Oxytocin-induced increase in N,N-dimethylglycine and time course of changes in oxytocin efficacy for autism social core symptoms

Molecular Autism

Miho Kuroda¹  Walid Yassin¹  Masaki Kojima¹  Yosuke Eriguchi¹  Hirotaka Kosaka²  Kiyoto Kasai³  Yosuke Kameno⁴  Seico Benner⁴  Chihiro Murayama⁴  Yasuhiko Kato⁴  Hitoshi Kuwabara⁴  Hidenori Yamasue⁵  Takashi Okada⁶  Norio Ozaki⁶  Toshio Munesue⁷  Tomoko Nishimura⁸  Kenji Tsuchiya⁸ 

[1] Department of Child Neuropsychiatry, School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, 113-8655, Tokyo, Japan;Department of Neuropsychiatry, Faculty of Medical Sciences, University of Fukui, 910-1193, Eiheiji, Fukui, Japan;Department of Neuropsychiatry, School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, 113-8655, Tokyo, Japan;Department of Psychiatry, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashiku, 431-3192, Hamamatsu City, Japan;Department of Psychiatry, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashiku, 431-3192, Hamamatsu City, Japan;United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, Osaka/Kanazawa/Hamamatsu/Chiba/Fukui, Japan;Department of Psychiatry, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, 466-8550, Nagoya, Aichi, Japan;Research Center for Child Mental Development, Kanazawa University, 13-1 Takara-machi, 920-8640, Kanazawa, Japan;United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, Osaka/Kanazawa/Hamamatsu/Chiba/Fukui, Japan;

关键词: Asperger;    Autism;    Clinical trial;    Developmental disorders;    Facial expression;    Metabolomics;    Neuropeptide;    N;    Oxytocin;    Plasticity;   

DOI  :  10.1186/s13229-021-00423-z

来源: Springer

【 摘 要 】

BackgroundOxytocin is expected as a novel therapeutic agent for autism spectrum disorder (ASD) core symptoms. However, previous results on the efficacy of repeated administrations of oxytocin are controversial. Recently, we reported time-course changes in the efficacy of the neuropeptide underlying the controversial effects of repeated administration; however, the underlying mechanisms remained unknown.MethodsThe current study explored metabolites representing the molecular mechanisms of oxytocin’s efficacy using high-throughput metabolomics analysis on plasma collected before and after 6-week repeated intranasal administration of oxytocin (48 IU/day) or placebo in adult males with ASD (N = 106) who participated in a multi-center, parallel-group, double-blind, placebo-controlled, randomized controlled trial.ResultsAmong the 35 metabolites measured, a significant increase in N,N-dimethylglycine was detected in the subjects administered oxytocin compared with those given placebo at a medium effect size (false discovery rate (FDR) corrected P = 0.043, d = 0.74, N = 83). Furthermore, subgroup analyses of the participants displaying a prominent time-course change in oxytocin efficacy revealed a significant effect of oxytocin on N,N-dimethylglycine levels with a large effect size (PFDR = 0.004, d = 1.13, N = 60). The increase in N,N-dimethylglycine was significantly correlated with oxytocin-induced clinical changes, assessed as changes in quantifiable characteristics of autistic facial expression, including both of improvements between baseline and 2 weeks (PFDR = 0.006, r = − 0.485, N = 43) and deteriorations between 2 and 4 weeks (PFDR = 0.032, r = 0.415, N = 37).LimitationsThe metabolites changes caused by oxytocin administration were quantified using peripheral blood and therefore may not directly reflect central nervous system changes.ConclusionOur findings demonstrate an association of N,N-dimethylglycine upregulation with the time-course change in the efficacy of oxytocin on autistic social deficits. Furthermore, the current findings support the involvement of the N-methyl-D-aspartate receptor and neural plasticity to the time-course change in oxytocin’s efficacy.Trial registration: A multi-center, parallel-group, placebo-controlled, double-blind, confirmatory trial of intranasal oxytocin in participants with autism spectrum disorders (the date registered: 30 October 2014; UMIN Clinical Trials Registry: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000017703) (UMIN000015264).

【 授权许可】

CC BY