Influence of dietary melatonin on photoreceptor survival in the rat retina: An ocular toxicity study

Abstract

Previous studies have shown that melatonin treatment increases the susceptibility of retinal photoreceptors to light-induced cell death. The purpose of this study was to evaluate under various conditions the potential toxicity of dietary melatonin on retinal photoreceptors. Male and female Fischer 344 (non-pigmented) and Long-Evans (pigmented) rats were treated with daily single doses of melatonin by gavage for a period of 14 days early in the light period or early in the dark period. In another group, rats were treated 3 times per week with melatonin early in the light period, and then exposed to high intensity illumination (1,000 −1,500 lux; HII) for two hours, and then returned to the normal cyclic lighting regime. At the end of the treatment periods, morphometric measurements of outer nuclear layer thickness (ONL; the layer containing the photoreceptors cell nuclei) were made at specific loci throughout the retinas. In male and female non-pigmented Fischer rats, melatonin administration increased the degree of photoreceptor cell death when administered during the nighttime and during the day when followed by exposure to HII. There were some modest effects of melatonin on photoreceptor cell death when administered to Fisher rats during the day or night without exposure to HII. Melatonin treatment caused increases in the degree of photoreceptor cell death when administered in the night to male pigmented Long-Evans rats, but melatonin administration during the day, either with or without exposure to HII, had little if any effect on photoreceptor cell survival. In pigmented female Long Evans rats, melatonin administration did not appear to have significant effects on photoreceptor cell death in any treatment group. The results of this study confirm and extend previous reports that melatonin increases the susceptibility of photoreceptors to light-induced cell death in non-pigmented rats. It further suggests that during the dark period, melatonin administration alone (i.e., no HII exposure) to pigmented male rats may have a toxic effect on retinal cells. These results suggest that dietary melatonin, in combination with a brief exposure to high intensity illumination, induces cellular disruption in a small number of photoreceptors. Chronic exposure to natural or artificial light and simultaneous intake of melatonin may potentially contribute to a significant loss of photoreceptor cells in the aging retina.

Melatonin as a Therapy for Traumatic Brain Injury: A Review of Published Evidence

“…One promising candidate is melatonin (MEL), a naturally occurring hormone that is also available as an over-the-counter dietary supplement. MEL possesses many of the fundamental characteristics of a central nervous system (CNS) therapeutic including low toxicity [ 10 , 11 , 12 ], an ability to cross the blood-brain-barrier [ 13 , 14 , 15 ], and receptors that bind MEL in the CNS [ 16 , 17 , 18 , 19 ]. While the therapeutic effects of MEL in human TBI remain understudied, MEL has demonstrated beneficial effects in pre-clinical models of several CNS disorders, including conditions with similar pathology and symptoms profiles, to TBI such as: Huntington’s disease [ 20 ], Alzheimer’s disease [ 21 ], amyotrophic lateral sclerosis [ 22 , 23 ], stroke [ 24 , 25 ], sepsis-induced brain dysfunction [ 21 ], and spinal cord injury [ 26 , 27 ].…”

Brain injury results in lower levels of melatonin receptors subtypes MT1 and MT2

“…MEL is produced throughout the body, with the primary site of production being the pineal gland. MEL is available as a medication and over-the-counter supplement and has a known low toxicity profile in both human and animal studies with few reported adverse effects even at very high doses [10]. Existing evidence shows endogenous MEL levels are altered in TBI-survivors in a time-point and biosample-dependent manner [11,12]; thus, MEL may be important in the body’s response to TBI and there may be an opportunity to improve outcomes via therapeutic administration of MEL.…”

Ocular disorders and the utility of animal models in the discovery of melatoninergic drugs with therapeutic potential

“…A later study in the P23H rat model of RP has revealed that exogenous melatonin prevents vision loss and circadian rhythmicity alteration [111]. However, and as already mentioned, Wiechmann and colleagues [105] have observed a greater loss of photoreceptor cells after melatonin intake plus exposure to bright light. This opposite effect may be explained by the different animal model used.…”

“…However, Wiechmann and colleagues [105] have observed a harmful effect of dietary melatonin on rat photoreceptor cell survival in response to bright light. Hence, it has been suggested that the time for melatonin intake during the day should be considered before the organization of a clinical trial [102].…”