公募シンポジウム

公募シンポジウム13【自閉スペクトラム症の診療標的としての酸化ストレス】

2021/10/1　13:00～15:00　ZOOM C会場 S13-1 5-アミノレブリン酸は胎生期バルプロ酸曝露ラットにおける脳酸化ストレスと自閉症様行動を抑制する 5-aminolevulinic acid inhibits oxidative stress and ameliorates autistic-like behaviors in prenatal valproic acid-exposed rats ^○松尾和哉¹^,²,塩田倫史²,福永浩司¹^,³ 1.東北大学大学院薬学研究科薬理学分野,2.熊本大学発生医学研究所ゲノム神経学分野,3.東北大学大学院薬学研究科先進脳創薬講座 ^○Kazuya Matsuo¹^,²,Norifumi Shioda²,Kohji Fukunaga¹^,³ 1.Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University ,2.Department of Genomic Neurology, Institute of Molecular Embryology and Genetics (IMEG), Kumamoto University,3.Department of CNS drug innovation, Graduate School of Pharmaceutical Sciences, Tohoku University Autism spectrum disorders (ASD) are defined by social impairment and repetitive behaviors caused by heterogeneous factors. Increasing evidence suggest that oxidative stress alongside mitochondrial dysfunction is associated with ASD onset and neuropathology. Here, we addressed whether targeting this pathophysiology in the brain is effective against ASD using model animals. Rats (gestational day 12.5) received a single dose of oral valproic acid (VPA; 600 mg/kg). The male offspring were given either drug from postnatal days 21 to 56: oral 5-aminolevulinic acid (5-ALA; 30 mg/kg) or intranasal oxytocin (OXT; 12 μg/kg). Behavioral analyses were conducted during this period to assess ASD-like socio-communicational impairment along with memory deficit. After that, brain pathology was investigated in the dorsal hippocampus. Prenatal VPA exposure induced ASD-like behavioral impairments in social behaviors, self-grooming, and learning in rats. Prenatal VPA exposure also decreased the number of parvalbumin-positive interneurons like ASD patients. Both 5-ALA and OXT significantly ameliorated these ASD-like phenotypes in VPA-exposed rats. In the dorsal hippocampus, oxidative damage and mitochondrial dysfunction were evident, with increased signal of 4-hydroxy-2-nonenal and aberrant enzymatic activities of electron transport chain, respectively. Notably, oxidative stress and mitochondrial dysfunction were improved by 5-ALA but not by OXT. In this study, we identified that 5-ALA is effective against prenatal VPA exposure-induced ASD-like behaviors in rats like OXT. 5-ALA may ameliorate ASD symptoms through mechanisms different from those of OXT, including oxidative stress and mitochondrial dysfunction.		2021/10/1　13:00～15:00　ZOOM C会場 S13-2 d-ROM を用いた自閉スペクトラム症児の酸化ストレス評価 Evaluation of oxidative stress in children with autism spectrum disorders using d-ROM ^○森本真仁徳島赤十字ひのみね総合療育センター薬剤課 ^○Masahito Morimoto Department of Pharmacy, Japanese Red Cross Tokushima Hinomine Rehabilitation Center for People with Disabilities In order to evaluate the relationship between autism spectrum disorder (ASD) and oxidative stress, we focused on Reactive oxygen metabolites (d-ROM), which can be measured rapidly in peripheral blood and is used for various diseases. d-ROM is a method for evaluating the state of oxidative stress in vivo by measuring the blood hydroperoxide concentration generated by active oxygen species and free radicals in vivo by a color reaction. First, d-ROM measurements were taken in typical development children (TD) aged 2-15 years. The subjects were divided into 3 groups of 2-6 years, 7-11 years, and 12-15 years, the d-ROM values were significantly higher in 2-6 years than in 7-11 years and 12-15 years. It was also confirmed that d-ROM does not affect gender differences. This suggests that the younger the age, the higher the value of d-ROM, similar to 8-OHdG. Next, the d-ROM of untreated ASD and TD were compared. The subjects were divided into two groups, 2-6 years and 7-15 years for both ASD and TD. As a result of the analysis, the d-ROM value was not significantly different between ASD and TD at 2-6 years, and ASD was significantly higher than TD at 7-15 years. This suggests that ASD aged 7-15 years is affected by oxidative stress. In addition, the ASD Rating Scale for parent interviews-relationships between texts. The revised (PARS) score and d-ROM showed a significant positive correlation in both age groups. Finally, we analyzed changes in oxidative stress, PARS score, and ADHD Rating Scale (ADHD-RS) before and after drug therapy in ASD (ASD/ADHD) with attention deficit hyperactivity disorder (ADHD). Post-treatment d-ROM levels, PARS and ADHD-RS scores were significantly reduced. In addition, a significant positive correlation was found between the d-ROM value and the change in PARS score before and after treatment, and a significant positive correlation was also found between the change in d-ROM value and ADHD-RS score before and after treatment. These results suggest that oxidative stress evaluation using d-ROM may be useful for therapeutic evaluation of children with ASD/ADHD.

2021/10/1　13:00～15:00　ZOOM C会場 S13-3 自閉スペクトラム症と脂質代謝 Lipid metabolism in autism spectrum disorder ^○臼井紀好大阪大学大学院医学系研究科神経細胞生物学講座 ^○Noriyoshi Usui Department of Neuroscience and Cell Biology, Graduate School of Medicine, Osaka University Autism spectrum disorder (ASD) is a heterogenous neurodevelopmental disorder that causes pervasive abnormalities in social communication as well as repetitive behaviors and restricted interests. It has been suggested that abnormalities of lipid metabolism contributing to ASD pathogenesis, however the mechanisms are not fully understood. Thus, we investigated the role of lipid metabolism in the pathophysiology of ASD. Using metabolomic approach, 48 significant metabolites involved in lipid biosynthesis and metabolism, oxidative stress, and synaptic function were identified in the plasma of ASD children. Among these, increased fatty acids (FAs), such as omega-3 (n-3) and omega-6 (n-6), showed correlations with clinical social interaction score and ASD diagnosis. Specific reductions of very-low-density lipoprotein (VLDL) and apoprotein B (APOB) in serum of ASD children also were found by large-scale lipoprotein analysis. VLDL-specific reduction in ASD was correlated with APOB, indicating VLDL-specific dyslipidemia associated with APOB in ASD children. These results demonstrated that the increases in FAs correlated positively with social interaction are due to VLDL-specific degradation. To support this idea, an increased activity of lipoprotein lipase (LPL), an enzyme responsible for the hydrolysis of core TG in chylomicrons and VLDL was found in ASD children. Together, our study provides novel insights into the lipid metabolism underlying ASD pathophysiology. In this symposium, we will discuss our latest findings.		2021/10/1　13:00～15:00　ZOOM C会場 S13-4 多種ラジカル消去活性測定法(MULTIS)による自閉スペクトラム症早期スクリーニング Application of Multiple Radical Scavenging Activity Assay (MULTIS) to Diagnostic Screening for Autism Spectrum Disorders ^○平山暁¹,松﨑秀夫² 1.筑波技術大学東西医学統合医療センター,2.福井大学子どものこころの発達研究センター ^○Aki Hirayama¹,Hideo Matsuzaki² １.Center for Integrative Medicine, Tsukuba University of Technology,２.Research Center for Child Mental Development, University of Fukui Oxidative stress is currently recognized as one possible mechanism underlying autism spectrum disorder (ASD). While abnormalities in the glutathione-related pathway are widely accepted, the results for other oxidative stress markers and antioxidants are highly variable and a comprehensive evaluation of oxidative stress-related reactions is required. For this purpose, we have developed the MULTIS method, an electron spin resonance-based technique measuring multiple free radical scavenging activities simultaneously. In this study, we evaluated the oxidative stress alterations in ASD by MULTIS in combination with conventional oxidative stress markers and applied it to diagnostic screening. Serum samples of 45 children with ASD and 58 age-matched children with typical development were analyzed after obtaining informed consent. The MULTIS method was used to create a serum scavenging-activity profile for multiple reactive oxygen species (ROS), namely hydroxyl radical (^•OH), alkoxyl radical (RO^•), alkylperoxyl radical (ROO^•), superoxide (O₂^•-) and singlet oxygen (¹O₂) were measured. 8-Hydroxy-2'-deoxyguanosine (8-OHdG), co-enzyme Q10, and its relative’s adiponectin and tocopherols were also evaluated. The ASD group showed decreased ^•OH and ¹O₂ scavenging activity with increased serum coenzyme Q10 oxidation rate, indicating a prooxidative tendency in ASD. By contrast, scavenging activities against O₂^•- and RO^•, as well as α-tocopherol and adiponectin levels, were increased in the ASD group, suggesting antioxidative shifts. In the subgroup analysis of 6-year-olds or younger, the combination of ^•OH, O₂^•-, and RO^• scavenging activities predicted ASD with high positive predictive value (0.867), positive likelihood (11.6), and percentage of correct classification (86.0%). These results indicate that oxidative stress in children with ASD is not simply elevated but rather shows a compensatory shift. MULTIS measurements may serve as a very powerful non-behavioural tool for the diagnosis of ASD in children.

2021/10/1　13:00～15:00　ZOOM C会場 S13-5 Autism spectrum disorder: Disturbance of the melatonin system and its implications Feng Han1, 3, Zhou-Yue Wu1, Ying-Mei Lu2 ^○Feng Han¹^,³, Zhou-Yue Wu¹, Ying-Mei Lu² １.Key Laboratory of Cardiovascular & Cerebrovascular Medicine, Drug Target and Drug Discovery Center, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China,２.Department of Physiology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, China,３.Institute of Brain Science, the Affiliated Brain Hospital of Nanjing Medical University, Nanjing 210029, China ^○Feng Han¹^,³, Zhou-Yue Wu¹, Ying-Mei Lu² １.Key Laboratory of Cardiovascular & Cerebrovascular Medicine, Drug Target and Drug Discovery Center, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China,２.Department of Physiology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 211166, China,３.Institute of Brain Science, the Affiliated Brain Hospital of Nanjing Medical University, Nanjing 210029, China Uncovering the pathological mechanisms and altered neurobiology of individuals with ASD will lead to innovative therapeutic methods. Psychotropic pharmacotherapy is extensively employed to alleviate emotional and behavioral symptoms in ASD, but no clinically available cure touches the pathological core of ASD. Accumulating evidence indicates that the pineal gland/melatonin system is associated with the progression of ASD. Some recent advances in the field is helping for 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 promote the development of novel therapeutic strategies against ASD. We anticipate that targeting the neurotransmitters upstream pathway and downstream of melatonin in brain will lead to potential therapeutic treatment for ASD.