The glial cell modulator ibudilast attenuates neuroinflammation and enhances retinal ganglion cell viability in glaucoma through protein kinase A signaling
Glaucoma is a neurodegenerative disease and the leading cause of irreversible blindness worldwide. Vision deficits in glaucoma result from the selective loss of retinal ganglion cells (RGC). Glial cell-mediated neuroinflammation has been proposed to contribute to disease pathophysiology, but whether...
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doaj-dfd113d9d3af4649a96a721bf43d51cd2021-03-22T12:44:22ZengElsevierNeurobiology of Disease1095-953X2016-09-0193156171The glial cell modulator ibudilast attenuates neuroinflammation and enhances retinal ganglion cell viability in glaucoma through protein kinase A signalingJorge L. Cueva Vargas0Nicolas Belforte1Adriana Di Polo2Department of Neuroscience and Centre de recherche de l‘Université de Montréal (CRCHUM), University of Montreal, Montreal, Quebec H2X 0A9, CanadaDepartment of Neuroscience and Centre de recherche de l‘Université de Montréal (CRCHUM), University of Montreal, Montreal, Quebec H2X 0A9, CanadaCorresponding author at: Department of Neuroscience, University of Montreal, CRCHUM, 900 rue Saint-Denis, Tour Viger, Room R09.720, Montreal, Quebec H2X 0A9, Canada.; Department of Neuroscience and Centre de recherche de l‘Université de Montréal (CRCHUM), University of Montreal, Montreal, Quebec H2X 0A9, CanadaGlaucoma is a neurodegenerative disease and the leading cause of irreversible blindness worldwide. Vision deficits in glaucoma result from the selective loss of retinal ganglion cells (RGC). Glial cell-mediated neuroinflammation has been proposed to contribute to disease pathophysiology, but whether this response is harmful or beneficial for RGC survival is not well understood. To test this, we characterized the role of ibudilast, a clinically approved cAMP phosphodiesterase (PDE) inhibitor with preferential affinity for PDE type 4 (PDE4). Here, we demonstrate that intraocular administration of ibudilast dampened macroglia and microglia reactivity in the retina and optic nerve hence decreasing production of proinflammatory cytokines in a rat model of ocular hypertension. Importantly, ibudilast promoted robust RGC soma survival, prevented axonal degeneration, and improved anterograde axonal transport in glaucomatous eyes without altering intraocular pressure. Intriguingly, ocular hypertension triggered upregulation of PDE4 subtype A in Müller glia, and ibudilast stimulated cAMP accumulation in these cells. Co-administration of ibudilast with Rp-cAMPS, a cell-permeable and non-hydrolysable cAMP analog that inhibits protein kinase A (PKA), completely blocked ibudilast-induced neuroprotection. Collectively, these data demonstrate that ibudilast, a safe and well-tolerated glial cell modulator, attenuates gliosis, decreases levels of proinflammatory mediators, and enhances neuronal viability in glaucoma through activation of the cAMP/PKA pathway. This study provides insight into PDE4 signaling as a potential target to counter the harmful effects associated with chronic gliosis and neuroinflammation in glaucoma.http://www.sciencedirect.com/science/article/pii/S0969996116300936GliosisNeurodegenerationcAMP Phosphodiesterase inhibitorOptic nerveOcular hypertension |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Jorge L. Cueva Vargas Nicolas Belforte Adriana Di Polo |
spellingShingle |
Jorge L. Cueva Vargas Nicolas Belforte Adriana Di Polo The glial cell modulator ibudilast attenuates neuroinflammation and enhances retinal ganglion cell viability in glaucoma through protein kinase A signaling Neurobiology of Disease Gliosis Neurodegeneration cAMP Phosphodiesterase inhibitor Optic nerve Ocular hypertension |
author_facet |
Jorge L. Cueva Vargas Nicolas Belforte Adriana Di Polo |
author_sort |
Jorge L. Cueva Vargas |
title |
The glial cell modulator ibudilast attenuates neuroinflammation and enhances retinal ganglion cell viability in glaucoma through protein kinase A signaling |
title_short |
The glial cell modulator ibudilast attenuates neuroinflammation and enhances retinal ganglion cell viability in glaucoma through protein kinase A signaling |
title_full |
The glial cell modulator ibudilast attenuates neuroinflammation and enhances retinal ganglion cell viability in glaucoma through protein kinase A signaling |
title_fullStr |
The glial cell modulator ibudilast attenuates neuroinflammation and enhances retinal ganglion cell viability in glaucoma through protein kinase A signaling |
title_full_unstemmed |
The glial cell modulator ibudilast attenuates neuroinflammation and enhances retinal ganglion cell viability in glaucoma through protein kinase A signaling |
title_sort |
glial cell modulator ibudilast attenuates neuroinflammation and enhances retinal ganglion cell viability in glaucoma through protein kinase a signaling |
publisher |
Elsevier |
series |
Neurobiology of Disease |
issn |
1095-953X |
publishDate |
2016-09-01 |
description |
Glaucoma is a neurodegenerative disease and the leading cause of irreversible blindness worldwide. Vision deficits in glaucoma result from the selective loss of retinal ganglion cells (RGC). Glial cell-mediated neuroinflammation has been proposed to contribute to disease pathophysiology, but whether this response is harmful or beneficial for RGC survival is not well understood. To test this, we characterized the role of ibudilast, a clinically approved cAMP phosphodiesterase (PDE) inhibitor with preferential affinity for PDE type 4 (PDE4). Here, we demonstrate that intraocular administration of ibudilast dampened macroglia and microglia reactivity in the retina and optic nerve hence decreasing production of proinflammatory cytokines in a rat model of ocular hypertension. Importantly, ibudilast promoted robust RGC soma survival, prevented axonal degeneration, and improved anterograde axonal transport in glaucomatous eyes without altering intraocular pressure. Intriguingly, ocular hypertension triggered upregulation of PDE4 subtype A in Müller glia, and ibudilast stimulated cAMP accumulation in these cells. Co-administration of ibudilast with Rp-cAMPS, a cell-permeable and non-hydrolysable cAMP analog that inhibits protein kinase A (PKA), completely blocked ibudilast-induced neuroprotection. Collectively, these data demonstrate that ibudilast, a safe and well-tolerated glial cell modulator, attenuates gliosis, decreases levels of proinflammatory mediators, and enhances neuronal viability in glaucoma through activation of the cAMP/PKA pathway. This study provides insight into PDE4 signaling as a potential target to counter the harmful effects associated with chronic gliosis and neuroinflammation in glaucoma. |
topic |
Gliosis Neurodegeneration cAMP Phosphodiesterase inhibitor Optic nerve Ocular hypertension |
url |
http://www.sciencedirect.com/science/article/pii/S0969996116300936 |
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