Melanocortins protect against brain damage and counteract cognitive decline in a transgenic mouse model of moderate Alzheimer׳s disease

Giuliani, Daniela; Galantucci, Maria; Neri, Laura; Canalini, Fabrizio; Calevro, Anita; Bitto, Alessandra; Ottani, Alessandra; Vandini, Eleonora; Sena, Paola; Sandrini, Maurizio; Squadrito, Francesco; Zaffe, Davide; Guarini, Salvatore

doi:10.1016/j.ejphar.2014.06.063

Cited by 28 publications

(34 citation statements)

References 62 publications

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“…The use of 7 to decrease food intake in mice demonstrates its utility as a probe for metabolic diseases such as obesity. Additionally, the current study's finding that melanocortin bivalent are well tolerated and functionally active in vivo indicates that they will also be useful probes for other disease states in which the melanocortin system plays a role including Alzheimer's disease, 18-19 sexual function, 3, 26 and social disorders. 27-28 …”

Section: Resultsmentioning

confidence: 82%

An in Vitro and in Vivo Investigation of Bivalent Ligands That Display Preferential Binding and Functional Activity for Different Melanocortin Receptor Homodimers

et al. 2016

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Pharmacological probes for the melanocortin receptors have been utilized for studying various disease states including cancer, sexual function disorders, Alzheimer's disease, social disorders, cachexia, and obesity. This study focused on the design and synthesis of bivalent ligands to target melanocortin receptor homodimers. Lead ligands increased binding affinity by 14- to 25-fold and increased cAMP signaling potency by 3- to 5-fold compared to their monovalent counterparts. Unexpectedly, different bivalent ligands showed preferences for particular melanocortin receptor subtypes depending on the linker that connected the binding scaffolds suggesting structural differences between the various dimer subtypes. Homobivalent compound 12 (CJL-1-140) possessed a functional profile that was unique from its monovalent counterparts providing evidence of the discrete effects of bivalent ligands. Lead compound 7 (CJL-1-87) significantly decreased feeding in mice after intracerebroventricular administration. To the best of our knowledge, this is the first report of a melanocortin bivalent ligand's in vivo physiological effects.

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Section: Resultsmentioning

confidence: 82%

An in Vitro and in Vivo Investigation of Bivalent Ligands That Display Preferential Binding and Functional Activity for Different Melanocortin Receptor Homodimers

et al. 2016

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“…In line with this, by depleting Treg, performing gene expression studies, conducting functional assays in isolated neurons, and generating bone marrow chimeric mice, we identified a strong and direct neuroprotective potential of NDP-MSH in inflammation-associated and progressive degenerative CNS diseases. The ability of melanocortins to reduce neuronal damage after traumatic brain injury or counteract cognitive decline in mice with Alzheimer's disease has already been discussed (44,45); however, the underlying molecular mechanisms…”

Section: Discussionmentioning

confidence: 99%

Melanocortin-1 receptor activation is neuroprotective in mouse models of neuroinflammatory disease

et al. 2016

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“…For example, α-MSH, through activation of MC4R, ameliorates brain damage and cognition decline in mammalian models of cerebral ischemia [43] and Alzheimer’s disease [44], respectively. We have also shown that α-MSH acts via MC4R to antagonize glutamate-induced excitotoxicity in developing chicken retinas [23].…”

Section: Discussionmentioning

confidence: 99%

Α-Melanocyte-Stimulating Hormone Protects Early Diabetic Retina from Blood-Retinal Barrier Breakdown and Vascular Leakage via MC4R

Cai

Yang

Hou

et al. 2018

Cell Physiol Biochem

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Background/Aims: Blood-retinal barrier (BRB) breakdown and vascular leakage is the leading cause of blindness of diabetic retinopathy (DR). Hyperglycemia-induced oxidative stress and inflammation are primary pathogenic factors of this severe DR complication. An effective interventional modality against the pathogenic factors during early DR is needed to curb BRB breakdown and vascular leakage. This study sought to examine the protective effects of α-Melanocyte-stimulating hormone (α-MSH) on early diabetic retina against vascular hyperpermeability, electrophysiological dysfunction, and morphological deterioration in a rat model of diabetes and probe the mechanisms underlying the α-MSH’s anti-hyperpermeability in both rodent retinas and simian retinal vascular endothelial cells (RF6A). Methods: Sprague Dawley rats were injected through tail vein with streptozotocin to induce diabetes. The rats were intravitreally injected with α-MSH or saline at Week 1 and 3 after hyperglycemia. In another 2 weeks, Evans blue assay, transmission electron microscopy, electroretinogram (ERG), and hematoxylin and eosin (H&E) staining were performed to examine the protective effects of α-MSH in diabetic retinas. The expression of pro-inflammatory factors and tight junction at mRNA and protein levels in retinas was analyzed. Finally, the α-MSH’s anti-hyperpermeability was confirmed in a high glucose (HG)-treated RF6A cell monolayer transwell culture by transendothelial electrical resistance (TEER) measurement and a fluorescein isothiocyanate-Dextran assay. Universal or specific melanocortin receptor (MCR) blockers were also employed to elucidate the MCR subtype mediating α-MSH’s protection. Results: Evans blue assay showed that BRB breakdown and vascular leakage was detected, and rescued by α-MSH both qualitatively and quantitatively in early diabetic retinas; electron microscopy revealed substantially improved retinal and choroidal vessel ultrastructures in α-MSH-treated diabetic retinas; scotopic ERG suggested partial rescue of functional defects by α-MSH in diabetic retinas; and H&E staining revealed significantly increased thickness of all layers in α-MSH-treated diabetic retinas. Mechanistically, α-MSH corrected aberrant transcript and protein expression of pro-inflammatory factor and tight junction genes in the diseased retinas; moreover, it prevented abnormal changes in TEER and permeability in HG-stimulated RF6A cells, and this anti-hyperpermeability was abolished by a universal MCR blocker or an antagonist specific to MC4R. Conclusions: This study showed previously undescribed protective effects of α-MSH on inhibiting BRB breakdown and vascular leakage, improving electrophysiological functions and morphology in early diabetic retinas, which may be due to its down-regulating pro-inflammatory factors and augmenting tight junctions. α-MSH acts predominantly on MC4R to antagonize hyperpermeability in retinal microvessel endothelial cells.

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Melanocortins protect against brain damage and counteract cognitive decline in a transgenic mouse model of moderate Alzheimer׳s disease

Cited by 28 publications

References 62 publications

An in Vitro and in Vivo Investigation of Bivalent Ligands That Display Preferential Binding and Functional Activity for Different Melanocortin Receptor Homodimers

An in Vitro and in Vivo Investigation of Bivalent Ligands That Display Preferential Binding and Functional Activity for Different Melanocortin Receptor Homodimers

Melanocortin-1 receptor activation is neuroprotective in mouse models of neuroinflammatory disease

Α-Melanocyte-Stimulating Hormone Protects Early Diabetic Retina from Blood-Retinal Barrier Breakdown and Vascular Leakage via MC4R

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