Effects of Daily Melatonin Supplementation on Visual Loss, Circadian Rhythms, and Hepatic Oxidative Damage in a Rodent Model of Retinitis Pigmentosa

Abstract

Retinitis pigmentosa (RP) is a group of inherited neurodegenerative diseases characterized by a progressive loss of visual function that primarily affect photoreceptors, resulting in the complete disorganization and remodeling of the retina. Progression of the disease is enhanced by increased oxidative stress in the retina, aqueous humor, plasma, and liver of RP animal models and patients. Melatonin has beneficial effects against age-related macular degeneration, glaucoma, and diabetic retinopathy, in which oxidative stress plays a key role. In the present study, we used the P23HxLE rat as an animal model of RP. Melatonin treatment (10 mg/kg b.w. daily in drinking water for 6 months) improved the parameters of visual function and decreased the rate of desynchronization of the circadian rhythm, both in P23HxLE and wild-type rats. Melatonin reduced oxidative stress and increased antioxidant defenses in P23HxLE animals. In wild-type animals, melatonin did not modify any of the oxidative stress markers analyzed and reduced the levels of total antioxidant defenses. Treatment with melatonin improved visual function, circadian synchronization, and hepatic oxidative stress in P23HxLE rats, an RP model, and had beneficial effects against age-related visual damage in wild-type rats.

Keywords: antioxidant; circadian rhythms; melatonin; neurodegeneration; oxidative stress; retina; retinitis pigmentosa; vision.

Figure 1

Visual acuity (VA) (A) and contrast sensitivity (CS) (B) values obtained in different treatment groups in P23HxLE and SDxLE rats: P23HxLE-vehicle, P23HxLE-MT, SDxLE-vehicle, and SDxLE-MT. Data obtained at P30, 60, 90, 120, and 180 by optometry on average between the anti- and clockwise directions. Data plots show the mean ± SEM (n = 5/group). Mann–Whitney U test: # p < 0.05 versus SDxLE animals, * p < 0.05 versus P23HxLE-vehicle animals. MT, melatonin.

Figure 2

Electroretinogram recordings. Scotopic a- (A) and b-wave (B) responses for flashes of 0.0002, 0.0015, 0.0092, 0.06, 0.38, 2.38, 23.19, 78, and 722 cd.s/m² intensities, and the double-flash protocol (C) recorded at P180 in the P23HxLE and SDxLE treatment groups: SDxLE-vehicle, SDxLE-MT, P23HxLE-MT, and P23HxLE-vehicle. Data plots show the mean ± SEM (n = 5). Mann–Whitney U test: # p < 0.05 versus SDxLE animals, * p < 0.05 versus P23HxLE-vehicle animals.

Figure 3

Core body temperature rhythms: representative actograms (up), periodograms (middle), and mean waveforms (down) obtained by analyzing P23HxLE (left) and SDxLE (right) rats without treatment, the vehicle (left), and treated with melatonin (right) at P180. The light/dark cycle is represented by dark and white horizontal bars.

Figure 4

Locomotor activity rhythms: representative actograms (up), periodograms (middle), and mean waveforms (down) obtained analyzing P23HxLE (left) and SDxLE (right) rats without treatment, the vehicle (left), and treated with melatonin (right) at P180. The light/dark cycle is represented by dark and white horizontal bars.

Figure 5

Hepatic levels of lipid peroxidation (A), oxidized proteins (B), nitrosative damage (C), and the GSH/GSSG ratio (D) in wild-type (SDxLE) rats and P23HxLE rats without treatment (vehicle) and those treated with melatonin (MT). Data represent the mean ± SEM (n = 5). Mann–Whitney U test: # p < 0.05 versus SDxLE animals, * p < 0.05 versus P23HxLE-vehicle animals.

Figure 6

Levels of antioxidant defenses: (A) total antioxidant capacity (TAC), (B) catalase (CAT), (C) superoxide dismutase (SOD), and (D) glutathione S-transferase (GST) enzyme activities analyzed in liver tissues of wild-type (SDxLE) rats and P23HxLE rats without treatment (vehicle) and treated with melatonin (MT). Data represent the mean ± SEM (n = 5). Mann–Whitney U test: # p < 0.05 versus SDxLE animals, * p < 0.05 versus P23HxLE-vehicle animals.