Neuroscience and Biobehavioral Reviews 99 (2019) 117–127 Contents lists available at ScienceDirect Neuroscience and Biobehavioral Reviews journal homepage: www.elsevier.com/locate/neubiorev Review article The evolutionarily conserved role of melatonin in CNS disorders and T behavioral regulation: Translational lessons from zebrafish Rafael Genarioa,1, Ana C.V.V. Giacominia,b,1, Konstantin A. Demind,f, Bruna E. dos Santosa, Natalia I. Marchioria, Angrey D. Volging, Alim Bashirzadeg,h, Tamara G. Amstislavskayag,h, ⁎ ⁎⁎ Murilo S. de Abreua,c, , Allan V. Kalueffe,f,g,i,j,k, a Bioscience Institute, University of Passo Fundo (UPF), Passo Fundo, RS, Brazil b Postgraduate Program in Environmental Sciences, University of Passo Fundo (UPF), Passo Fundo, Brazil c The International Zebrafish Neuroscience Research Consortium (ZNRC), Slidell, LA,USA d Institute of Experimental Medicine, Almazov National Medical Research Centre, Ministry of Healthcare of Russian Federation, St. Petersburg, Russia e School of Pharmacy, Southwest University, Chongqing, China f Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia g Laboratory of Translational Biopsychiatry, Research Institute of Physiology and Basic Medicine, Novosibirsk, Russia h Department of Neuroscience, Novosibirsk State University, Novosibirsk, Russia i Ural Federal University, Ekaterinburg, Russia j Granov’s Russian Scientific Research Center of Radiology and Surgical Technologies, Ministry of Healthcare of Russian Federation, Pesochny, Russia k Almazov National Medical Research Centre, Ministry of Healthcare of Russian Federation, St. Petersburg, Russia ARTICLE INFO ABSTRACT Keywords: Melatonin is an important hormone regulating circadian rhythm, neuroprotection and neuroimmune processes. Melatonin However, its exact physiological roles in brain mechanisms remain poorly understood. Here, we summarize the Animal model mounting evidence implicating melatonin in brain disorders and behavior, based on clinical and experimental Genetic model studies in-vivo. In addition to rodent models, the zebrafish (Danio rerio) is becoming increasingly utilized in Behavioral regulation biomedical and neuroscience research. Here, we discuss melatonin neurobiology of zebrafish, and parallel these CNS findings with clinical and rodent data. We also discuss the genomic effects of melatonin in zebrafish, andem- phasize the growing utility of zebrafish models to study melatonin neurobiology and drug discovery. 1. Introduction Dubocovich et al., 1997; Nonno et al., 1998; Sugden et al., 1997; Teh and Sugden, 1998)) and Mtnr1b (Ki = 0.18-0.48 nM (Beresford et al., 1998; Melatonin (methoxyindole, n-acetyl-5-methoxytryptamine) is a pineal Dubocovich et al., 1997; Nonno et al., 1998; Sugden et al., 1997; Teh and gland hormone secreted at night under normal light/dark conditions Sugden, 1998)), expressed in different organs, including the brain. (Gastel et al., 1998; Reiter, 1991). Its production follows the stimulation Through these receptors, melatonin regulates circadian rhythm, sleep, of the postganglionic nerve terminals of the sympathetic nervous system, hunger and temperature (Brzezinski et al., 2005; Scheer and Czeisler, releasing norepinephrine that activates pinealocytes to produce melatonin 2005) as well as the expression of several important circadian genes, in- (Pandi-Perumal et al., 2008; Schomerus and Korf, 2006; Simonneaux, cluding Clock1a, Per1b and Per2 in mammalian brain and some other 2003). To a much lesser extent, melatonin is produced by the retina, la- organs (Khan et al., 2016). Normal circadian rhythm is critical for the crimal gland, gastrointestinal tract, skin and ovary (Ahmad et al., 2016; health of an organism (Evans and Davidson, 2013), as its disturbances Reiter et al., 2014). Melatonin is not stored in the producing cells, and is often trigger psychiatric disorders, such as depression and anxiety released after biosynthesis, peaking during the night (Arendt, 1995; (Billiard et al., 1994; Germain and Kupfer, 2008; Kaplan and Harvey, Schomerus and Korf, 2006; Tan et al., 2015; Wurtman et al., 1963). In 2009; Liu et al., 2007; Tapia-Osorio et al., 2013). mammals, physiological effects of melatonin are exerted through several Melatonin has several other critical physiological roles, exerting melatonin receptors, Mtnr1a (Ki = 0.08-0.88 nM (Beresford et al., 1998; anti-inflammatory (Celinski et al., 2014; Gonciarz et al., 2012, 2011), ⁎ Corresponding authors at: Bioscience Institute, University of Passo Fundo, Passo Fundo, Brazil. ⁎⁎ Corresponding authors at: School of Pharmacy, Southwest University, Chongqing, China. E-mail addresses: [email protected] (M.S. de Abreu), [email protected] (A.V. Kalueff). 1 Shared first authorship https://doi.org/10.1016/j.neubiorev.2018.12.025 Received 7 November 2018; Received in revised form 12 December 2018; Accepted 20 December 2018 Available online 03 January 2019 0149-7634/ © 2019 Elsevier Ltd. All rights reserved. R. Genario, et al. Neuroscience and Biobehavioral Reviews 99 (2019) 117–127 antioxidant (Ahmad et al., 2016), anti-cancer (Asghari et al., 2017; psychiatric illnesses (Kupfer, 2015), and melatonin shows anxiolytic Mills et al., 2005; Reiter et al., 2014; Srinivasan et al., 2008), immuno- effects (Wilhelmsen et al., 2011) in oncological (Hansen et al., 2014) modulating (Ángeles Esteban et al., 2013; Carrillo-Vico et al., 2013) and pediatric patients (Marseglia et al., 2015a). Depression is also a and pancreas-regulating effects (Mulder et al., 2009; Peschke, 2008; common CNS disorder (MÉNard et al., 2016) often associated with low Peschke et al., 2006). Anti-inflammatory effects of melatonin involve production, aberrant metabolism of melatonin (Crasson et al., 2004; reducing pro-inflammatory cytokines interleukins (IL) IL-1, IL-6 and Khaleghipour et al., 2012) and altered Mtnr1a and Mtnr1b receptor tumor necrosis factor alpha (TNF-α) in plasma, brain and other organs signaling (Cardinali et al., 2012). In patients with the delayed sleep (Celinski et al., 2014; Gonciarz et al., 2012, 2011). Here, we summarize phase syndrome, melatonin supplementation improves sleep and re- the mounting evidence on the critical role of melatonin in CNS dis- duces depressive symptoms (Rahman et al., 2010), whereas anti- orders and behavior in both clinical and experimental studies in-vivo, depressant effects of buspirone are potentiated by melatonin in patients focusing on important translational lessons what can be learnt from with major depression (Fava et al., 2012), also improving their cogni- animal models. tive performance (Targum et al., 2015). Neurodegenerative diseases are characterized by overt cognitive 2. Clinical effects of melatonin in CNS disorders deficits (Poletti et al., 2012; Seeley et al., 2009) due to apoptosis and neurodegeneration (Wang, 2005). Presenting as progressive motor, One of the best-studied clinical effects of melatonin is its pro-hyp- cognitive and emotional deficits, Huntington's disease (Reilmann et al., notic action (Altun and Ugur-Altun, 2007; Reiter, 2003). Melatonin 2014; Walker, 2007) is often accompanied by reduced plasma levels of supplementation can be used as the main treatment of insomnia, to melatonin (Kalliolia et al., 2014) and aberrant metabolism of its pre- normalize the circadian cycle (Auld et al., 2017; Cardinali et al., 2016; cursor tryptophan (Stoy et al., 2005). Amyotrophic lateral sclerosis Golombek et al., 2015). For example, melatonin is used in patients with (ALS) is a fatal neurodegenerative disease linked to progressive de- secondary insomnia (Auld et al., 2017; Brzezinski et al., 2005; generation of motor neurons (Kiernan et al., 2011; Nagase et al., 2016; Golombek et al., 2015), whereas melatonin-related drugs (e.g., ra- Robberecht, 2000). In ALS patients, high doses of melatonin reduce melteon (Kuriyama et al., 2014) and agomelatine (Kupfer, 2006)) im- oxidative damage and delay neurodegeneration (Weishaupt et al., prove sleep quality. Additionally, melatonin can serve as a therapy for 2006). Other neurodegenerative disorders responding to therapeutic neurodegenerative disorders (Dowling et al., 2005; Zhang et al., 2016), effects of melatonin include Parkinson's (Hwang, 2013), Alzheimer’s depression (Bouwmans et al., 2018; Cardinali et al., 2012), epilepsy diseases (Smith et al., 2000) and multiple sclerosis (Gilgun-Sherki et al., (Jain et al., 2015) and autism (Andersen et al., 2008; Malow et al., 2004), collectively supporting an important neuroprotective role of this 2012)(Table 1). hormone in vivo (Furio et al., 2007; Zhang et al., 2016). Furthermore, melatonin exerts therapeutic effects in neonatal hy- Melatonin is an efficient antioxidant that easily penetrates through poxic-ischemic encephalopathy, due to its neuroprotective effects as an biological membranes and exerts pleiotropic actions on multiple cells antioxidant and agent that reduces brain injury in these patients (Aly (Milczarek et al., 2010). This hormone also plays an important role in et al., 2015). Melatonin also improves the overall quality of life, in- gestation. For example, women with abnormally functioning placentae creasing the rate of survival and reducing tumor progression in patients during severe preeclampsia display lower melatonin levels (Marseglia with inoperable brain metastases (Lissoni et al., 1994). Melatonin et al., 2015b; Nakamura et al., 2001). The high perinatal susceptibility supplementation improves mood and cognitions in patients with de- to