Novel test strategies for in vitro seizure liability assessment

Abstract

Introduction The increasing incidence of mental illnesses and neurodegenerative diseases results in a high demand for drugs targeting the central nervous system (CNS). These drugs easily reach the CNS, have a high affinity for CNS targets, and are prone to cause seizures as an adverse drug reaction. Current seizure liability assessment heavily depends on in vivo or ex vivo animal models and is therefore ethically debated, labor intensive, expensive, and not always predictive for human risk. Areas covered The demand for CNS drugs urges the development of alternative safety assessment strategies. Yet, the complexity of the CNS hampers reliable detection of compound-induced seizures. This review provides an overview of the requirements of in vitro seizure liability assays and highlights recent advances, including micro-electrode array (MEA) recordings using rodent and human cell models. Expert opinion Successful and cost-effective replacement of in vivo and ex vivo models for seizure liability screening can reduce animal use for drug development, while increasing the predictive value of the assays, particularly if human cell models are used. However, these novel test strategies require further validation and standardization as well as additional refinements to better mimic the human in vivo situation and increase their predictive value.

Molecular and functional characterization of different BrainSphere models for use in neurotoxicity testing on microelectrode arrays

“…Another application can be envisioned in drug development for safety or efficacy evaluation, e.g. for seizure liability assessment [142][143][144][145]. In addition, interference of compounds with neurotransmitter systems might also be an indication for their developmental neurotoxicity (DNT) potential.…”

Direct Current Stimulation in Cell Culture Systems and Brain Slices—New Approaches for Mechanistic Evaluation of Neuronal Plasticity and Neuromodulation: State of the Art

“…However, embryonic and neuronal stem cell-derived neurons are ethically debated and furthermore have the disadvantage of extensive cell culture prior use [ 76 ]. In seizure liability assessment research, hiPSC-derived neuronal models have already been introduced as alternative in vitro models for drug screening [ 77 ]. In combination with non-invasive recording of drug-induced alterations of spontaneous activity using MEAs, this recent review concludes that further validation and standardization is needed to mimic the human in vivo situation.…”

The initiator of neuroexcitotoxicity and ferroptosis in ischemic stroke: Glutamate accumulation

“…Glutamate concentrations are highest in teleneuron and up to 100 mM in synaptic vesicles ( Riveros et al, 1986 ; Burger et al, 1989 ; Shupliakov et al, 1992 ). When an action potential reaches the presynaptic terminal, Ca 2+ influx via voltage-gated calcium channels (VGCC) triggers the fusion of vesicles loaded with neurotransmitter with the cell membrane, thereby releasing neurotransmitter in the synaptic cleft ( Nishimune et al, 2016 ; Liang et al, 2021 ; Tukker and Westerink, 2021 ; Fedorovich and Waseem, 2022 ). Glutamate is secreted into the synaptic gap where it can diffuse around the neuron and interact with surrounding targets ( Clewett et al, 2017 ), closest to the axon terminal is the postsynaptic membrane, which contains a large number of membrane-associated proteins, these “postsynaptic densities (PSD)” can be seen under the electron microscope ( Kennedy, 1997 ; Xu Y. et al, 2021 ), PSDs contains a large number of glutamate receptors, which bind to glutamate and then trigger the postsynaptic cell to complete the synaptic transmission of glutamate signals from the presynaptic to the postsynaptic cell ( Guo and Cordeiro, 2008 ; Terauchi and Umemori, 2012 ; Katayama et al, 2017 ).…”