Title of Research:

Proposal of a new AOP for the neurotoxicity and developmental
neurotoxicity assessment of glutamate receptor binding agoniststhat cause learning and memory impairment.
Principal Investigator:
Yuko Sekino, PhD (Project Professor, , The University of Tokyo) 1-1-1 Yayoi, Bunkyo-ku, Tokyo
113-8657, Japan (tel)+81-3-5841-4355, (e-mail) yukos@g.ecc.u-tokyo.ac.jp
Collaborators
Hiroyuki Yamazaki, PhD (Associate Professor, Faculty of Social Welfare, Gunma University ofHealth and Welfare) 191-1, Kawamagari-machi, Maebashi, Gunma, 371- 0852, Japan(tel) 027-253-0294 (e-mail) yamazaki@shoken-gakuen.ac.jp
Yonehiro Kanemura, MD, PhD (Director, Department of Biomedical Research and Innovation
Institute for Clinical Research, National Hospital Organization Osaka National Hospital) 2-1-14
Hoenzaka, Chuo-ku, Osaka 540-0006, Japan(tel)+ 81-6-6942-1331, (e-mail) kanemura.yonehiro.hk@mail.hosp.go.jp
Daiju Yamazaki, PhD (Section Chief, Division of Pharmacology, National Institute of HealthSciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki City, Kanagawa, 210-9501, JAPAN(tel)+81-44-270-6642, (e-mail) daiju-y@nihs.go.jp
Noriko Koganezawa, PhD (Associate Professor, Department of Pharmacology, Gunma
University Graduate School of Medicine) 3-39-22, Showa-machi, Maebashi, Gunma, 371- 8511,
Japan (tel) 027-220-8052, (e-mail) n-koganezawa@gunma-u.ac.jp
Summary of Research:
When the actin-binding protein drebrin which forms dendritic spines of neurons is eliminated byNMDA-type glutamate activity, the spines become thinner and eventually disappear. Loss ofdendritic spines impairs learning and memory. In this study, we developed an image analysis
algorithm that automatically counts the number of drebrin immunostained clusters in 3-weeks
cultured rat fetal hippocampal-derived neurons. Next, we measured changes in the number ofdrebrin clusters caused by chemical substances. This research resulted in a proposal submitted
an Adverse Expression Pathway (AOP) to OECD. The AOP started from the binding of thecompound to the NMDA-type glutamate receptor as a molecular initiation event (MIE) , and end at
the impairment of learning and memory as the adverse event (AO). The new proposal wadregistered as Wiki475. We will collect evidence to complete AOP-Wiki475 in the future.
Timeline:
March 1, 2020 –Topics:
Poster presentation in 2022 ICCA-LRI & NITE Workshop “Proposal of a new AOP for theneurotoxicity and developmental neurotoxicity assessment of glutamate receptor binding agoniststhat cause learning and memory impairment.”
Publications:
Mase S, Mitsuoka T, Koganezawa N, Shirao T, Sekino Y, "Drebrin cluster analysis using cultured
hippocampal neurons"ISRN-2022, Web, March 2022
Sekino Y., "The neurochemistry of addiction and strategies for substance abuse prevention" 69th
Annual meeting of Hokkaido Pharmaceutical Sciences, Web, May 2022
Shogo Mase, Toshinari Mitsuoka, Noriko Koganezawa, Hiroyuki Yamazaki, Yuuichi Kato, Izuo
Tsutsui, Hiroshi Kawabe, Tomoaki Shirao, Yuko Sekino "Quantitative analysis of developmental
neurotoxicity using drebrin immunocytochemical images of cultured rat hippocampal neurons" The49th Annual Meeting of the Japanese Society of Toxicology, Sapporo, June 2022
Shogo Mase, Toshinari Mitsuoka, Noriko Koganezawa, Hiroyuki Yamazaki, Yuuichi Kato, Izuo
Tsutsui, Hiroshi Kawabe, Tomoaki Shirao, Yuko Sekino, "High-content analysis using drebrin
immunocytochemical images of cultured rat hippocampal neurons" Japan Basic and ClinicalPharmacology Week 2022, Dec 2022
Yuko Sekino, "Collecting Evidence for Enlightenment Activities to Prevent Illegal Drug Use byYouth" Research Report on Subsidies for the Ministry of Health, Labor and Welfare Administration
Promotion Research Project (FY2022)