Contents lists available at ScienceDirect Biomedicine & Pharmacotherapy journal homepage: www.elsevier.com/locate/biopha Review Autism spectrum disorder (ASD): Disturbance of the melatonin system and its implications Zhou-yue Wu a , Shu-dai Huang a , Jin-jun Zou a , Qin-xin Wang a , Muhammad Naveed a , Hai-nan Bao a , Wei Wang a , Kohji Fukunaga b , Feng Han a, * a Key Laboratory of Cardiovascular & Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China b Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan ARTICLE INFO Keywords: Autism spectrum disorder Melatonin Neurodevelopmental Sleep disturbances Circadian rhythms ABSTRACT The molecular mechanisms underlying autism spectrum disorder (ASD) remain elusive, which limits the man- agement options available in the clinic. Accumulating evidence indicates that the pineal gland/melatonin system is associated with the progression of ASD. Here, we review recent advances in our understanding of various mechanisms involving pathological process of ASD, including the abnormal breakdown of melatonin synthesis, the disturbance of intracellular MTNR1A signaling, the effects exerted by melatonin on hippocampal protein serine/threonine kinases, and immune dysregulation/inflammation during ASD. We believe that an in-depth understanding of the interplay between the action of the melatonin system and the onset of autism could pro- mote the development of novel therapeutic strategies against ASD. We anticipate that targeting the neuro- transmitters upstream pathway and downstream of melatonin in brain will lead to potential therapeutic treat- ment for ASD. 1. Introduction Autism spectrum disorder (ASD) is a cluster of sophisticated lifelong neurodevelopmental disorders caused by impairments of the central nervous system (CNS). Special features of ASD patients include deficits in social communication/interaction, restricted interests, and repetitive patterns of behavior [1,2]. Currently, ASD affects approximately 1% of the population worldwide [3,4]. Psychotropic pharmacotherapy is ex- tensively employed to alleviate emotional and behavioral symptoms in ASD, but no clinically available cure touches the pathological core of ASD. Melatonin is an indoleamine secreted from the pineal gland under the guidance of the circadian rhythm, with L-tryptophan as an indirect precursor [5–7]. The majority of melatonin can be found in the hy- pothalamic suprachiasmatic nucleus (SCN) and cerebrospinal fluid (CSF), and this compound exerts an anti-inflammatory effect in mul- tiple sclerosis (MS) [8–14]. Additionally, melatonin is known for its antioxidant impact under certain circumstances [13,15–25]. The pleiotropic molecule also takes part in the repair of DNA damage [12,13,18,21,22,24,26–28]. Moreover, accumulated evidence has sup- ported melatonin as a significant player in sleep/wake cycle regulation [29], biological rhythms [30], and especially neuroprotection [30–32]. Multiple neurotransmitters are involved in different aspects of the melatonin system. The upstream neurotransmitters include serotonin (5-HT) and other related proteases, reflecting the influences of mela- tonin synthesis abnormality in ASD. Also, gene variation can affect some upstream neurotransmitters in the upstream. Meanwhile, 6-hy- droxymelatonin, one downstream metabolite, is widely used to detect for melatonin in clinics. Abnormal release patterns and concentrations of melatonin, along with a disturbing cell signaling network, collec- tively make patients face the risk factors of ASD. This complex process is often affected by the environment [33], heredity [34], maternal melatonin levels [35], synthesis, and metabolic pathways [36]. New insights into these associations could, therefore, greatly benefit ASD https://doi.org/10.1016/j.biopha.2020.110496 Received 18 January 2020; Received in revised form 25 June 2020; Accepted 2 July 2020 Abbreviations: TPH, tryptophan hydroxylase; AANAT, alkylamine N-acetyltransferase; ASMT, acetylserotonin O-methyltransferase; ASD, autism spectrum disorder; SCN, suprachiasmatic nucleus; CSF, cerebrospinal fluid; DNA, Deoxyribonucleic Acid; MT, melatonin; MTNR1A, Melatonin receptor 1A; MTNR1B, Melatonin re- ceptor 1B; 6-SM, 6-sulfatoxymelatonin; 5-HTP, 5-hydroxytryptophan; NAS, N-acetyl serotonin; B-SNPs, B- single nucleotide polymorphism; 50-UTR, 50-untranslated region; SNP, single nucleotide polymorphism; CYP1A2, cytochrome P1A2; CaMKII, Calmodulin-Dependent Protein Kinase II; PKC, protein kinase C; VPA, valproate; GPCR, G Protein-Coupled Receptor; GTPases, GTP hydrolases; PKA, protein kinase A; ERK, extracellular regulated protein kinases; MAPK, mitogen-activated protein kinase; LTP, long-term potentiation ⁎ Corresponding author. E-mail address: fenghan169@njmu.edu.cn (F. Han). Biomedicine & Pharmacotherapy 130 (2020) 110496 0753-3322/ © 2020 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/). T