Related Experiment Video
Updated: Jul 22, 2026
Pharmacologic Induction of Epidermal Melanin and Protection Against Sunburn in a Humanized Mouse Model
Published on: September 7, 2013
Activation of Melanocortin Receptors MC 1 and MC 5 Attenuates Retinal Damage in Experimental Diabetic Retinopathy
S Rossi1, R Maisto2, C Gesualdo1
1Multidisciplinary Department of Medical-Surgical and Dental Specialties, Second University of Naples, 80138 Naples, Italy.
Abstract:
We hypothesize that melanocortin receptors (MC) could activate tissue protective circuit in a model of streptozotocin- (STZ-) induced diabetic retinopathy (DR) in mice. At 12-16 weeks after diabetes induction, fluorescein angiography (FAG) revealed an approximate incidence of 80% microvascular changes, typical of DR, in the animals, without signs of vascular leakage. Occludin progressively decreased in the retina of mice developing retinopathy. qPCR of murine retina revealed expression of two MC receptors, Mc1r and Mc5r. The intravitreal injection (5 μL) of the selective MC1 small molecule agonist BMS-470539 (33 μmol) and the MC5 peptidomimetic agonist PG-901 (7.32 nM) elicited significant protection with regular course and caliber of retinal vessels, as quantified at weeks 12 and 16 after diabetes induction. Mouse retina homogenate settings indicated an augmented release of IL-1α, IL-1β, IL-6, MIP-1α, MIP-2α, MIP-3α, and VEGF from diabetic compared to nondiabetic mice. Application of PG20N or AGRP and MC5 and MC1 antagonist, respectively, augmented the release of cytokines, while the agonists BMS-470539 and PG-901 almost restored normal pattern of these mediators back to nondiabetic values. Similar changes were quantified with respect to Ki-67 staining. Finally, application of MC3-MC4 agonist/antagonists resulted to be inactive with respect to all parameters under assessment.
Insights
Melanocortin receptors (MC) activation protects against diabetic retinopathy (DR) in mice by restoring retinal vessel integrity and reducing inflammatory markers. This suggests a potential therapeutic pathway for managing DR complications.
Area of Science:
- Ophthalmology
- Endocrinology
- Pharmacology
Background:
- Diabetic retinopathy (DR) is a major complication of diabetes, characterized by retinal microvascular changes.
- Current treatments for DR have limitations, necessitating the exploration of novel therapeutic targets.
- Melanocortin receptors (MC) are implicated in various physiological processes, including inflammation and tissue protection.
Purpose of the Study:
- To investigate the potential of melanocortin receptors (MC) to activate tissue-protective circuits in a mouse model of streptozotocin-induced diabetic retinopathy (STZ-DR).
- To evaluate the therapeutic efficacy of MC1 and MC5 receptor agonists in mitigating DR-associated vascular and inflammatory changes.
Main Methods:
- Induction of DR in mice using streptozotocin (STZ).
- Assessment of retinal microvascular changes using fluorescein angiography (FAG) and quantification of occludin levels.
- Intravitreal administration of selective MC1 (BMS-470539) and MC5 (PG-901) receptor agonists.
- Measurement of inflammatory mediators (cytokines, VEGF) and cell proliferation (Ki-67) in retinal homogenates.
- Evaluation of MC3-MC4 receptor agonists/antagonists for comparison.
Main Results:
- STZ-induced diabetes led to significant microvascular changes (80% incidence) and decreased occludin in retinal vessels by 12-16 weeks.
- Intravitreal injection of MC1 and MC5 agonists (BMS-470539 and PG-901) significantly protected retinal vessels, maintaining regular caliber and course.
- Diabetic retinas showed elevated levels of inflammatory cytokines (IL-1α, IL-1β, IL-6) and VEGF; agonists restored these to near-normal levels.
- MC1 and MC5 antagonists exacerbated cytokine release, while agonists normalized it, correlating with Ki-67 staining.
- MC3-MC4 receptor agonists/antagonists showed no significant effect on assessed parameters.
Conclusions:
- Activation of melanocortin receptors, specifically MC1 and MC5, demonstrates significant protective effects against diabetic retinopathy in a mouse model.
- MC agonists appear to modulate inflammatory pathways and preserve retinal vascular integrity, offering a potential therapeutic strategy for DR.
- MC1 and MC5 receptors represent promising targets for the development of novel treatments to prevent or manage diabetic retinopathy.
