Therapeutic Potential of Antioxidants and Hybrid TEMPOL Derivatives in Ocular Neurodegenerative Diseases: A Glimpse into the Future

Abstract

Reactive oxygen species play a significant role in the pathogenesis of various ocular neurodegenerative diseases especially glaucoma, age-related macular degeneration (AMD), and ocular ischemic stroke. Increased oxidative stress and the accumulation of ROS have been implicated in the progression of these diseases. As a result, there has been growing interest in exploring potential therapeutic and prophylactic strategies involving exogenous antioxidants. In recent years, there have been significant advancements in the development of synthetic therapeutic antioxidants for targeting reactive oxygen species (ROS) in neurodegenerative diseases. One area of focus has been the development of hybrid TEMPOL derivatives. In the context of ocular diseases, the application of next-generation hybrid TEMPOL antioxidants may offer new avenues for neuroprotection. By targeting ROS and reducing oxidative stress in the retina and optic nerve, these compounds have the potential to preserve retinal ganglion cells and trabecular meshwork and protect against optic nerve damage, mitigating irreversible blindness associated with these diseases. This review seeks to highlight the potential impact of hybrid TEMPOL antioxidants and their derivatives on ocular neurodegenerative disorders.

Keywords: SA-10; SA-2; SA-9; TEMPOL derivatives; glaucoma; hybrid small molecules; neuroprotection; nitric oxide; oxidative stress; reactive oxygen species; retina ganglion cells; trabecular meshwork.

Figure 1

Graphical representation of antioxidants as possible therapeutic alternatives for ocular neurodegenerative diseases. Excessive ROS generated from aging, UV radiation, and elevated IOP among others results in the development of oxidative stress in ocular tissues. The release of these free radicals activates inflammation, hypoxia, and damages the retina. Ultimately, pathological processes such as inflammation and optic neuropathies are triggered. To circumvent or slow down these cascade of events, superoxide dismutase (SOD) mimetic small molecule radical scavenger TEMPOL or its hybrid TEMPOL antioxidant therapies are reported to demonstrate promising therapeutic benefits in oxidative stress-mediated ocular diseases.

Figure 2

A schematic diagram depicting a summary of some signaling pathways in oxidative stress. Apart from intracellular signals, such as cellular energy status and hypoxia stress, extracellular cues including aging, high IOP, and UV radiation play essential roles in activating ROS generation intracellularly. PI3/AKT/mTOR pathways are activated, which activates downstream transcription factors such as the hypoxia response element (HRE), NF-KB, and NRF2/ARE pathways. These pathways induce angiogenesis, inflammation, and potentially inhibit antioxidant enzyme systems which culminate in apoptosis.

Figure 3

Molecular structure of synthetic prostaglandin (PG) analogues (A) PGF2α, (B) unoprostone, (C) latanoprost, (D) travoprost, (E) tafluprost, (F) bimatoprost.

Figure 4

Chemical structure of latanoprostene bunod (Vyzulta) depicting the hydrolysis of the ester prodrug to two active products (1) latanoprost acid (2) nitric oxide donor that subsequently release NO and the inactive metabolite 1,4-butanediol.

Figure 5

Schematic diagram showing the mechanism of action of NO donating compounds in the trabecular meshwork. NO is a 30 Da diatomic gasotransmitter that easily penetrates the TM and activates the heterodimeric enzyme soluble guanylate cyclase, and results in the downstream activation of cyclic guanosine monophosphate (cGMP). This results in the phosphorylation of protein kinase G thus allowing the efflux of potassium that causes relaxation of the TM thereby promoting outflow through the conventional pathway.

Figure 6

Proposed mechanism of action of synthetic hybrid NO donor and antioxidant small molecule SA-2 in ocular neurodegenerative disorders. The redox nitroxide antioxidant moiety 4-hydroxy TEMPOL (in red) acts as a superoxide dismutase (SOD) mimetic and inhibits oxidative damage in the trabecular meshwork, retina, and other ocular tissue. In particular, it scavenges superoxide radical and prevents the generation of peroxynitrite and depletion of NO bioavailability. The release of NO at physiologic concentrations from the sydnonimine NO prodrug (in blue) activates soluble guanylate cyclase to cause a downstream upregulation of cyclic GMP. This results in the relaxation of the trabecular meshwork, thus leading to a decrease in intraocular pressure and exerting neuroprotective effects.

Figure 7

Chemical structures of SIN-1 (a known NO donor), OT-440, TEMPOL, OT-551 (a prodrug of TEMPOL), synthetic hybrid small molecules SA-2, SA-9, and SA-10 containing NO donor and TEMPOL functionalities.