NDP-α-MSH induces intense neurogenesis and cognitive recovery in Alzheimer transgenic mice through activation of melanocortin MC4 receptors

Giuliani, Daniela; Neri, Laura; Canalini, Fabrizio; Calevro, Anita; Ottani, Alessandra; Vandini, Eleonora; Sena, Paola; Zaffe, Davide; Guarini, Salvatore

doi:10.1016/j.mcn.2015.05.004

Cited by 35 publications

(48 citation statements)

References 67 publications

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“…21–36 Many of these studies focus on the development of bivalent ligands for their use as high affinity imaging tools or targeting agents for melanoma. 24–36 Given that chemical probes for the five melanocortin receptor subtypes (MC1-5R) have been utilized to study several diseases and disorders including Alzheimer’s disease, 44–46 sexual function disorders, 47, 48 social disorders, 49, 50 cachexia, 51–56 and obesity; 21, 57, 58 it is of interest to study the biological functions of bivalent ligands targeting these receptors. The limited reports of the in vitro functional effects of melanocortin homobivalent have all shown increased functional potency (up to 16-fold).…”

Section: Introductionmentioning

confidence: 99%

A Direct in Vivo Comparison of the Melanocortin Monovalent Agonist Ac-His-DPhe-Arg-Trp-NH₂ versus the Bivalent Agonist Ac-His-DPhe-Arg-Trp-PEDG20-His-DPhe-Arg-Trp-NH₂: A Bivalent Advantage

Lensing

Adank

Wilber

et al. 2017

ACS Chem. Neurosci.

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Bivalent ligands targeting putative melanocortin receptor dimers have been developed and characterized in vitro, however studies of their functional in vivo effects have been limited. The current report compares the effects of homobivalent ligand CJL-1-87, Ac-His-DPhe-Arg-Trp-PEDG20-His-DPhe-Arg-Trp-NH2, to monovalent ligand CJL-1-14, Ac-His-DPhe-Arg-Trp-NH2 on energy homeostasis in mice after central intracerebroventricular (ICV) administration into the lateral ventricle of the brain. Bivalent ligand CJL-1-87 had noteworthy advantages as an anti-obesity probe over CJL-1-14 in a fasting-refeeding in vivo paradigm. Treatment with CJL-1-87 significantly decreased food intake compared to CJL-1-14 or saline (50% less intake 2 to 8 hours after treatment). Furthermore, CJL-1-87 treatment decreased the respiratory exchange ratio (RER) without changing the energy expenditure indicating that fats were being burned as the primary fuel source. Additionally, CJL-1-87 treatment significantly lowered body fat mass percentage 6 hours after administration (p < 0.05) without changing the lean mass percentage. The bivalent ligand significantly decreased insulin, C-peptide, leptin, GIP, and resistin plasma levels compared to levels after CJL-1-14 or saline treatments. Alternatively, ghrelin plasma levels were significantly increased. Serum stability of CJL-1-87 and CJL-1-14 (T1/2 = 6.0 h and 16.8 h, respectively) was sufficient to permit physiological effects. The differences in binding affinity of CJL-1-14 compared to CJL-1-87 are speculated as a possible mechanism for the bivalent ligand’s unique effects. We also provide in vitro evidence for the formation of a MC3R-MC4R heterodimer complex, for the first time to our knowledge, that may be an unexploited neuronal molecular target. Regardless of the exact mechanism, the advantageous ability of CJL-1-87 compared to CJL-1-14 to increase in vitro binding affinity, increase the duration of action in spite of decreased serum stability, decrease in vivo food intake, decrease mice’s body fat percent, and differentially affect mouse hormone levels demonstrates the distinct characteristics achieved from the current melanocortin agonist bivalent design strategy.

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Section: Introductionmentioning

confidence: 99%

A Direct in Vivo Comparison of the Melanocortin Monovalent Agonist Ac-His-DPhe-Arg-Trp-NH₂ versus the Bivalent Agonist Ac-His-DPhe-Arg-Trp-PEDG20-His-DPhe-Arg-Trp-NH₂: A Bivalent Advantage

Lensing

Adank

Wilber

et al. 2017

ACS Chem. Neurosci.

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“…Behavioral tests of these animals showed improved cognitive function (Table 1). Increased neurogenesis and decreased neuroinflammation were also described (Giuliani et al 2015).…”

Section: Journal Of Endocrinologymentioning

confidence: 97%

“…The neuroprotective properties of melanocortin agonists have been demonstrated in several models of neurodegeneration (Giuliani et al 2017). In different mouse models of AD-like pathology, such as in Tg2576 mice (Giuliani et al 2014b(Giuliani et al , 2015, TgCRND8 mice (Ma & McLaurin 2014) and in APP/PS1/P301L mice (Giuliani et al 2014a), intraperitoneal (i.p.) injection of the melanocortin analog NDP-α-MSH (Nle 4 , D-Phe 7 )-α melanocyte-stimulating hormone) or α-MSH for several weeks improved synaptic plasticity and decreased neuronal loss, Aβ levels, tau phosphorylation in brain.…”

Section: Journal Of Endocrinologymentioning

confidence: 99%

The impact of anorexigenic peptides in experimental models of Alzheimer’s disease pathology

Maletı́nská

Popelová

Železná

et al. 2019

Journal of Endocrinology

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Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder in the elderly population. Numerous epidemiological and experimental studies have demonstrated that patients who suffer from obesity or type 2 diabetes mellitus have a higher risk of cognitive dysfunction and AD. Several recent studies demonstrated that food intake-lowering (anorexigenic) peptides have the potential to improve metabolic disorders and that they may also potentially be useful in the treatment of neurodegenerative diseases. In this review, the neuroprotective effects of anorexigenic peptides of both peripheral and central origins are discussed. Moreover, the role of leptin as a key modulator of energy homeostasis is discussed in relation to its interaction with anorexigenic peptides and their analogs in AD-like pathology. Although there is no perfect experimental model of human AD pathology, animal studies have already proven that anorexigenic peptides exhibit neuroprotective properties. This phenomenon is extremely important for the potential development of new drugs in view of the aging of the human population and of the significantly increasing incidence of AD.

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“…The MC4R agonist is also targeted for treating male and female sexual dysfunction [8]. Moreover, Alzheimer transgenic mice showed neurogenesis and cognitive recovery through the MC4R activation [9]. It has been suggested that the MC4R agonists can also treat autism and schizophrenia through activation of the central oxytocin system [10].…”

Section: Introductionmentioning

confidence: 99%

Novel approaches to the design of bioavailable melanotropins

Zhou

Cai

2017

Expert Opinion on Drug Discovery

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Introduction The melanocortin system is a primordial and critical system for survival, involved in a wide variety of physiological functions. It includes melanocortin receptors (MCRs) and melanotropin ligands (MCLs). MCRs are important drug targets that can regulate several key physiological processes. Extensive efforts have been made to develop peptide and peptidomimetics targeting melanocortin receptors including MC1R, MC3R, MC4R and MC5R. Most research is focused on developing potent and selective melanotropins. However, developing bioavailable melanotropins remains challenging. Areas covered Herein, the authors summarize promising strategies for developing bioavailable MCLs by using cyclized N-methylated melanotropins, and using cyclotide and tetrapeptide as templates. They discuss their unique advantages in oral availability and targeting MCRs in the central nervous system or in peripheral tissues. Finally, they discuss the observed differences in thepharmacology of MCRs between in vitro and in vivo tests. Expert opinion N-methylated cyclized melanotropins have great potential to become bioavailable drugs targeting MCRs in the brain, while MCR-grafted cyclotides tend to target MCRs in peripheral tissue. A better understanding of the biased signaling process is a new challenge and opportunity for the future discovery of bioavailable MCLs.

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NDP-α-MSH induces intense neurogenesis and cognitive recovery in Alzheimer transgenic mice through activation of melanocortin MC4 receptors

Cited by 35 publications

References 67 publications

A Direct in Vivo Comparison of the Melanocortin Monovalent Agonist Ac-His-DPhe-Arg-Trp-NH₂ versus the Bivalent Agonist Ac-His-DPhe-Arg-Trp-PEDG20-His-DPhe-Arg-Trp-NH₂: A Bivalent Advantage

A Direct in Vivo Comparison of the Melanocortin Monovalent Agonist Ac-His-DPhe-Arg-Trp-NH₂ versus the Bivalent Agonist Ac-His-DPhe-Arg-Trp-PEDG20-His-DPhe-Arg-Trp-NH₂: A Bivalent Advantage

The impact of anorexigenic peptides in experimental models of Alzheimer’s disease pathology

Novel approaches to the design of bioavailable melanotropins

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NDP-α-MSH induces intense neurogenesis and cognitive recovery in Alzheimer transgenic mice through activation of melanocortin MC4 receptors

Cited by 35 publications

References 67 publications

A Direct in Vivo Comparison of the Melanocortin Monovalent Agonist Ac-His-DPhe-Arg-Trp-NH2 versus the Bivalent Agonist Ac-His-DPhe-Arg-Trp-PEDG20-His-DPhe-Arg-Trp-NH2: A Bivalent Advantage

A Direct in Vivo Comparison of the Melanocortin Monovalent Agonist Ac-His-DPhe-Arg-Trp-NH2 versus the Bivalent Agonist Ac-His-DPhe-Arg-Trp-PEDG20-His-DPhe-Arg-Trp-NH2: A Bivalent Advantage

The impact of anorexigenic peptides in experimental models of Alzheimer’s disease pathology

Novel approaches to the design of bioavailable melanotropins

Contact Info

Product

Resources

About

A Direct in Vivo Comparison of the Melanocortin Monovalent Agonist Ac-His-DPhe-Arg-Trp-NH₂ versus the Bivalent Agonist Ac-His-DPhe-Arg-Trp-PEDG20-His-DPhe-Arg-Trp-NH₂: A Bivalent Advantage

A Direct in Vivo Comparison of the Melanocortin Monovalent Agonist Ac-His-DPhe-Arg-Trp-NH₂ versus the Bivalent Agonist Ac-His-DPhe-Arg-Trp-PEDG20-His-DPhe-Arg-Trp-NH₂: A Bivalent Advantage