Role of cyclic AMP in the eye with glaucoma

Abstract

Glaucoma is characterized by a slow and progressive degeneration of the optic nerve, including retinal ganglion cell (RGC) axons in the optic nerve head (ONH), leading to visual impairment. Despite its high prevalence, the biological basis of glaucoma pathogenesis still is not yet fully understood, and the factors contributing to its progression are currently not well characterized. Intraocular pressure (IOP) is the only modifiable risk factor, and reduction of IOP is the standard treatment for glaucoma. However, lowering IOP itself is not always effective for preserving visual function in patients with primary open-angle glaucoma. The second messenger cyclic adenosine 3′,5′-monophosphate (cAMP) regulates numerous biological processes in the central nervous system including the retina and the optic nerve. Although recent studies revealed that cAMP generated by adenylyl cyclases (ACs) is important in regulating aqueous humor dynamics in ocular tissues, such as the ciliary body and trabecular meshwork, as well as cell death and growth in the retina and optic nerve, the functional role and significance of cAMP in glaucoma remain to be elucidated. In this review, we will discuss the functional role of cAMP in aqueous humor dynamics and IOP regulation, and review the current medications, which are related to the cAMP signaling pathway, for glaucoma treatment. Also, we will further focus on cAMP signaling in RGC growth and regeneration by soluble AC as well as ONH astrocytes by transmembrane ACs to understand its potential role in the pathogenesis of glaucoma neurodegeneration

Neuroprotection in Glaucoma: Old and New Promising Treatments

“…cAMP is a second messenger involved in many different cellular pathways. It is pivotal in controlling AH secretion/reabsorption [251] and in regulating neurotrophin gene expression for RGC survival [252]. In fact, hypotonizing drugs such as alpha-agonists and beta-blockers plus forskolin and melatonin (although with different mechanisms) all impinge on cAMP production, neat AH secretion, and neuroprotection.…”

Inhibition of cAMP/PKA Pathway Protects Optic Nerve Head Astrocytes against Oxidative Stress by Akt/Bax Phosphorylation-Mediated Mfn1/2 Oligomerization

“…Since oxidative stress has long been thought to be an important pathophysiological mechanism in many neurodegenerative diseases including glaucoma [3, 10, 14–16], the activation of the cyclic adenosine 3′,5′-monophosphate (cAMP)/protein kinase A (PKA) signaling pathway exacerbates vulnerability to oxidative stress in ONH astrocytes [7]. The ubiquitous second messenger cAMP in the central nervous system contributes to numerous biological processes including cell growth and death [17–20]. Upon stimulation, cAMP synthesis and its degradation are tightly regulated by adenylyl cyclases and cyclic nucleotide phosphodiesterases (PDEs), respectively [18].…”

“…Upon stimulation, cAMP synthesis and its degradation are tightly regulated by adenylyl cyclases and cyclic nucleotide phosphodiesterases (PDEs), respectively [18]. Accumulating evidence indicates that the increased level of cAMP is associated with the unstimulated glaucomatous ONH astrocytes from patients with POAG [21] as well as experimental glaucoma [7, 20]. Nevertheless, the precise cellular and molecular mechanism(s) of the activation of the cAMP/PKA signaling pathway underlying astrocyte dysfunction in glaucomatous ONH degeneration remains to be determined.…”

Coenzyme Q and its role in glaucoma

“…[ 1 ] Yet, even now, IOP remains the only modifiable risk factor for the pathogenesis of glaucoma. [ 2 ] However, research on other neurodegenerative disorders such as Parkinsonism, Lebers Hereditary Optic Atrophy and Huntington's disease is giving hope that neuromodulation could one day become part of our armamentarium in the management of glaucoma. [ 3 ] As focus shifts to non-IOP lowering modalities, newer agents are being studied for their role in this disease process.…”