.
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].
Nitric Oxide Releasing Molecules (NORMS) and the IOP
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.
Figure 21.The release of nitric oxide from LBN [Adopted from
Ref. 124; J. Ocul. Pharma. and Therap., 34(2018) 52-60].
Carbon monoxide, CORMS and the ocular system
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
From the results obtained by CO-based IOP-lowering it is expected that
the action is because of soluble guanylyl cyclase(sGC)enhancement.
CO-dependent sGC activation of sGC by CORM-3imparts an increase in the
outflow of AqH as given in Figure 23,linkingthepathways, TM
with Schlemm’s canal. It is expected that CO exhibits this action
byreducing the volume of TM cell [136].