Adverse Outcome Pathway on chronic binding of antagonist to N-methyl-D-aspartate receptors during brain development leading to neurodegeneration with impairment in learning and memory in aging

Abstract

This Adverse Outcome Pathway (AOP) on chronic binding of antagonist to N-methyl-Daspartate receptors (NMDARs) during brain development leading to neurodegeneration with impairment in learning and memory in aging, has been developed under the auspices of the OECD AOP Development Programme, overseen by the Extended Advisory Group on Molecular Screening and Toxicogenomics (EAGMST), which is an advisory group under the Working Group of the National Coordinators for the Test Guidelines Programme (WNT). The AOP has been reviewed internally by the EAGMST, externally by experts nominated by the WNT, and has been endorsed by the WNT and the Working Party on Hazard Assessment (WPHA) in June 2018. Through endorsement of this AOP, the WNT and the WPHA express confidence in the scientific review process that the AOP has undergone and accept the recommendation of the EAGMST that the AOP be disseminated publicly. Endorsement does not necessarily indicate that the AOP is now considered a tool for direct regulatory application. The Joint Meeting of the Chemicals Committee and the Working Party on Chemicals, Pesticides and Biotechnology agreed to declassification of this AOP in September 2018. This document is being published under the responsibility of the Joint Meeting of the Chemicals Committee and the Working Party on Chemicals, Pesticides and Biotechnology. The outcome of the internal and external reviews are publicly available respectively in the AOP Wiki and the eAOP Portal of the AOP Knowledge Base at the following links: [internal review] [external review].

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“…The suggested AOs are increased/decreased depression and increased agitation for serotonin receptors, epileptic seizures for GABA receptors (AOP10; [75,76]) and impairment of learning and memory for glutamate receptors (AOP12; AOP13; AOP48; [74,77,78]). There are also available AOPs related to activation of cholinergic receptors [79], while dopamine receptors are completely neglected in AOP framework.…”