence Program (UNKP). This work is dedicated to the 650th anniversary of the University of Pecs.

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  1. Department of Anatomy, MTA-PTE “Lendulet” PACAP Research Team, University of Pecs, Pecs, Hungary

    Tamas Atlasz, Alexandra Vaczy, Dora Werling, Peter Kiss, Andrea Tamas, Eszter Fabian, Timea Kvarik, Barbara Mammel, Bese Danyadi, Emese Lokos & Dora Reglodi

  2. Department of Sportbiology, University of Pecs, Pecs, Hungary

    Tamas Atlasz

  3. Janos Szentagothai Research Center, University of Pecs, Pecs, Hungary

    Tamas Atlasz

  4. Department of Biochemistry and Medical Chemistry, University of Pecs, Pecs, Hungary

    Krisztina Kovacs

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  1. Tamas Atlasz
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Correspondence to Tamas Atlasz .

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  1. Department of Anatomy MTA-PTE “Lendulet” PACAP Research Team, University of Pecs, Pecs, Hungary

    Dora Reglodi

  2. Department of Anatomy MTA-PTE “Lendulet” PACAP Research Team, University of Pecs, Pecs, Hungary

    Andrea Tamas

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Atlasz, T. et al. (2016). Protective Effects of PACAP in the Retina. In: Reglodi, D., Tamas, A. (eds) Pituitary Adenylate Cyclase Activating Polypeptide — PACAP. Current Topics in Neurotoxicity, vol 11. Springer, Cham. https://doi.org/10.1007/978-3-319-35135-3_30

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