Melatonin protects the retina from experimental nonexudative age‐related macular degeneration in mice

Abstract

Nonexudative age‐related macular degeneration (NE‐AMD) represents the leading cause of blindness in the elderly. Currently, there are no available treatments for NE‐AMD. We have developed a NE‐AMD model induced by superior cervical ganglionectomy (SCGx) in C57BL/6J mice, which reproduces the disease hallmarks. Several lines of evidence strongly support the involvement of oxidative stress in NE‐AMD‐induced retinal pigment epithelium (RPE) and outer retina damage. Melatonin is a proven and safe antioxidant. Our aim was analysing the effect of melatonin in the RPE/outer retina damage within experimental NE‐AMD. The treatment with melatonin starting 48 h after SCGx, which had no effect on the ubiquitous choriocapillaris widening, protected visual functions and avoided Bruch´s membrane thickening, RPE melanin content, melanosome number loss, retinoid isomerohydrolase (RPE65)‐immunoreactivity decrease, and RPE and hotoreceptor ultrastructural damage induced within experimental NE‐AMD exclusively located at the central temporal (but not nasal) region. Melatonin also prevented the increase in outer retina/RPE oxidative stress markers and a decrease in mitochondrial mass at 6 weeks post‐SCGx. Moreover, when the treatment with melatonin started at 4 weeks post‐SCGx, it restored visual functions and reversed the decrease in RPE melanin content and RPE65‐immunoreactivity. These findings suggest that melatonin could become a promising safe therapeutic strategy for NE‐AMD.

Influence of Circadian Rhythm in the Eye: Significance of Melatonin in Glaucoma

“…However, its role in sleepdisorder regulation could be used as coadjutant treatment of ocular surface diseases due to the improvement in sleep disorders. In the posterior pole of the eye, the effect of circadian rhythm is not clear but melatonin properties such as antioxidant and antiangiogenic effects could be important to enhance other main treatments for AMD or other retinal diseases [94,[160][161][162].…”

“…Concerning the therapeutic use of melatonin in AMD, different studies confirmed its antioxidant and antiangiogenic properties, which provide a protective effect on photoreceptors and retinal pigment epithelium against oxidative stress, apoptosis, and mitochondrial DNA damage [94,[160][161][162].…”

“…It has to be pointed out that combined therapy for glaucoma control is a common method when monotherapy is no longer effective [238]. Consequently, this combination of melatonin with other hypotensive compounds could not only be beneficial in terms of IOP reduction, but also for its antioxidant and antiangiogenic properties [93][94][95][160][161][162]239] as mentioned in point 2.5 retinal diseases. Furthermore, there are some studies which show promising results about a possible slow down vision worsening over time in glaucoma.…”

Nutraceutical Strategies for Suppressing NLRP3 Inflammasome Activation: Pertinence to the Management of COVID-19 and Beyond

“…Recent epidemiology has established that diabetics treated with the drug metformin are at notably lower risk for AMD than other diabetics that are comparably controlled; this could reflect a protective role for AMPK in this syndrome [225,226]. Urinary levels of the melatonin metabolite 6-sulfatoxymelatonin have been reported to be low in patients with AMD, and melatonin administration is protective in a mouse model of dry AMD [227][228][229][230]. Although the decreased risk for AMD associated with frequent spinach ingestion has been attributed to lutein, little attention has been paid to the fact that spinach is extraordinarily rich in betaine, and also a fine source of folate.…”

Mitochondrial Dysfunction and Endoplasmic Reticulum Stress in Age Related Macular Degeneration, Role in Pathophysiology, and Possible New Therapeutic Strategies

“…In an experimental model of nonexudative AMD in mice induced by superior cervical ganglionectomy (SCG), melatonin administered as subcutaneous pellets, was capable to significantly preserve visual functions as well as RPE and outer retinal structure, and also prevented the increase of oxidative stress markers. These results were observed when the melatonin treatment was started both at 48 h and 4 weeks post-SCG, which means that melatonin could not only prevent, but also slow or reverse nonexudative-AMD progression [ 206 ]. On a photoreceptor degeneration mice model induced by an intraperitoneal administration of N-methyl-N-nitrosourea (MNU), melatonin was injected into the vitreous body, and was able to ameliorate effectively the MNU induced photoreceptor degeneration and also improved the visual signal transmission within inner retinal circuits by inhibiting apoptosis and mitigating oxidative stress [ 207 ].…”