Intravitreal Delivery of Melatonin Is Protective Against the Photoreceptor Loss in Mice: A Potential Therapeutic Strategy for Degenerative Retinopathy

Abstract

Melatonin is a circadian hormone with potent cytoprotective effects. Retinitis pigmentosa (RP) comprises a heterogeneous group of inherent retinopathies that characterized by the photoreceptor death in bilateral eyes. The N-methyl-N-nitrosourea (MNU) administered mouse is a type of chemically induced RP model with rapid progressive rate. We intend to study the melatonin mediated effects on the MNU administered mice. Melatonin was delivered into the vitreous body of the MNU administered mice. Subsequently, the melatonin treated mice were subjected to histological analysis, optokinetic behavior tests, spectral-domain optical coherence tomography (SD-OCT), and electroretinogram (ERG) examination. Multi-electrodes array (MEA) was used to analyze the status of visual signal transmission within retinal circuits. Biochemical analysis was performed to quantify the expression levels of antioxidative enzymes, oxidative stress markers, and apoptotic factors in the retinas. The intravitreal injection of melatonin ameliorated effectively the MNU induced photoreceptor degeneration. Melatonin therapy mitigated the spontaneous firing response, and preserved the basic configurations of visual signal pathway in MNU administered mice. MEA is effective to evaluate the pharmacological effects on retina. Of note, the cone photoreceptors in degenerative retinas were rescued efficiently by melatonin therapy. Melatonin afforded these protective effects by modulating the apoptotic cascades and alleviating the oxidative stress. These findings suggest that melatonin could act as an alternative treatment for degenerative retinopathy. Melatonin Frontiers in Pharmacology | www.frontiersin.org

Melatonin Maintains Inner Blood–Retinal Barrier by Regulating Microglia via Inhibition of PI3K/Akt/Stat3/NF-κB Signaling Pathways in Experimental Diabetic Retinopathy

“…Based on the available literature, intravitreal melatonin (50–150 μg/kg body weight) did not induce retinal morphological changes in guinea pigs ( 34 ); even the high dose from 100 to 300 µg/kg body weight did not have any significant detrimental effects on the photoreceptor survival or visual function on mouse retina ( 33 ), indicating a wide safe dose range for intravitreal injection of melatonin. In a recent study, intravitreal delivery of melatonin (150–250 μg/kg body weight) could well maintain the thickness of the outer nuclear layer in the chemical-induced retinitis pigmentosa mouse model ( 35 ). In our study, we used Sprague-Dawley rats with the body weight about 150 g; the calculated dose range for intravitreal administration of melatonin was about 15~45 μg.…”

Intravitreous delivery of melatonin affects the retinal neuron survival and visual signal transmission: in vivo and ex vivo study

“…Melatonin shows robust potency to detoxify the free radicals and oxygen derivatives, thereby improving the homeostasis of retinas (Blasiak et al., 2016 ). In ophthalmological experiments, melatonin can be delivered through the intravitreal route to exert its therapeutic actions (García-Caballero et al., 2018 ; Li et al., 2019 ). However, the exact pharmacokinetic and toxic aspects for this delivery approach remain to be clarified.…”

“…Intravitreally delivered melatonin alleviates the retinal ganglion cells (RGCs) death in a rabbit model with glaucomatous pathology (Arranz-Romera et al., 2019 ). Intravitreal delivery of melatonin also alleviates the photoreceptor apoptosis and preserves the visual signal pathway in a mice model with retinal degeneration (Li et al., 2019 ). This delivery approach not only ensures higher melatonin concentration in the targeted tissue, but also avoids side effects on these unwanted organs.…”

“…On the other hand, intravitreal injection of melatonin at doses ranging from 50 to150 µg/kg does not produce any morphological changes. Furthermore, another study shows that intravitreal injection of melatonin at doses ranging from 50 to 150 µg/kg is able to ameliorate the N-methyl-N-nitrosourea (MNU) induced photoreceptor apoptosis (Li et al., 2019 ), suggesting that intravitreal injection of melatonin at rational doses (50–150 µg/kg) would be therapeutic. Thus clarifying the toxic effects and safe dose of intravitreal melatonin is of special importance.…”

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

“…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 ].…”