公募シンポジウム

公募シンポジウム7【脳に悪さをする物質たち・・臨床例から分子メカニズムまで】

2021/9/30　17:00～19:00　ZOOM B会場 S7-1 抗生物質が誘発する脳症：興奮/抑制調節障害に対するニューラル・マス・モデリング法による解析の試み Antibiotics-induced encephalopathy: a neural mass modeling approach to disturbed excitatory/inhibitory circuit balance ^○山本直樹¹^,²,中谷善彦²,田宗秀隆³^,⁴ 1.国際医療福祉大学基礎医学研究センター,2.国際医療福祉大学薬学部薬物治療学,3.東京大学大学院医学研究科神経細胞生物学,4.東京都立多摩総合医療センター精神神経科 ^○Naoki Yamamoto¹^,²,Yoshihiko Nakatani²,Hidetaka Tamune³^,⁴ 1.Center for Basic Medical Research,2.Department of Pharmacotherapeutics, School of Pharmaceutical Sciences, International University of Health and Welfare,3.WINGS-LST, Department of Cellular Neurobiology, Graduate School of Medicine, University of Tokyo,4.Department of Neuropsychiatry, Tokyo Metropolitan Tama Medical Center Cefepime is a clinically useful fourth-generation cephalosprin with a broad-spectrum antibiotics feature. However, presumably due to additional GABA-A antagonistic action, some of the patients after treatment revealed a profound delirious state known as cefepime-encephalopathy. On EEG of all three cases, we observed typical Triphasic wave-like generalized periodic discharges with a high negative component (Tri-HNC). The mechanism of substance related- and/or organic-induction of tri-phasic wave EEG pattern during disturbance of consciousness is not well characterized. We hypothesized that excitatory and inhibitory (E/I) neuronal imbalance was essential for cefepime-induced encephalopathy based on the features seen on the EEG, and neural mass modeling in silico was performed to simulate the Tri-HNC EEG pattern. Our neural mass modeling well reproduced the Tri-HNC and a characteristic feature seen on EEG in the course of recovery. Based on these observations, we have now further investigated the effects of cefepime on the GABA-A receptor-mediated cellular and molecular functions in detail.		2021/9/30　17:00～19:00　ZOOM B会場 S7-2 有機ヒ素化合物ジフェニルアルシン酸中毒による神経症状の発症メカニズムの理解とそれに基づいた治療法提案の試み Understanding of cellular and molecular mechanism of neurological symptoms induced by an organic arsenical, diphenylarsinic acid, and challenge to therapeutics ^○根岸隆之名城大学薬学部 ^○Takayuki Negishi Faculty of Pharmacy, Meijo University An arsenic poisoning had occurred Kamisu, Ibaraki, Japan in 2003, where people used the well water contaminated with arsenicals mainly composed of diphenylarsinic acid (DPAA) developed cerebellar symptoms (vertigo, tremor, walking difficulty, etc.). DPAA is a non-natural organic arsenical, which was used for the syntheses of gaseous chemical weapons, diphenylcyanoarsine and diphenylchloroarsine. We tried to elucidate the precise cellular and molecular mechanism of DPAA-induced cerebellar symptoms, which was completely unknown then. First, we reported DPAA-induced activation and traces of oxidative stress in cerebellar astrocytes in vivo and in vitro and abnormal behaviors, including reversible hyper locomotion and long-lasting learning and memory impairment, in male rats subchronically exposed to DPAA via drinking water. Furthermore, at the cellular and molecular level, we revealed DPAA-induced aberrant activation of cultured rat cerebellar astrocytes: transient cell growth and subsequent cell death, activation of mitogen-activated protein (MAP) kinases (p38MAPK, SAPK/JNK, and ERK1/2), up-regulation of expression/phosphorylation of transcription factors [CREB, c-Jun, and c-Fos], and increased secretion of brain-active cytokines (MCP-1, adrenomedullin, FGF2, CXCL1, and IL-6) and glutathione as well as up-regulation of the oxidative stress responsive factors [Nrf2, heme oxygenase-1 (HO-1), Hsp70]. Finally, we explored inhibitors against aberrant activation of astrocytes and could identify thiol-containing chemicals such as N-acetyl-L-cysteine and dimercaptosuccinic acid as potential inhibitors rather than antioxidative radical scavengers such as Trolox and Tiron. These findings would be helpful for proposing possible therapeutics against DPAA poisoning that may occur in the future.

2021/9/30　17:00～19:00　ZOOM B会場 S7-3 超分子ペプチドの設計と脳梗塞の再生治療 Supramolecular peptide design for regenerative medicine of ischemic stroke ^○味岡逸樹¹^,²,村岡貴博²^,³,渡辺豪²^,⁴ 1.東京医科歯科大学,2.神奈川県立産業技術総合研究所,3.東京農工大学,4.北里大学 ^○Itsuki Ajioka¹^,²,Takahiro Muraoka²^,³,Go Watanabe²^,⁴ 1.Tokyo Medical and Dental University,2.Kanagawa Institute of Industrial Science and Technology (KISTEC),3.Tokyo University of Agriculture and Technology,4.Kitasato University While small-molecule and middle-molecule drugs are the golden standard approach in drug discovery, macromolecule cannot be standard for drug development. A macromolecule has a large molecular weight generated by the polymerization reaction of small molecules. Thus, a polymerized macromolecule becomes one molecule in which molecules are covalently bound to each other. Since the biodegraded products of a synthesized polymer become unclear, a macromolecule is hard to be adapted for the safety test of medical application. On the other hand, a supramolecule fits for medical application. A supramolecule is a small self-assembling molecule that accumulates by non-covalent bonds such as hydrogen bonds and hydrophobic interactions. Since the biodegraded products of supramolecule are the original small molecule, a supramolecule is suitable for medical application as far as the original small molecule is biocompatible. Driven by the research development in physics and chemistry, supramolecular materials have undergone industrial application as liquid crystals and organic semiconductors. However, the medical application of supramolecular materials is mostly unexplored. In this symposium, we would like to outline the supramolecular peptides developed by combining the wisdom of computational physics and supramolecular chemistry and their application to injured brain regeneration.		2021/9/30　17:00～19:00　ZOOM B会場 S7-4 覚醒剤メタンフェタミンの依存性および毒性への抑制分子群 Protective effects of novel molecules on the toxicity of methamphetamine ^○新田淳美富山大学 ^○Atsumi Nitta Department of Pharmaceutical Therapy & Neuropharmacology, Faculty of Pharmaceutical Sciences, University of Toyama Chronic exposure to methamphetamine causes adaptive changes in brain, which underlie dependence symptoms. We have found new molecules, Shati/Nat8l, and transmembrane protein 168 (TMEM168), which were identified in the nucleus accumbens (NAc) of mice with methamphetamine (METH) treatment, and have protective effects on the toxicity of methamphetamine. Overexpression of Shati/Nat8l in the NAc, attenuated METH-induced hyperlocomotion, locomotor sensitization, and conditioned place preference in mice. Moreover, the Shati/Nat8l overexpression in the NAc attenuated the elevation of extracellular dopamine levels induced by METH in in vivo microdialysis experiments. These behavioral and neurochemical alterations were inhibited by treatment with selective group II metabotropic glutamate receptor type 2 and 3 (mGluR2/3) antagonist. The injection of peptidase inhibitor of NAAG or the perfusion of NAAG itself reduced the basal levels of extracellular dopamine in the NAc of naive mice. These results indicate that Shati/Nat8l in the NAc, but not in the dS, plays an important suppressive role in the behavioral responses to METH by controlling the dopaminergic system via activation of group II mGluRs. We overexpressed TMEM168 in the (NAc). Methamphetamine-induced hyperlocomotion and conditioned place preference were attenuated in the mice. We identified extracellular matrix protein osteopontin as an interacting partner of TMEM168, by conducting immunoprecipitation in cultured COS-7 cells. TMEM168 overexpression induced the enhancement of extracellular and intracellular osteopontin. Similarly, osteopontin enhancement was also observed in the nucleus accumbens of NAc-TMEM mice, in in vivo studies. Furthermore, the infusion of osteopontin proteins into the nucleus accumbens of mice was found to inhibit methamphetamine-induced hyperlocomotion and conditioned place preference. Our studies suggest that the TMEM168-regulated osteopontin system is a novel target pathway for the therapy of methamphetamine dependence, via regulating the dopaminergic function in the NAc.