Activation of Neuropeptide Y Receptors Modulates Retinal Ganglion Cell Physiology and Exerts Neuroprotective Actions In Vitro

João Martins; Filipe Elvas; Dan Brudzewsky; Tânia Martins; Bogdan Kolomiets; Pedro Tralhão; Casper R Gøtzsche; Cláudia Cavadas; Miguel Castelo-Branco; David P D Woldbye; Serge Picaud; Ana R Santiago; António F Ambrósio

doi:10.1177/1759091415598292

Activation of Neuropeptide Y Receptors Modulates Retinal Ganglion Cell Physiology and Exerts Neuroprotective Actions In Vitro

João Martins, Filipe Elvas, Dan Brudzewsky, Tânia Martins, Bogdan Kolomiets, Pedro Tralhão, Casper R Gøtzsche, Cláudia Cavadas, Miguel Castelo-Branco, David P D Woldbye, Serge Picaud, Ana R Santiago, António F Ambrósio

15 Citations (Scopus)

Abstract

Neuropeptide Y (NPY) is expressed in mammalian retina but the location and potential modulatory effects of NPY receptor activation remain largely unknown. Retinal ganglion cell (RGC) death is a hallmark of several retinal degenerative diseases, particularly glaucoma. Using purified RGCs and ex vivo rat retinal preparations, we have measured RGC intracellular free calcium concentration ([Ca^2þ]_i) and RGC spiking activity, respectively. We found that NPY attenuated the increase in the [Ca^2þ]_i triggered by glutamate mainly via Y₁ receptor activation. Moreover, (Leu³¹,Pro³⁴) NPY, a Y₁/Y₅ receptor agonist, increased the initial burst response of OFF-type RGCs, although no effect was observed on RGC spontaneous spiking activity. The Y₁ receptor activation was also able to directly modulate RGC responses by attenuating the NMDA-induced increase in RGC spiking activity. These results suggest that Y₁ receptor activation, at the level of inner or outer plexiform layers, leads to modulation of RGC receptive field properties. Using in vitro cultures of rat retinal explants exposed to NMDA, we found that NPY pretreatment prevented NMDA-induced cell death. However, in an animal model of retinal ischemia-reperfusion injury, pretreatment with NPY or (Leu³¹,Pro³⁴) NPY was not able to prevent apoptosis or rescue RGCs. In conclusion, we found modulatory effects of NPY application that for the first time were detected at the level of RGCs. However, further studies are needed to evaluate whether NPY neuroprotective actions detected in retinal explants can be translated into animal models of retinal degenerative diseases.

Original language	English
Journal	A S N Neuro
Volume	7
Issue number	4
Pages (from-to)	1-21
Number of pages	21
ISSN	1759-0914
DOIs	https://doi.org/10.1177/1759091415598292
Publication status	Published - 1 Jul 2015

Keywords

Animals
Animals, Newborn
Calcium
Cells, Cultured
Disease Models, Animal
Electroretinography
Gene Expression Regulation
Guanosine 5'-O-(3-Thiotriphosphate)
In Situ Nick-End Labeling
Male
Neuropeptide Y
Peptide Fragments
Protein Binding
RNA, Messenger
Rats
Rats, Long-Evans
Rats, Wistar
Receptors, Neuropeptide Y
Retinal Diseases
Retinal Ganglion Cells
Sulfur Isotopes
Transcription Factor Brn-3A

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Martins, J., Elvas, F., Brudzewsky, D., Martins, T., Kolomiets, B., Tralhão, P., Gøtzsche, C. R., Cavadas, C., Castelo-Branco, M., Woldbye, D. P. D., Picaud, S., Santiago, A. R., & Ambrósio, A. F. (2015). Activation of Neuropeptide Y Receptors Modulates Retinal Ganglion Cell Physiology and Exerts Neuroprotective Actions In Vitro. A S N Neuro, 7(4), 1-21. https://doi.org/10.1177/1759091415598292

Martins, J, Elvas, F, Brudzewsky, D, Martins, T, Kolomiets, B, Tralhão, P, Gøtzsche, CR, Cavadas, C, Castelo-Branco, M, Woldbye, DPD, Picaud, S, Santiago, AR & Ambrósio, AF 2015, 'Activation of Neuropeptide Y Receptors Modulates Retinal Ganglion Cell Physiology and Exerts Neuroprotective Actions In Vitro', A S N Neuro, vol. 7, no. 4, pp. 1-21. https://doi.org/10.1177/1759091415598292

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title = "Activation of Neuropeptide Y Receptors Modulates Retinal Ganglion Cell Physiology and Exerts Neuroprotective Actions In Vitro",

abstract = "Neuropeptide Y (NPY) is expressed in mammalian retina but the location and potential modulatory effects of NPY receptor activation remain largely unknown. Retinal ganglion cell (RGC) death is a hallmark of several retinal degenerative diseases, particularly glaucoma. Using purified RGCs and ex vivo rat retinal preparations, we have measured RGC intracellular free calcium concentration ([Ca2{\th}]i) and RGC spiking activity, respectively. We found that NPY attenuated the increase in the [Ca2{\th}]i triggered by glutamate mainly via Y1 receptor activation. Moreover, (Leu31,Pro34) NPY, a Y1/Y5 receptor agonist, increased the initial burst response of OFF-type RGCs, although no effect was observed on RGC spontaneous spiking activity. The Y1 receptor activation was also able to directly modulate RGC responses by attenuating the NMDA-induced increase in RGC spiking activity. These results suggest that Y1 receptor activation, at the level of inner or outer plexiform layers, leads to modulation of RGC receptive field properties. Using in vitro cultures of rat retinal explants exposed to NMDA, we found that NPY pretreatment prevented NMDA-induced cell death. However, in an animal model of retinal ischemia-reperfusion injury, pretreatment with NPY or (Leu31,Pro34) NPY was not able to prevent apoptosis or rescue RGCs. In conclusion, we found modulatory effects of NPY application that for the first time were detected at the level of RGCs. However, further studies are needed to evaluate whether NPY neuroprotective actions detected in retinal explants can be translated into animal models of retinal degenerative diseases.",

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author = "Jo{\~a}o Martins and Filipe Elvas and Dan Brudzewsky and T{\^a}nia Martins and Bogdan Kolomiets and Pedro Tralh{\~a}o and G{\o}tzsche, {Casper R} and Cl{\'a}udia Cavadas and Miguel Castelo-Branco and Woldbye, {David P D} and Serge Picaud and Santiago, {Ana R} and Ambr{\'o}sio, {Ant{\'o}nio F}",

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doi = "10.1177/1759091415598292",

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T1 - Activation of Neuropeptide Y Receptors Modulates Retinal Ganglion Cell Physiology and Exerts Neuroprotective Actions In Vitro

AU - Martins, João

AU - Elvas, Filipe

AU - Brudzewsky, Dan

AU - Martins, Tânia

AU - Kolomiets, Bogdan

AU - Tralhão, Pedro

AU - Gøtzsche, Casper R

AU - Cavadas, Cláudia

AU - Castelo-Branco, Miguel

AU - Woldbye, David P D

AU - Picaud, Serge

AU - Santiago, Ana R

AU - Ambrósio, António F

N1 - © The Author(s) 2015.

PY - 2015/7/1

Y1 - 2015/7/1

N2 - Neuropeptide Y (NPY) is expressed in mammalian retina but the location and potential modulatory effects of NPY receptor activation remain largely unknown. Retinal ganglion cell (RGC) death is a hallmark of several retinal degenerative diseases, particularly glaucoma. Using purified RGCs and ex vivo rat retinal preparations, we have measured RGC intracellular free calcium concentration ([Ca2þ]i) and RGC spiking activity, respectively. We found that NPY attenuated the increase in the [Ca2þ]i triggered by glutamate mainly via Y1 receptor activation. Moreover, (Leu31,Pro34) NPY, a Y1/Y5 receptor agonist, increased the initial burst response of OFF-type RGCs, although no effect was observed on RGC spontaneous spiking activity. The Y1 receptor activation was also able to directly modulate RGC responses by attenuating the NMDA-induced increase in RGC spiking activity. These results suggest that Y1 receptor activation, at the level of inner or outer plexiform layers, leads to modulation of RGC receptive field properties. Using in vitro cultures of rat retinal explants exposed to NMDA, we found that NPY pretreatment prevented NMDA-induced cell death. However, in an animal model of retinal ischemia-reperfusion injury, pretreatment with NPY or (Leu31,Pro34) NPY was not able to prevent apoptosis or rescue RGCs. In conclusion, we found modulatory effects of NPY application that for the first time were detected at the level of RGCs. However, further studies are needed to evaluate whether NPY neuroprotective actions detected in retinal explants can be translated into animal models of retinal degenerative diseases.

AB - Neuropeptide Y (NPY) is expressed in mammalian retina but the location and potential modulatory effects of NPY receptor activation remain largely unknown. Retinal ganglion cell (RGC) death is a hallmark of several retinal degenerative diseases, particularly glaucoma. Using purified RGCs and ex vivo rat retinal preparations, we have measured RGC intracellular free calcium concentration ([Ca2þ]i) and RGC spiking activity, respectively. We found that NPY attenuated the increase in the [Ca2þ]i triggered by glutamate mainly via Y1 receptor activation. Moreover, (Leu31,Pro34) NPY, a Y1/Y5 receptor agonist, increased the initial burst response of OFF-type RGCs, although no effect was observed on RGC spontaneous spiking activity. The Y1 receptor activation was also able to directly modulate RGC responses by attenuating the NMDA-induced increase in RGC spiking activity. These results suggest that Y1 receptor activation, at the level of inner or outer plexiform layers, leads to modulation of RGC receptive field properties. Using in vitro cultures of rat retinal explants exposed to NMDA, we found that NPY pretreatment prevented NMDA-induced cell death. However, in an animal model of retinal ischemia-reperfusion injury, pretreatment with NPY or (Leu31,Pro34) NPY was not able to prevent apoptosis or rescue RGCs. In conclusion, we found modulatory effects of NPY application that for the first time were detected at the level of RGCs. However, further studies are needed to evaluate whether NPY neuroprotective actions detected in retinal explants can be translated into animal models of retinal degenerative diseases.

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KW - Animals, Newborn

KW - Calcium

KW - Cells, Cultured

KW - Disease Models, Animal

KW - Electroretinography

KW - Gene Expression Regulation

KW - Guanosine 5'-O-(3-Thiotriphosphate)

KW - In Situ Nick-End Labeling

KW - Male

KW - Neuropeptide Y

KW - Peptide Fragments

KW - Protein Binding

KW - RNA, Messenger

KW - Rats

KW - Rats, Long-Evans

KW - Rats, Wistar

KW - Receptors, Neuropeptide Y

KW - Retinal Diseases

KW - Retinal Ganglion Cells

KW - Sulfur Isotopes

KW - Transcription Factor Brn-3A

U2 - 10.1177/1759091415598292

DO - 10.1177/1759091415598292

M3 - Journal article

C2 - 26311075

SN - 1759-0914

VL - 7

SP - 1

EP - 21

JO - A S N Neuro

JF - A S N Neuro

IS - 4

ER -

Activation of Neuropeptide Y Receptors Modulates Retinal Ganglion Cell Physiology and Exerts Neuroprotective Actions In Vitro

Abstract

Keywords

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