title: The glial cell modulator ibudilast attenuates neuroinflammation and enhances retinal ganglion cell viability in glaucoma through protein kinase A signaling.
abstract: 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.
authors.affiliation: Department of Neuroscience and Centre de recherche de l'Université de Montréal (CRCHUM), University of Montreal, Montreal, Quebec H2X 0A9, Canada.
authors.forename: Jorge L
authors.initials: JL
authors.lastname: Cueva Vargas
authors.affiliation: Department of Neuroscience and Centre de recherche de l'Université de Montréal (CRCHUM), University of Montreal, Montreal, Quebec H2X 0A9, Canada.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Belforte
authors.affiliation: Department of Neuroscience and Centre de recherche de l'Université de Montréal (CRCHUM), University of Montreal, Montreal, Quebec H2X 0A9, Canada. Electronic address: adriana.di.polo@umontreal.ca.
authors.forename: Adriana
authors.initials: A
authors.lastname: Di Polo
mesh_terms: D000818:Animals; D001370:Axonal Transport / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004195:Disease Models, Animal; D005901:Glaucoma / Q000150:complications; D005911:Gliosis / Q000378:metabolism; D007429:Intraocular Pressure / Q000187:drug effects; D008297:Male; D009457:Neuroglia / Q000187:drug effects* / Q000378:metabolism; D009798:Ocular Hypertension / Q000150:complications; D009900:Optic Nerve / Q000187:drug effects / Q000503:physiopathology; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D012160:Retina / Q000187:drug effects* / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000187:drug effects*; D007212:Indolizines; D011720:Pyrazoles
chemical_list: D017868:Cyclic AMP-Dependent Protein Kinases; D011725:Pyridines; C038366:ibudilast; D007212:Indolizines; D011720:Pyrazoles
keywords: Gliosis; Neurodegeneration; Ocular hypertension; Optic nerve; cAMP Phosphodiesterase inhibitor