The nitric oxide-guanylate cyclase pathway and glaucoma

Abstract

Glaucoma is a prevalent optic neuropathy characterized by the progressive dysfunction and loss of retinal ganglion cells (RGCs) and their optic nerve axons, which leads to irreversible visual field loss. Multiple risk factors for the disease have been identified, but elevated intraocular pressure (IOP) remains the primary risk factor amenable to treatment. Reducing IOP however does not always prevent glaucomatous neurodegeneration, and many patients progress with the disease despite having IOP in the normal range. There is increasing evidence that nitric oxide (NO) is a direct regulator of IOP and that dysfunction of the NO-Guanylate Cyclase (GC) pathway is associated with glaucoma incidence. NO has shown promise as a novel therapeutic with targeted effects that: 1) lower IOP; 2) increase ocular blood flow; and 3) confer neuroprotection. The various effects of NO in the eye appear to be mediated through the activation of the GC- guanosine 3:5'-cyclic monophosphate (cGMP) pathway and its effect on downstream targets, such as protein kinases and Ca channels. Although NO-donor compounds are promising as therapeutics for IOP regulation, they may not be ideal to harness the neuroprotective potential of NO signaling. Here we review evidence that supports direct targeting of GC as a novel pleiotrophic treatment for the disease, without the need for direct NO application. The identification and targeting of other factors that contribute to glaucoma would be beneficial to patients, particularly those that do not respond well to IOP-dependent interventions.

Retrospective Chart Review on Real-World Use of Latanoprostene Bunod 0.024% in Treatment-Naïve Patients with Open-Angle Glaucoma

“…Unlike other IOPlowering monotherapies, LBN provides a novel dual mechanism of action for improving aqueous humor outflow by targeting the uveoscleral pathway through the action of latanoprost acid and targeting the TM/Schlemm's canal through the action of NO [19,20]. The latter action is important given the central role of the TM/ Schlemm's canal in aqueous humor outflow along with the observation of decreased NO levels in the aqueous humor and in plasma of glaucoma patients [21][22][23][24][25].…”

Future Therapeutic Strategies in the Glaucoma Management

“…Ouabain lowers the secretion of AqH by about 62% by inhibiting NKA pump. In addition, the use of sodium nitroprusside (SNP) on bovine and porcine eyes cut the second messenger cGMP and protein kinase G, thereby inhibiting NKA pump thereby inhibiting the secretion of AqH, and thus reducing IOP [19].…”

Influence of new treatment modalities on adherence in glaucoma

“…A novel prostaglandin agonist which donates nitric oxide while metabolizing was also recently launched. Latanoprostene bunod metabolizes to latanoprost acid (increasing uveoscleral outflow) and butanediol mononitrate (increasing conventional outflow by direct action of the released NO at the trabecular meshwork) [10].…”