Zebrafish Bioassay for Screening Therapeutic Candidates Based on Melanotrophic Activity.

Ted I Hong,Patrick Scheerer,Cheol-Hee Kim,Gunnar Kleinau,Kyu-Seok Hwang,Tae-Ik Choi,Seung-Hyun Jung,Jeong Kyu Bang

doi:10.3390/ijms22179313

Abstract

In this study, we used the zebrafish animal model to establish a bioassay by which physiological efficacy differential of alpha-melanocyte-stimulating hormone (α-MSH) analogues could be measured by melanosome dispersion in zebrafish larvae. Brain-skin connection research has purported the interconnectedness between the nervous system and skin physiology. Accordingly, the neuropeptide α-MSH is a key regulator in several physiological processes, such as skin pigmentation in fish. In mammals, α-MSH has been found to regulate motivated behavior, appetite, and emotion, including stimulation of satiety and anxiety. Several clinical and animal model studies of autism spectrum disorder (ASD) have already demonstrated the effectiveness of α-MSH in restoring the social deficits of autism. Therefore, we sought to analyze the effect of synthetic and naturally-occurring α-MSH variants amongst different species. Our results showed that unique α-MSH derivatives from several fish species produced differential effects on the degree of melanophore dispersion. Using α-MSH human form as a standard, we could identify derivatives that induced greater physiological effects; particularly, the synthetic analogue melanotan-II (MT-II) exhibited a higher capacity for melanophore dispersion than human α-MSH. This was consistent with previous findings in an ASD mouse model demonstrating the effectiveness of MT-II in improving ASD behavioral symptoms. Thus, the melanophore assay may serve as a useful screening tool for therapeutic candidates for novel drug discovery.

Highlights

Α-melanocyte-stimulating hormone (MSH) acts as the endogenous ligand for melanocortin receptor 1 (MC1R), which is expressed on the cell membrane of teleost melanophores and plays a key role in skin pigmentation [5,6]
Our findings showed that the synthetic α-MSH analogue, melanotan-II (MT-II), exhibited the highest potency among the derivatives tested, which corresponded to high efficacy in behavioral studies conducted in a mouse model of autism spectrum disorder (ASD) [7]
Distinct sets of compounds act via specific G-protein-coupled receptors (GPCRs), setting off signaling cascades that alter intracellular concentration of cyclic adenosine monophosphate

Summary

Introduction

Melanocortins are a family of peptides initially discovered as factors involved in the regulation of skin color in frogs. Melanocortin peptides derive from the protein precursor, pro-opiomelanocortin (POMC) [2]. POMC expression has been detected in various central and peripheral locales, such as the hypothalamus, skin, and placenta [3]; the major site of expression is the pituitary gland [4]. Tissue-specific post-translational processing of POMC preproprotein produces several mature hormones including four distinct melanocortin peptides—adrenocorticotrophic hormone (ACTH), α-melanocyte-stimulating hormone (MSH), β-MSH, and γ-MSH. Α-MSH acts as the endogenous ligand for melanocortin receptor 1 (MC1R), which is expressed on the cell membrane of teleost melanophores and plays a key role in skin pigmentation [5,6]. Research has demonstrated that α-MSH analogues show effectiveness as a pharmacological therapeutic for ASD [7,8]

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