Figure 23.Diagram displaying theproduction andflow of aqueous humour (AqH). (a) AqHproduced at the ciliary body in the eye flows (green arrows) through two routes independently that control AqH dynamics: (i) via the trabecular meshwork (TM) and Schlemm’s canal (purple arrow) (conventional route) and (ii) via the uveoscleral tract (orange arrow)(non-conventional route). (b) The balance of (AqH) production at the ciliary body and elimination in the anterior chamber establishes intraocular pressure (IOP) in the eye. The yearlyrate of incidenceof uveitis (a sight-threatening inflammatory disease of the eye)at the age between 20 and 60 years for both males and females is estimatedto be with a frequency of 38–714 per 1,00,000 persons [137]. CORM-A1 is an example of CO-releasing compounds tested for its effect on uveoretinitis and is the first example of water soluble CO-releaser. Figure 24andScheme 4may be referred for knowing the structural details and CO-releasing process.Nicoletti et al. [138] showed that CORM-A1is helpful in autoimmune responsive in uveoretinitis.
Figure 24. Chemical structure of CORM-A1
Scheme 4. Mechanism of CO release fromCORM-A1
Hydrogen Sulphide and ophthalmic Diseases
Being third latest member of gasotransmitters after NO and CO, H2S has also been reported to exhibitnumerous roles in maintaining normal physiological conditions [139].The generation of H2S as discussed in its biosynthesis section mainly involves the catalytic intervention of CBS, 3MST, CSE and CAT. The same enzymatic actions have been found operational in all mammalian eyeballs confined to several locations. Any irregularity in such a distribution results in eye defects. So many investigations have been reported detailing H2S donors as IOP regulating compounds, retinal cell protection, antioxidative stress and ocular protein modulation. Thus, H2S donors represent promising drugs applicable in treating manifold ophthalmic diseases as discussed below:
Among different factors responsible for ocular defects as is known IOP is the main reason for glaucoma neuropathy [140] and finally it is stability between AqH of ciliary body and outflow AqH that matters [141].By facilitating cyclic adenosine monophosphate (cAMP) the outflow could be enhanced [142]. By allowing H2S-donors like L-Cysteine and sodium hydrosulfide (NaHS)to act on adenylyl cyclase and ATP-sensitivepotassium channels (KATP) therefore could increase cAMP concentrations and could make the outflow ofAqH easy [143].Similar investigation conducted by Módiset al. reveals that H2S inhibits phosphodiesterase (PDE) and enriches intramitochondrial cAMP levels and results in the excitation of protein kinase A (PKA) to infusebioenergetic consequences [144]. Similarly, another compoundGYY4137 [Figure 25 ] has furnished positive results in stabilizing IOP[145, 146].
Figure 30: Chemical structure of GYY4137
Concluding Remarks and Future Outlook
Gasotransmitters are, therefore, outstanding molecules having significant biological signalling role. Considering the fact that the scientific world is eager to design and develop molecular scaffolds in this context to be declared as medical or clinical relevant, so many questions are underway to be resolved. Half-life period, solubility, chemical environment effects, pH, thermodynamics and kinetics, all are among the queries being investigated in this field.The ocular diseases and the factors responsible for such impairments do contain mechanistic pathways half answered in relevance with gasotransmitters. Drug delivery challenges, transportation, combinatory implications of drugs, optoelectronic effects, etc. need to be explored in a more deepened way. Moreover, could synthetic chemists bring forth a molecular system of synergetic effect in a view to declare molecular designs having potentiality of releasing more than one ‘gasotransmitter’molecules?