Melatonin delays photoreceptor degeneration in a mouse model of autosomal recessive retinitis pigmentosa

Abstract

Retinitis pigmentosa (RP) comprises a group of incurable inherited retinal degenerations. Targeting common processes, instead of mutation-specific treatment, has proven to be an innovative strategy to combat debilitating retinal degeneration. Growing evidence indicates that melatonin possesses a potent activity against neurodegenerative disorders by mitigating cell damage associated with apoptosis and inflammation. Given the pleiotropic role of melatonin in central nervous system, the aim of the present study was to investigate whether melatonin would afford protection against retinal degeneration in autosomal recessive RP (arRP). Rd10, a well-characterized murine model of human arRP, received daily intraperitoneal injection of melatonin (15 mg/kg) between postnatal day (P) 13 and P30. Retinas treated with melatonin or vehicle were harvested for analysis at P30 and P45, respectively. The findings showed that melatonin could dampen the photoreceptors death and delay consequent retinal degeneration. We also observed that melatonin weakened the expression of glial fibrillary acidic protein (GFAP) in Müller cells. Additionally, melatonin could alleviate retinal inflammatory response visualized by IBA1 staining, which was further corroborated by downregulation of inflammation-related genes, such as tumor necrosis factor alpha (Tnf-α), chemokine (C-C motif) ligand 2 (Ccl2), and chemokine (C-X-C motif) ligand 10 (Cxcl10). These data revealed that melatonin could ameliorate retinal degeneration through potentially attenuating apoptosis, reactive gliosis, and microglial activation in rd10 mice. Moreover, these results suggest melatonin as a promising agent improving photoreceptors survival in human RP.

Ocular Clocks: Adapting Mechanisms for Eye Functions and Health

“…Finally, melatonin drives the modulation of rod dark adaptation and thus it potentially protects the retina from light-induced damage during the day. 110 Consistently with these experimental findings, several studies have shown that administration of exogenous melatonin can protect photoreceptors from apoptosis in mouse models of retinitis pigmentosa 111 , 112 and that melatonin signaling is involved in the modulation of rod and cone photoreceptor viability during aging. 113 , 114 A protective effect of melatonin on photoreceptor cells has been also observed in humans since administration of exogenous melatonin (3 mg) delayed the progression of age related macular degeneration (AMD) in a few patients.…”

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

“…For P23H rats carrying a mutation defect, adding melatonin into the drinking water alleviates the photoreceptors loss and visual impairments (Lax et al, 2011). Daily injection of melatonin also retards the photoreceptor degeneration in the rd10 and rds mice (Liang et al, 2001;Xu et al, 2017). More excitingly, a clinical investigation shows that the age-related macular degeneration (AMD) patients have lower melatonin level, and the oral melatonin supplements delay the macular degeneration and improve the visual acuity of these patients (Crooke et al, 2017).…”

Mechanisms of Photoreceptor Death in Retinitis Pigmentosa

“…Pharmacological inhibition of microglial activation and cytokine release has been shown to reduce photoreceptor cell death [ 107 , 108 ]. Down-regulation of pathways involved in innate immunity and inflammation were also found to reduce retinal degeneration and preserve photoreceptor function in Rho P347S mice [ 109 ].…”