.

Figure 13. GC-1-directed therapy for glaucoma is pleiotropic in its action.Increased levels of cGMP are shown to have pleiotropic targets that are beneficial in the treatment of glaucoma. These are: (a) relaxation of the trabecular meshwork to increase AqHoutflow facility,which leads to lowering in IOP,(b) increasing blood flow to the retina, choroid and optic nerve head, (c) prevention of degeneration of retinal ganglion cells through mechanisms that may involve downstream kinase pathways. As shown in Figure 11 , the cGMP concentrations in the eye can be increased in two ways: (i) by the use of GC-1 stimulators and activators, which aim to increase production of cGMP; or (ii) by the use of PDE inhibitors which prevent the decomposition of cGMP into 5’GMPin the cell to increase its bioavailability.

The clinical investigations revealthat glaucoma is associated with increased IOP. In case of open angle glaucoma (OAG), the finding of high IOP suggests imbalance between AqH generation and outflow. It is estimated that more than sixty million people suffer from primary open angle glaucoma (POAG) at the world level, showing a possible graphic projection of about seventy nine million by the end of 2020 and more than hundred million by 2040 [109,110]. The general form of glaucoma is indicative ofhigh intraocular pressure (IOP) and hence is known asocular hypertension. From the available data it is clear that 1/3rd of glaucomatous patients (vision loss)show normotensive IOP (normotensive glaucoma; NTG) and this disease have major impact of age factor i.e., increases with age, with impendent of IOP. This shows that this mechanistic approach is not the sole explanation of the cause of this defect [111]. Thus, considering reduction in IOP is not the whole treatment for this disease. Hence, a number of evidences support NO as an efficient regulator of this type of hypertension in association with guanylate cyclase (GC). NO as a therapeutic option for this treatment has shown positive results indecreasing IOP, stabilize ocular blood pressure and confer neuroprotection. Therefore, current therapeutics considers both IOP-dependent and IOP-independent targetmechanisms of the disease [112-114].

Several NORMS have been tested in animal models including mice, monkey and rabbit to record the impact of these NO-donors on IOP.In case of a normotensive rabbit animal model, theapplication of nitroglycerin, Sodium nitroprusside (SNP), isosorbide dinitrate (ISDN) and sodium nitrite (Figure14) showed a suitable decrease in IOP effective for one to two hours. The concentration dependent analysis showed that SNP and nitroglycerin or glyceryl trinitrate(GTN) are active at lowering the IOP till 0.1% and 0.03%, respectively is maintained, and on the other hand doses higher than 0.1% and 0.03% of the two NO-donors were found ineffective [115]. Similarly, other studies reported by Kotikoski et al . [116] in normotensive rabbits using SNP, spermine NONOate and S-nitrosothiol (Figure 15 ), applied topically or intravitreal way showed similar effect of lowering IOP for 2-5 h duration. Behar-Cohen’s group also reported the similar type of investigation using 3-morpholinosydnonimine (SIN-1) or S-nitro-N-acetylpenicillamine (SNAP), (Figure 16) and the results indicated a swift fall in IOP [117].

Figure14. Structure of some nitric oxide donors

Figure 15. Chemical structure ofspermine NONOate

Figure 16. Chemical Structure of SIN-1 and SNAP

The Studies reported bySugiyamaet al. [118] showing the hypotensive outcome of compounds shown inFigure 17 encompassing both the NO-releasing and NO-sequestering sensitivity. Kimuraet al. [119] found that SNP and nipradilol reduce IOP, but latanoprost (Figure 18) was found not so effective IOP. However, the combinatory drug application of latanoprost with SNPor nipradilol showedconsiderable reduction in IOP than SNPor nipradilol when used separately. This proposes the use of synergistic effective compound like latanoprost for well pronounced IOP lowering results.

Figure 17. Chemical structure of nipradiol

Figure 18. Chemicalstructure of latanoprost

Non-arteritic anterior ischemic optic neuropathy (NAION), a common eye problem generally found middle-aged group (though no age group is safe) is linked with phosphodiesterase (PDE) inhibitors (such asSildenafil)presumably due to hypotensive effect and vasorelaxation [120]. Hence, sildenafil (a well known NORM)finds the application inlowering the blood pressure [121]. Several recent reports describe the use of erectile dysfunction (ED)drugs (Figure 19 )questioning these drugs as responsible agents forNAION. Many factors have been elaborated to set this beliefof contribution towards NAION. Therefore, among warning factors such possibilities of side effects must be highlighted [122].As the same vision defects have been found among patients aftersildenafil consumption [123]. It is established that PDE 5 (phosphodiesterase in the corpus cavernosum) along getsinhibitedby using the ED drugs, escaping degradation of 3′-5′-cyclic guanosine monophosphate (cGMP) to guanosine 5′-monophosphate (5′GMP).The NO linkage with guanylyl cyclase creates conformational modification in this enzyme, followed by catalytic cGMP generation from guanosine 5′-triphosphate (GTP), stimulating penis towards erection as has been displayed in Figure 20 .

Figure 19. Structure of sildenafil andother similar ED drugs

Figure 20. NO–cGMP routes for relaxation of arterial and trabecular smooth muscle

Another familiar example of NO-donor usable in lowering IOP is NO-bonded Latanoprost acid (LA) called as Latanoprostene bunod (LBN) and is generally referred for topical treatment, and its action of releasing NO is prostaglandin equivalent. The role of this compound inoutflow of AqH has been described in Figure10 and the mechanism of NO-release is given inFigure 21.

Glaucoma as discussed earlier is an optic neuropathy and is considered as the major cause of eye defectsin advanced countries (125-131). A sequential treatment plan has been devised by the “European Glaucoma Society”suggesting the reduction of IOP as the first step, followed by medically supervised laser surgery of neural network called as “the trabecular meshwork” (TM) andfiltering surgery of galucoma. As the main threat for glaucoma is elevated IOP, hence is thefirst target to be corrected in the treatment plan [134]. Meanwhile CO is also expected to play a role in lowering IOP like NO. Although very less literature reports are available justifying the use of CORMS in this context. However, some of the directions imposed for this view have been enlightened below:

Bucolo and Drago have recently updatedthat CO can furnish significant results of multiscale applications in treating eye impairments especially glaucoma [131].CORM-3 as shown in Figure 22 is a famous CO-releaser when studied by Stagni et al. To find the role of CO in treating ocular system defects found that the compound resulted in lowering IOP in the rabbit animal models they selected for the experiment [135].The drug potency in the respective tests indicated that after 24 hours of the consumption the IOP-lowering effect was seen for 30 minutes.Ingestion1% dose was seen maximal six hour duration.

Figure 22. Chemical structure of CORM-3