Histamine H₃ receptor antagonist/nitric oxide donors as novel promising therapeutic hybrid-tools for glaucoma and retinal neuroprotection

Glaucoma is a degenerative optic neuropathy in which the degeneration of optic nerve and blindness occur. The main cause is a malfunction of ciliary processes (protrusions of the ciliary bodies) resulting in increased intraocular pressure (IOP). Ocular hypertension (OHT) causes ischemic events leading to retinal ganglion cell (RGC) depletion and blindness. Histaminergic and nitrergic systems are involved in the regulation of IOP. Therefore, we developed novel hybrid compounds that target histamine H₃ receptor (H₃R) with nitric oxide (NO) releasing features (ST-1989 and ST-2130). After H₃R binding was proven in vitro, we investigated their effects in two OHT models in New Zealand White rabbits. Compound ST-1989 showed the highest NO elevation, together with antioxidative and anti-inflammatory features partly superior to the co-administered H₃R antagonist (ciproxifan) and NO donor (molsidomine). This hybrid compound demonstrated IOP reduction in both OHT models induced by intravitreal injection of hypertonic saline and carbomer into the anterior chamber of the eye, respectively. Ocular perfusion and photoreceptor neuroprotection were evaluated in a model of ischemia/reperfusion (I/R) of the ophthalmic artery induced by repeated sub-tenon injections of endothelin-1 (ET-1), twice a week for six weeks. Compound ST-1989 counteracts retinal degeneration reducing ophthalmic artery resistance index and increasing photoreceptor responses, thus rescuing RGCs. Our results indicate that compound ST-1989 is a promising molecule with long-lasting hypotensive effects and good effectiveness in reducing inflammation, oxidative stress, and RGCs apoptosis. In conclusion, these hybrid compounds could be a novel strategy to combat glaucomatous blindness and RGC depletion for ocular diseases involving retinal damage.