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PACAP Is Protective in a Rat Model of Retinopathy of Prematurity

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Abstract

The oxygen-induced retinopathy (OIR) is a well-established rodent model of retinopathy of prematurity (ROP), which is one of the most common causes of childhood visual impairment affecting preterm babies. Pituitary adenylate cyclase-activating polypeptide (PACAP) is known to have neuroprotective effects. Several studies have revealed the presence of PACAP and its receptors in the retina and reported its protective effects in ischemic and diabetic retinopathy. In this study, we investigated whether PACAP administration can influence the vascular changes in the rat OIR model. OIR was generated by placing the animals in daily alternating 10/50 oxygen concentrations from postnatal day (PD) 0 to PD14 then returned them to room air. Meanwhile, animals received PACAP or saline intraperitoneally or intravitreally from PD1 to PD8 or on PD11, PD14, and PD17, respectively. On PD19 ± 1, the retinas were isolated and the vessels were visualized by isolectin staining. The percentage of avascular to whole retinal areas and the number of branching points were measured. Change in cytokine expression was also determined. Intravitreal treatment with PACAP remarkably reduced the extent of avascular area compared to the non- and saline-treated OIR groups. Intraperitoneal PACAP injection did not influence the vascular extent. Retinal images of room-air controls did not show vascular alterations. No changes in the number of vessel branching were observed after treatments. Alterations in cytokine profile after local PACAP injection further supported the protective role of the peptide. This is the first study to examine the effects of PACAP in ROP. Although the exact mechanism is still not revealed, the present results show that PACAP treatment can ameliorate the vascular changes in the animal model of ROP.

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References

  • Atlasz T, Babai N, Kiss P, et al. (2007) Pituitary adenylate cyclase activating polypeptide is protective in bilateral carotid occlusion-induced retinal lesion in rats. Gen Comp Endocrinol 153:108–114

    Article  CAS  PubMed  Google Scholar 

  • Atlasz T, Szabadfi K, Kiss P, et al. (2010) Pituitary adenylate cyclase activating polypeptide in the retina: focus on the retinoprotective effects. Ann N Y Acad Sci 1200:128–139

    Article  CAS  PubMed  Google Scholar 

  • Atlasz T, Szabadfi K, Kiss P, et al. (2011) Effects of PACAP in UV-A radiation-induced retinal degeneration models in rats. J Mol Neurosci 43:51–57

    Article  CAS  PubMed  Google Scholar 

  • Atlasz T, Vaczy A, Werling D, et al. (2016) Neuroprotective effects of PACAP in the retina. In: Reglodi D, Tamas A (eds) Pituitary adenylate cyclase activating polypeptide—PACAP. Springer Nature, New York in press

    Google Scholar 

  • Babai N, Atlasz T, Tamas A, et al. (2005) Degree of damage compensation by various PACAP treatments in monosodium glutamate-induced retina degeneration. Neurotox Res 8:227–233

    Article  CAS  PubMed  Google Scholar 

  • Beharry KD, Valencia GB, Lazarro DR, Aranda JV (2016) Pharmacologic interventions for the prevention and treatment of retinopathy of prematurity. Semin Perinatol 40:189–202

    Article  PubMed  Google Scholar 

  • Borba JC, Henze IP, Silveira MS, et al. (2005) 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 156:193–201

    Article  CAS  Google Scholar 

  • Cheng H, Ding Y, Yu R, Chen J, Wu C (2014) 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 9:e108090

    Article  PubMed  PubMed Central  Google Scholar 

  • Clason TA, Girard BM, May V, Parsons RL (2016) Activation of MEK/ERK signaling by PACAP in guinea pig cardiac neurons. J Mol Neurosci 59:309–316

    Article  CAS  PubMed  Google Scholar 

  • Connor KM, Krah NM, Dennison RJ, et al. (2009) Quantification of oxygen-induced retinopathy in the mouse: a model of vessel loss, vessel regrowth and pathological angiogenesis. Nat Protoc 4:1565–1573

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Coorey NJ, Shen W, Chung SH, Zhu L, Gillies MC (2012) The role of glia in retinal vascular disease. Clin Exp Optom 95:266–281

    Article  PubMed  Google Scholar 

  • Csanaky K, Doppler W, Tamas A, Kovacs K, Toth G, Reglodi D (2014) Influence of terminal differentiation and PACAP on the cytokine, chemokine and growth factor secretion of mammary epithelial cells. J Mol Neurosci 52:28–36

    Article  CAS  PubMed  Google Scholar 

  • D'Amico AG, Maugeri G, Reitano R, et al. (2015) PACAP modulates expression of hypoxia-inducible factors in streptozotocin-induced diabetic rat retina. J Mol Neurosci 57:501–509

    Article  PubMed  Google Scholar 

  • Danyadi B, Szabadfi K, Reglodi D, et al. (2014) PACAP application improves functional outcome of chronic retinal ischemic injury in rats—evidence from electroretinographic measurements. J Mol Neurosci 54:293–299

    Article  CAS  PubMed  Google Scholar 

  • Denes V, Czotter N, Lakk M, Berta G, Gabriel R (2014) PAC1-expressing structures of neural retina alter their PAC1 isoform splicing during postnatal development. Cell Tissue Res 355:279–288

    Article  CAS  PubMed  Google Scholar 

  • DeNiro M, Al-Mohanna FH, Al-Mohanna FA (2011) Inhibition of reactive gliosis prevents neovascular growth in the mouse model of oxygen-induced retinopathy. PLoS One 6:e222244

    Article  Google Scholar 

  • Endo K, Nakamachi T, Seki T, et al. (2011) Neuroprotective effect of PACAP against NMDA-induced retinal damage in the mouse. J Mol Neurosci 43:22–29

    Article  CAS  PubMed  Google Scholar 

  • Fruttiger M (2007) Development of retinal vasculature. Angiogenesis 10:77–88

    Article  PubMed  Google Scholar 

  • Fulton AB, Hansen RM, Moskowitz A, Akula JD (2009) The neurovascular retina in retinopathy of prematurity. Prog Retin Eye Res 28:452–482

    Article  PubMed  PubMed Central  Google Scholar 

  • Girard BM, Malley SE, Mathews MM, May V, Vizzard MA (2016) Intravesical PAC1 receptor antagonist, PACAP(6-38), reduces urinary bladder frequency and pelvic sensitivity in NGF-OE mice. J Mol Neurosci 59:290–299

    Article  CAS  PubMed  Google Scholar 

  • Hellström A, Smith LE, Dammann O (2013) Retinopathy of prematurity. Lancet 26:1445–1457

  • Horvath G, Reglodi D, Brubel R, et al. (2014) Investigation of possible functions of PACAP in human trophoblast cells. J Mol Neurosci 54:320–330

    Article  CAS  PubMed  Google Scholar 

  • Ismail JA, Poppa V, Kemper LE, et al. (2003) Immunohistologic labeling of murine endothelium. Cardiovasc Pathol 12:82–90

    Article  PubMed  Google Scholar 

  • Kiss P, Atlasz T, Szabadfi K, et al. (2011) Comparison between PACAP- and enriched environment-induced retinal protection in MSG-treated newborn rats. Neurosci Lett 487:400–405

    Article  CAS  PubMed  Google Scholar 

  • Lang B, Zhao L, McKie L, et al. (2010) GABAergic amacrine cells and visual function are reduced in PAC1 transgenic mice. Neuropharmacology 58:215–225

    Article  CAS  PubMed  Google Scholar 

  • Matsumoto M, Nakamachi T, Watanabe J, et al. (2016) Pituitary adenylate cyclase-activating polypeptide (PACAP) is involved in adult mouse hippocampal neurogenesis after stroke. J Mol Neurosci 59:270–279

    Article  CAS  PubMed  Google Scholar 

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

    CAS  Google Scholar 

  • Njaine B, Martins RA, Santiago MF, Linden R, Silveira MS (2010) Pituitary adenylyl cyclase-activating polypeptide controls the proliferation of retinal progenitor cells through downregulation of cyclin D1. Eur J Neurosci 32:311–321

    Article  PubMed  Google Scholar 

  • Njaine B, Rocha-Martins M, Vieira-Vieira CH, et al. (2014) Pleiotropic functions of pituitary adenylyl cyclase-activating polypeptide on the retinal ontogenesis: involvement of KLF4 in the control of progenitor cell proliferation. J Mol Neurosci 54:430–442

    Article  CAS  PubMed  Google Scholar 

  • Penn JS, Henry MM, Tolman BL (1994) Exposure to alternating hypoxia and hyperoxia causes severe proliferative retinopathy in the newborn rat. Pediatr Res 36:724–731

    Article  CAS  PubMed  Google Scholar 

  • Racz B, Gallyas F Jr, Kiss P, et al. (2006) The neuroprotective effects of PACAP in monosodium glutamate-induced retinal lesion involves inhibition of proapoptotic signaling pathways. Regul Pept 37:20–26

    Article  Google Scholar 

  • Reglodi D, Renaud J, Tamas A, et al. (2015) Novel tactics for neuroprotection in Parkinson’s disease: role of antibiotics, polyphenols and neuropeptides. Prog Neurobiol. doi:10.1016/j.pneurobio.2015.10.004

  • Seki T, Shioda S, Ogino D, Nakai Y, Arimura A, Koide R (1997) Distribution and ultrastructural localization of a receptor for pituitary adenylate cyclase activating polypeptide and its mRNA in the rat retina. Neurosci Lett 238:127–130

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Seki T, Itoh H, Nakamachi T, et al. (2011) Suppression of rat retinal ganglion cell death by PACAP following transient ischemia induced by high intraocular pressure. J Mol Neurosci 43:30–34

    Article  CAS  PubMed  Google Scholar 

  • Shioda S, Nakamachi T (2015) PACAP as a neuroprotective factor in ischemic neuronal injuries. Peptides 72:202–207

    Article  CAS  PubMed  Google Scholar 

  • Somogyvari-Vigh A, Reglodi D (2004) Pituitary adenylate cyclase activating polypeptide: a potential neuroprotective peptide. Review. Curr Pharm Des 10:2861–2889

    Article  CAS  PubMed  Google Scholar 

  • Szabadfi K, Szabo A, Kiss P, et al. (2014) PACAP promotes neuron survival in early experimental diabetic retinopathy. Neurochem Int 64:84–91

    Article  CAS  PubMed  Google Scholar 

  • Szabadfi K, Reglodi D, Szabo A, et al. (2016) Pituitary adenylate cyclase activating polypeptide, a potential therapeutic agent for diabetic retinopathy in rats: focus on the vertical information processing pathway. Neurotox Res 29:432–446

    Article  CAS  PubMed  Google Scholar 

  • Szabo A, Danyadi B, Bognar E, et al. (2012) Effect of PACAP on MAP kinases, Akt and cytokine expressions in rat retinal hypoperfusion. Neurosci Lett 523:93–98

    Article  CAS  PubMed  Google Scholar 

  • Varga B, Szabadfi K, Kiss P, et al. (2011) PACAP improves functional outcome in excitotoxic retinal lesion: an electroretinographic study. J Mol Neurosci 43:44–50

    Article  CAS  PubMed  Google Scholar 

  • Vaudry D, Falluel-Morel A, Bourgault S, et al. (2009) Pituitary adenylate cyclase activating polypeptide and its receptors: 20 years after the discovery. Pharmacol Rev 61:283–357

    Article  CAS  PubMed  Google Scholar 

  • Wada Y, Nakamachi T, Endo K, et al. (2013) PACAP attenuates NMDA-induced retinal damage in association with modulation of the microglia/macrophage status into an acquired deactivation subtype. J Mol Neurosci 51:493–502

    Article  CAS  PubMed  Google Scholar 

  • Werling D, Reglodi D, Kiss P, et al. (2014) Investigation of PACAP fragments and related peptides in chronic retinal hypoperfusion. J Ophthalmol 2014:563812

    Article  PubMed  PubMed Central  Google Scholar 

  • Yan Y, Zhou X, Pan Z, Ma J, Waschek JA, DiCicco-Bloom E (2013) Pro- and anti-mitogenic actions of pituitary adenylate cyclase-activating polypeptide in developing cerebral cortex: potential mediation by developmental switch of PAC1 receptor mRNA isoforms. J Neurosci 33:3865–3878

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This study was supported by OTKA K104984, OTKA PD109644, Arimura Foundation, Bolyai Scholarship of the Hungarian Academy of Sciences, PTE AOK Research Grant, National Brain Research Program KTIA_13_NAP-A-III/5, New National Excellence Program.

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Authors and Affiliations

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

    Timea Kvarik, Barbara Mammel, Dora Reglodi, Dora Werling, Brigitta Bede, Alexandra Vaczy, Eszter Fabian, Peter Kiss, Andrea Tamas & Tamas Atlasz

  2. Department of Obstetrics and Gynecology, University of Pecs, Pecs, Hungary

    Timea Kvarik, Barbara Mammel, Tibor Ertl & Judit Gyarmati

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

    Krisztina Kovacs

  4. Department of Medical Chemistry, University of Szeged, Szeged, Hungary

    Gabor Toth

  5. Department of Sportbiology, University of Pecs, Ifjusag utja 6, Pecs, 7624, Hungary

    Tamas Atlasz

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

    Tamas Atlasz

Authors
  1. Timea Kvarik
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  2. Barbara Mammel
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  3. Dora Reglodi
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  4. Krisztina Kovacs
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  5. Dora Werling
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  6. Brigitta Bede
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  7. Alexandra Vaczy
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  8. Eszter Fabian
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  9. Gabor Toth
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  10. Peter Kiss
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  11. Andrea Tamas
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  12. Tibor Ertl
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  13. Judit Gyarmati
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  14. Tamas Atlasz
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Corresponding author

Correspondence to Tamas Atlasz.

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Animal housing and care and application of experimental procedures were in accordance with institutional guidelines under approved protocols (No: BA02/2000–15024/2011, University of Pecs following the European Community Council directive).

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Kvarik, T., Mammel, B., Reglodi, D. et al. PACAP Is Protective in a Rat Model of Retinopathy of Prematurity. J Mol Neurosci 60, 179–185 (2016). https://doi.org/10.1007/s12031-016-0797-5

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  • DOI: https://doi.org/10.1007/s12031-016-0797-5

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