Abstract
Glaucoma is a progressive optic neuropathy and is the second most common cause of irreversible blindness globally. Elevated intraocular pressure (IOP) is the only major risk factor, which is modifiable, however, disease progression is common despite IOP control, supporting the involvement of pressure-independent mechanisms such as oxidative stress, mitochondrial dysfunction, and neurotrophic imbalance which leads to retinal ganglion cell (RGC) loss. Current treatments mainly focus on lowering IOP, with little to no direct neuroprotective efficacy highlighting the need for multi-targeted therapeutic strategies. This thesis explores a novel trifunctional hybrid compound (THFC) JDB (JDB023) that can target three signaling pathways simultaneously: prostaglandin (PG), nitric oxide (NO) and hydrogen sulfide (H₂S) signaling pathways. It was tested for IOP lowering activity in normotensive New Zealand albino rabbits at various concentrations (0.01% – 0.5 %) and the optimum concentration of 0.1% was found to produce the maximum effect on lowering IOP in 2 h which lasted for 10 h. Interestingly, JDB showed a concentration-dependent increase in its hypotensive effect when used in combination with glutathione ethyl ester (GSH-EE), with JDB 0.1% and GSH-EE 5% achieving a maximum reduction of 54.83 ± 1.48% in IOP that lasted for 54 h, indicating its ability to potentiate the bioavailability of H₂S. This optimal combination was then tested in a carbomer based glaucomatous rabbit model. Both acute and chronic treatment studies were carried out. The maximum IOP reduction of 42.9 ± 5.18% for 48 h and 44.5 ± 12.16% on Day 17 were observed after acute and chronic treatments, respectively. The neuroprotective effects were evaluated in an ex vivo bovine retina model of oxidative stress. The related TFHC AMP (AMP249) preserved retinal laminar architecture, significantly upregulated phosphorylated Nrf2, restored expression of NRN1 and shifted the processing of BDNF from pro-apoptotic pro-BDNF to neuroprotective dimer of BDNF. All major layers of the retina remained structurally preserved in ocular hypertensive (OHT) animals that were treated with JDB 0.1% and GSH-EE 5% which was qualitatively analyzed by histological evaluation. The future studies should include evaluating the downstream regulators of Nrf2 and BDNF and receptor activation of TrkB. And evaluate neuroprotective effects of the novel compound in a OHT model.