Spermine oxidase: A promising therapeutic target for neurodegeneration in diabetic retinopathy

Abstract

Diabetic Retinopathy (DR), is a significant public health issue and the leading cause of blindness in working-aged adults worldwide. The vision loss associated with DR affects patients' quality of life and has negative social and psychological effects. In the past, diabetic retinopathy was considered as a vascular disease; however, it is now recognized to be a neuro-vascular disease of the retina. Current therapies for DR, such as laser photocoagulation and anti-VEGF therapy, treat advanced stages of the disease, particularly the vasculopathy and have adverse side effects. Unavailability of effective treatments to prevent the incidence or progression of DR is a major clinical problem. There is a great need for therapeutic interventions capable of preventing retinal damage in DR patients. A growing body of evidence shows that neurodegeneration is an early event in DR pathogenesis. Therefore, studies of the underlying mechanisms that lead to neurodegeneration are essential for identifying new therapeutic targets in the early stages of DR. Deregulation of the polyamine metabolism is implicated in various neurodegenerative diseases, cancer, renal failure, and diabetes. Spermine Oxidase (SMOX) is a highly inducible enzyme, and its dysregulation can alter polyamine homeostasis. The oxidative products of polyamine metabolism are capable of inducing cell damage and death. The current review provides insight into the SMOX-regulated molecular mechanisms of cellular damage and dysfunction, and its potential as a therapeutic target for diabetic retinopathy. Structural and functional changes in the diabetic retina and the mechanisms leading to neuronal damage (excitotoxicity, loss of neurotrophic factors, oxidative stress, mitochondrial dysfunction etc.) are also summarized in this review. Furthermore, existing therapies and new approaches to neuroprotection are discussed.

Keywords: Diabetic retinopathy; Neurodegeneration; Neuroprotection; Oxidative stress; Polyamine metabolism; Spermine oxidase.

Figure 1.

The polyamine metabolic pathway. A diagrammatic representation of the synthesis and oxidation of polyamines. Abbreviations used: SMOX, spermine oxidase; APAO, N (1)-acetyl polyamine oxidase; SSAT, spermine spermidine acetyl transferase.

Figure 2.

A proposed mechanism for SMOX-induced neurodegeneration in the diabetic retina.

Figure 3:

Current treatments and future strategies for DR. Treatment can be implemented in the non-proliferative or the proliferative stages of DR based on the disease course and progression. The three treatment modalities currently being used are: laser photocoagulation, vitrectomy and intravitreal treatment with anti-VEGF agent or corticosteroid therapy. Future strategies that are currently under investigation include antioxidants and neuroprotective agents. The figure was created using Servier Medical Art https://smart.servier.com/