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Melatonin for Autism Spectrum Disorder: Beyond Sleep Disturbances
Autism-Open Access

Autism-Open Access
Open Access

ISSN: 2165-7890

+44 1223 790975

Editorial - (2018) Volume 8, Issue 2

Melatonin for Autism Spectrum Disorder: Beyond Sleep Disturbances?

Dario Siniscalco1*, Nicola Antonucci2 and Rita Rezzani3
1Department of Experimental Medicine, Division of Pharmacology, University of Campania, via S. Maria di Costantinopoli, 16 - 80138 Napoli, Italy, E-mail: info@antonucci.eu
2Biomedical Centre for Autism Research and Treatment, 70124 Bari, Italy, E-mail: info@antonucci.eu
3Department of Clinical and Experimental Sciences, Division of Anatomy and Physiopathology, University of Brescia, 25121 Brescia, Italy, E-mail: info@antonucci.eu
*Corresponding Author: Dario Siniscalco, Department of Experimental Medicine, Division of Pharmacology, University of Campania, Via S. Maria Di Costantinopoli, 16 - 80138 Napoli, Italy, Tel: +39 (0)81 5665880 Email: ,

Autism spectrum disorder (ASD) affected subjects often suffer from sleep disturbances [1]. Among these, altered time duration, night-time awakenings and anxiety before sleep are reported [2]. Day time behaviour disturbances could affect the onset of sleep problems in ASD [3]. Melatonin (N-acetyl-5-methoxy tryptamine) is a methoxyindole responsible for regulating sleep. This molecule is mainly synthesized and secreted by the pineal gland at night under normal light/dark conditions. As hormone, it carries molecular information about the 24-hours light/dark cycle (circadian rhythm) to the body structures [4]. Its signalling transduction mechanism takes place through activation of G-protein coupled receptors (MT1 and MT2 receptor subtypes) [5]. Interestingly, lower night-time melatonin and melatonin metabolite levels have been reported in ASD children. Several clinical studies demonstrated significative improvements in sleep parameters with exogenous melatonin supplementation in ASD subjects [6]. Recently, a double-blind randomized placebo-controlled study reported 3-month efficacy and safety of a novel paediatric appropriate prolonged release melatonin for insomnia in ASD children and adolescents [7]. Moreover, it is noteworthy to consider that melatonin is also a powerful anti-oxidant molecule [8]. It is able to act as scavenger of free radical species, as well as to enhance endogenous anti-oxidative system and mitochondrial metabolism [9]. Impaired biochemical processes are related to ASD, among others: oxidative stress, endoplasmic reticulum stress, decreased methylation capacity, altered ratio between anti-oxidant reduced glutathione (GSH) and oxidized one (GSSG) [10]. Melatonin supplementation in ASD could exert ameliorative effects in autistic core symptoms, through restoration of disrupted anti-oxidant pathways. Strong inflammation states and immune system dysfunctions have been associated with ASD [11]. Pro-inflammatory cytokines are aberrantly up-regulated in plasma of ASD children [12]. Melatonin acts as pleiotropic molecule also in the regulation of the immune system [13]. This hormone freely moves through blood brain barrier [14] and could restore altered neuro-immune cross-talk. Indeed, as immune-modulatory effect, melatonin is able to stimulate the production of natural killer (NK) cells and lymphocytes CD4+ cells and the inhibition of CD8+ cells [15]. To note, it has been demonstrated that NK cells are strongly decreased in ASD children, indicating a defect in the immune counterregulatory functions [16]. Lastly, mitochondrial dysfunction is present in a significant subgroup of ASD children [17]. Melatonin is also capable of preventing mitochondrial impairment, energy failure, and apoptosis in oxidatively-damaged mitochondria [18]. Interestingly, melatonin helps in regulating hippocampal neural plasticity and in contributing to change in neuronal excitability in mouse [19]. Beyond ASD core symptoms, melatonin could also impact several ASD associated co-morbid conditions, such as anxiety, depression, pain, and gastrointestinal dysfunctions [20]. Melatonin could take a role in regulating gut-brain signalling [21]. This aspect is very important, as the gut-brain axis plays a key role in the development of ASD [22]. Alteration of this signalling axis is associated with low-mild gut inflammation, dysbiosis, gastrointestinal symptoms, and increased intestinal permeability. Restoring gut homeostasis with melatonin could repair all these co-morbidities.

Taken together, all these data highlight a possible molecular mechanism of action for melatonin in ASD management. Experimental and clinical studies addressing molecular effects of melatonin in ASD behavioural symptoms, beyond sleep issues, could offer novel perspectives in ASD research and possible treatment options.

References

  1. Goldman SE, Alder ML, Burgess HJ, Corbett BA, Hundley R, et al. (2017) Characterizing Sleep in Adolescents and Adults with Autism Spectrum Disorders. J Autism Dev Disord 47: 1682-1695.
  2. Baddam SKR, Canapari CA, Noordt SJR, Crowley MJ (2018) Sleep Disturbances in Child and Adolescent Mental Health Disorders: A Review of the Variability of Objective Sleep Markers. Med Sci 6: E46
  3. Malhi P, Kaur A, Singhi P, Sankhyan N (2018) Sleep Dysfunction and Behavioral Daytime Problems in Children with Autism Spectrum Disorders: A Comparative Study. Indian J Pediatr pp: 1-6.
  4. Claustrat B, Leston J (2015) Melatonin: Physiological effects in humans. Neurochirurgie 61: 77-84.
  5. Reppert SM (1997) Melatonin receptors: Molecular biology of a new family of G protein-coupled receptors. J Biol Rhythms 12: 528-531.
  6. Rossignol DA, Frye RE (2014) Melatonin in autism spectrum disorders. Curr Clin Pharmacol 9: 326-334.
  7. Maras A, Schroder CM, Malow BA, Findling RL, Breddy J, et al. (2018) Long-Term Efficacy and Safety of Pediatric Prolonged-Release Melatonin for Insomnia in Children with Autism Spectrum Disorder. J Child Adolesc Psychopharmacol 1: 1-12.
  8. Reiter RJ, Acuna-Castroviejo D, Tan DX, Burkhardt S (2001) Free radical-mediated molecular damage. Mechanisms for the protective actions of melatonin in the central nervous system. Ann N Y Acad Sci 939: 200-215.
  9. Hardeland R (2005) Antioxidative protection by melatonin: Multiplicity of mechanisms from radical detoxification to radical avoidance. Endocrine 27: 119-130.
  10. Siniscalco D, Antonucci N (2013) Possible use of Trichuris suis ova in autism spectrum disorders therapy. Med Hypotheses 81: 1-4.
  11. Siniscalco D, Schultz S, Brigida AL, Antonucci N (2018) Inflammation and Neuro-Immune Dysregulations in Autism Spectrum Disorders. Pharmaceuticals 11: E56.
  12. Inga Jácome MC, Morales Chacòn LM, Vera Cuesta H, Maragoto Rizo C, Whilby Santiesteban M, et al. (2016) Peripheral Inflammatory Markers Contributing to Comorbidities in Autism. Behav Sci 6: E29.
  13. Carrillo-Vico A, Guerrero JM, Lardone PJ, Reiter RJ (2005) A reviews of the multiple actions of melatonin on the immune system. Endocrine 27: 189-200.
  14. Reiter RJ, Tan DX, Manchester LC, Pilar Terron M, Flores LJ, et al. (2007) Medical implications of melatonin: Receptor-mediated and receptor-independent actions. Adv Med Sci 52: 11-28.
  15. Cardinali DP, Esquifino AI, Srinivasan V, Pandi-Perumal SR (2008) Melatonin and the immune system in aging. Neuroimmunomodulation 15: 272-278.
  16. Siniscalco D, Mijatovic T, Bosmans E, Cirillo A, Kruzliak P, et al. (2016) Decreased Numbers of CD57+CD3- Cells Identify Potential Innate Immune Differences in Patients with Autism Spectrum Disorder. In Vivo 30: 83-89.
  17. Rose S, Frye RE, Slattery J, Wynne R, Tippett M, et al. (2014) Oxidative stress induces mitochondrial dysfunction in a subset of autism lymphoblastoid cell lines in a well-matched case control cohort. PLoS One 9: e85436.
  18. Acuna-Castroviejo D, Escames G, Rodriguez MI, Lopez LC (2007) Melatonin role in the mitochondrial function. Front Biosci 12: 947-963.
  19. El-Sherif Y, Tesoriero J, Hogan MV, Wieraszko A (2003) Melatonin regulates neuronal plasticity in the hippocampus. J Neurosci Res 72: 454-460.
  20. Gagnon K, Godbout R (2018) Melatonin and Comorbidities in Children with Autism Spectrum Disorder. Curr Dev Disord Rep 5: 197-206.
  21. Anderson G, Vaillancourt C, Maes M, Reiter RJ (2017) Breastfeeding and the gut-brain axis: Is there a role for melatonin? Biomol Concepts 8: 185-195.
  22. Siniscalco D, Brigida AL, Antonucci N (2018) Autism and neuro-immune-gut link. AIMS Mol Sci 5: 166-172.
Citation: Siniscalco D (2018) Melatonin for Autism Spectrum Disorder: Beyond Sleep Disturbances?. Autism Open Access 8: e142.

Copyright: © 2018 Siniscalco D, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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