Ocular delivery of PACAP1-27 protects the retina from ischemic damage in rodents

Dora Werling, Dora Reglodi, William A. Banks, Therese S. Salameh, Krisztina Kovacs, Timea Kvarik, Alexandra Vaczy, Laszlo Kovacs, Flora Mayer, Bese Danyadi, Emese Lokos, A. Tamás, G. Tóth, Zsolt Biro, Tamas Atlasz

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

PURPOSE. Pituitary adenylate cyclase activating polypeptide (PACAP) is neuroprotective in neuronal injuries. Bilateral common carotid artery occlusion (BCCAO) causes chronic hypoperfusion-induced degeneration in the rat retina, where we proved the retinoprotective effect of intravitreal PACAP. Although this route of administration is a common clinical practice in several diseases, easier routes are clinically important. Our aim was to investigate the potential retinoprotective effects of PACAP eye drops in BCCAO-induced ischemic retinopathy. METHODS. After performing BCCAO in rats, the right eyes were treated with PACAP1-27 eye drops (1 μg/drop, 2 × 1 drops/day for 5 days), containing different vehicles: saline, water for injections, thiomersal or benzalkonium solution for ophthalmic use (SOCB). Histology and immunohistochemistry were performed 2 weeks after surgery, while molecular analysis was performed 24 hours after BCCAO. Passage of PACAP1-27 through the ocular layers was tested with radioactive PACAP-SOCB in mice. RESULTS. Bilateral common carotid artery occlusion led to a severe degeneration of all retinal layers. Solution for ophthalmic use was the most effective vehicle for delivering PACAP (PACAP-SOCB), significantly ameliorating BCCAO-induced damage. The massive upregulation of GFAP was not observed in retinas treated with PACAP-SOCB eye drops. PACAP-SOCB treatment also increased activation of the protective Akt and ERK1/2 in hypoperfused retinas. The cytokine profile showing upregulation in different cytokines was attenuated by PACAPSOCB. Radioactive PACAP reached the retina when delivered in SOCB-containing eye drops. CONCLUSIONS. PACAP1-27, delivered in the SOCB vehicle as eye drops, was retinoprotective in ischemic retinopathy, providing the basis for future therapeutic administration.

Original languageEnglish
Pages (from-to)6683-6691
Number of pages9
JournalInvestigative Ophthalmology and Visual Science
Volume57
Issue number15
DOIs
Publication statusPublished - Dec 1 2016

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Pituitary Adenylate Cyclase-Activating Polypeptide
Ophthalmic Solutions
Retina
Rodentia
Common Carotid Artery
Up-Regulation
Thimerosal
Cytokines
Benzalkonium Compounds
Retinal Degeneration
Histology
Immunohistochemistry
Injections

Keywords

  • Eye drops
  • Ischemia
  • Neuropeptide
  • Retina

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

Werling, D., Reglodi, D., Banks, W. A., Salameh, T. S., Kovacs, K., Kvarik, T., ... Atlasz, T. (2016). Ocular delivery of PACAP1-27 protects the retina from ischemic damage in rodents. Investigative Ophthalmology and Visual Science, 57(15), 6683-6691. https://doi.org/10.1167/iovs.16-20630

Ocular delivery of PACAP1-27 protects the retina from ischemic damage in rodents. / Werling, Dora; Reglodi, Dora; Banks, William A.; Salameh, Therese S.; Kovacs, Krisztina; Kvarik, Timea; Vaczy, Alexandra; Kovacs, Laszlo; Mayer, Flora; Danyadi, Bese; Lokos, Emese; Tamás, A.; Tóth, G.; Biro, Zsolt; Atlasz, Tamas.

In: Investigative Ophthalmology and Visual Science, Vol. 57, No. 15, 01.12.2016, p. 6683-6691.

Research output: Contribution to journalArticle

Werling, D, Reglodi, D, Banks, WA, Salameh, TS, Kovacs, K, Kvarik, T, Vaczy, A, Kovacs, L, Mayer, F, Danyadi, B, Lokos, E, Tamás, A, Tóth, G, Biro, Z & Atlasz, T 2016, 'Ocular delivery of PACAP1-27 protects the retina from ischemic damage in rodents', Investigative Ophthalmology and Visual Science, vol. 57, no. 15, pp. 6683-6691. https://doi.org/10.1167/iovs.16-20630
Werling, Dora ; Reglodi, Dora ; Banks, William A. ; Salameh, Therese S. ; Kovacs, Krisztina ; Kvarik, Timea ; Vaczy, Alexandra ; Kovacs, Laszlo ; Mayer, Flora ; Danyadi, Bese ; Lokos, Emese ; Tamás, A. ; Tóth, G. ; Biro, Zsolt ; Atlasz, Tamas. / Ocular delivery of PACAP1-27 protects the retina from ischemic damage in rodents. In: Investigative Ophthalmology and Visual Science. 2016 ; Vol. 57, No. 15. pp. 6683-6691.
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AU - Werling, Dora

AU - Reglodi, Dora

AU - Banks, William A.

AU - Salameh, Therese S.

AU - Kovacs, Krisztina

AU - Kvarik, Timea

AU - Vaczy, Alexandra

AU - Kovacs, Laszlo

AU - Mayer, Flora

AU - Danyadi, Bese

AU - Lokos, Emese

AU - Tamás, A.

AU - Tóth, G.

AU - Biro, Zsolt

AU - Atlasz, Tamas

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N2 - PURPOSE. Pituitary adenylate cyclase activating polypeptide (PACAP) is neuroprotective in neuronal injuries. Bilateral common carotid artery occlusion (BCCAO) causes chronic hypoperfusion-induced degeneration in the rat retina, where we proved the retinoprotective effect of intravitreal PACAP. Although this route of administration is a common clinical practice in several diseases, easier routes are clinically important. Our aim was to investigate the potential retinoprotective effects of PACAP eye drops in BCCAO-induced ischemic retinopathy. METHODS. After performing BCCAO in rats, the right eyes were treated with PACAP1-27 eye drops (1 μg/drop, 2 × 1 drops/day for 5 days), containing different vehicles: saline, water for injections, thiomersal or benzalkonium solution for ophthalmic use (SOCB). Histology and immunohistochemistry were performed 2 weeks after surgery, while molecular analysis was performed 24 hours after BCCAO. Passage of PACAP1-27 through the ocular layers was tested with radioactive PACAP-SOCB in mice. RESULTS. Bilateral common carotid artery occlusion led to a severe degeneration of all retinal layers. Solution for ophthalmic use was the most effective vehicle for delivering PACAP (PACAP-SOCB), significantly ameliorating BCCAO-induced damage. The massive upregulation of GFAP was not observed in retinas treated with PACAP-SOCB eye drops. PACAP-SOCB treatment also increased activation of the protective Akt and ERK1/2 in hypoperfused retinas. The cytokine profile showing upregulation in different cytokines was attenuated by PACAPSOCB. Radioactive PACAP reached the retina when delivered in SOCB-containing eye drops. CONCLUSIONS. PACAP1-27, delivered in the SOCB vehicle as eye drops, was retinoprotective in ischemic retinopathy, providing the basis for future therapeutic administration.

AB - PURPOSE. Pituitary adenylate cyclase activating polypeptide (PACAP) is neuroprotective in neuronal injuries. Bilateral common carotid artery occlusion (BCCAO) causes chronic hypoperfusion-induced degeneration in the rat retina, where we proved the retinoprotective effect of intravitreal PACAP. Although this route of administration is a common clinical practice in several diseases, easier routes are clinically important. Our aim was to investigate the potential retinoprotective effects of PACAP eye drops in BCCAO-induced ischemic retinopathy. METHODS. After performing BCCAO in rats, the right eyes were treated with PACAP1-27 eye drops (1 μg/drop, 2 × 1 drops/day for 5 days), containing different vehicles: saline, water for injections, thiomersal or benzalkonium solution for ophthalmic use (SOCB). Histology and immunohistochemistry were performed 2 weeks after surgery, while molecular analysis was performed 24 hours after BCCAO. Passage of PACAP1-27 through the ocular layers was tested with radioactive PACAP-SOCB in mice. RESULTS. Bilateral common carotid artery occlusion led to a severe degeneration of all retinal layers. Solution for ophthalmic use was the most effective vehicle for delivering PACAP (PACAP-SOCB), significantly ameliorating BCCAO-induced damage. The massive upregulation of GFAP was not observed in retinas treated with PACAP-SOCB eye drops. PACAP-SOCB treatment also increased activation of the protective Akt and ERK1/2 in hypoperfused retinas. The cytokine profile showing upregulation in different cytokines was attenuated by PACAPSOCB. Radioactive PACAP reached the retina when delivered in SOCB-containing eye drops. CONCLUSIONS. PACAP1-27, delivered in the SOCB vehicle as eye drops, was retinoprotective in ischemic retinopathy, providing the basis for future therapeutic administration.

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KW - Ischemia

KW - Neuropeptide

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