Structure-Activity Relationship of Neuroactive Steroids, Midazolam, and Perampanel towards Mitigating Tetramine-Triggered Activity in Murine Hippocampal Neuronal Networks

Antrobus S, Pressly B, Nik AM, Wulff H, Pessah IN.

Toxicological Sciences, 2021

Summary:

TETS is a potent convulsant, triggering abnormal spike activity in cultured neuronal networks.  Potential therapeutic candidates for TETS neurotoxicity were evaluated by a number of methods, including in a multiwell multielectrode array recordings.  TETS has shown to increase burst frequency and synchronicity with MEA recordings.

Physiological parameters of primary neuronal/glia co-cultures can be quantitatively measured with two rapid throughput assays: Ca2+ sensitive indicators; and MEAs to measure patterns of electrical spike activity.  Electrical spike activity patterns are useful to identify seizurogenic agents.  In vitro assays have a high prediction for in vivo applications especially for agents that overexcite the central nervous system.  The authors analyzed five neuroactive steroids to reverse the spike patterns caused by TETS and restore control patterns of activity.  

Neuronal/glia co-cultures were elevated by the Maestro MEA system and used to evaluate acute effect of TETS and therapeutic candidates.  Data was analyzed for spike frequency, burst characteristics and synchronicity. TETS significantly increased the mean firing rate, burst frequency and network synchronicity.  Addition of MDZ or ALLO in the absence of TETS suppressed normal activity.