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

Abstract

Intravitreal delivery can maximize the intensity of therapeutic agents and extend their residence time within ocular tissue. Melatonin is a lipophilic molecule that crosses freely biological barriers and cell membranes. This study intends to investigate the effects of intravitreally delivered melatonin on mouse retina. The visual function of administered mice is assessed by electrophysiological and behavior examinations three weeks after intravitreal delivery. Moreover, multi-electrode array (MEA) was used to assess the electrical activities of retinal ganglion cells (RGCs). We found that intravitreal delivery of high dosage melatonin (400–500 µg/kg) destroyed the retinal architecture and impaired the visual function of mice. Conversely, the melatonin administration at low dose (100–300 µg/kg) did not have any significant effects on the photoreceptor survival or visual function. As shown in the MEA recording, the photoreceptors activity of the central region was more severely disturbed by the high dose melatonin. A pronounced augment of the spontaneous firing frequency was recorded in these mice received high dosage melatonin, indicating that intravitreal delivery of high dosage melatonin would affect the electrical activity of RGCs. Immunostaining assay showed that the vitality of cone photoreceptor was impaired by high dose melatonin. These findings suggest that intravitreal melatonin is not always beneficial for ocular tissues, especially when it is administered at high dosage. These data add new perspectives to current knowledge about melatonin delivery at the ocular level. Further therapeutic strategies should take into consideration of these risks that caused by delivery approach.

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

“…Melatonin was demonstrated to contribute beneficial effects in DR ( 16 , 18 ). As for melatonin delivery, intraperitoneal injection ( 31 ), oral administration ( 32 ), and intravitreal injection ( 33 ) were all used and tested the protective effects of melatonin on retinas in experimental animal models. In our study, considering the blood–ocular barrier and the possible side effects of systemic high-dose administration, we chose intravitreal injection to deliver melatonin directly into the eye.…”

“…In our study, considering the blood–ocular barrier and the possible side effects of systemic high-dose administration, we chose intravitreal injection to deliver melatonin directly into the eye. 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 ).…”

Improved intravitreal injection procedure in mice with electroretinographic evaluation of results

“…Преимуществом электроретинографии является неинвазивность и простота проведения. Можно многократно прижизненно регистрировать ЭРГ у одного испытуемого животного, наблюдая эффект какого-либо воздействия в динамике сколь угодно долгое время (Tao et al 2020).…”

Therapeutic Effects of Melatonin on Ocular Diseases: Knowledge Map and Perspective

“…In the current treatment of ophthalmic diseases, the ocular surface is the most common drug delivery route, and the eye drops have been widely used for delivering melatonin in animal experiments; however, their bioavailability should be further examined owing to the ocular barriers ( Dal Monte et al, 2020 ). For bypassing the barriers, the efficacy of intravitreal injection is also examined, especially in treating retinal diseases; however, the previous study reported that the high-dose melatonin injection resulted in degeneration of retinal cells ( Yilmaz et al, 2004 ; Sande et al, 2014 ; Tao et al, 2020 ). Therefore, the potential toxicity of melatonin must be further scrutinized for both the ocular surface and retina, and the proper dosages for treatment must be determined, which may be different in various ocular diseases and individuals.…”