Ionotropic GABA receptor antagonism-induced adverse outcome pathways for potential neurotoxicity biomarkers

Abstract

Antagonism of ionotropic GABA receptors (iGABARs) can occur at three distinct types of receptor binding sites causing chemically induced epileptic seizures. Here we review three adverse outcome pathways, each characterized by a specific molecular initiating event where an antagonist competitively binds to active sites, negatively modulates allosteric sites or noncompetitively blocks ion channel on the iGABAR. This leads to decreased chloride conductance, followed by depolarization of affected neurons, epilepsy-related death and ultimately decreased population. Supporting evidence for causal linkages from the molecular to population levels is presented and differential sensitivity to iGABAR antagonists in different GABA receptors and organisms discussed. Adverse outcome pathways are poised to become important tools for linking mechanism-based biomarkers to regulated outcomes in next-generation risk assessment.

Keywords: adverse outcome pathway; antagonist; chloride channel; cross-species extrapolation; epileptic seizure; ionotropic γ-aminobutyric acid receptor; metabotropic GABA receptor; neurotoxicity biomarker; neurotransmission; risk assessment.