What question did this study set out to answer?

This research aims to understand the neurotoxic effects of marinobufagin (MBG) and its potential role in seizures.

May 27, 2026Naunyn-Schmiedeberg s Archives of Pharmacology0 citationsOpen Access

Central toxic effects of an antitumoral bufadienolide: In silico targets and in vivo findings

RSRayran Walter Ramos de Sousa AAAntônia Amanda Cardoso de Almeida GFGabriel da Silva Fernandes

Key Points

This research aims to understand the neurotoxic effects of marinobufagin (MBG) and its potential role in seizures.
Investigated physicochemical and pharmacokinetic profiles using in silico platforms.
Examined pro-convulsive action of MBG using pharmacological modulators and in vitro acetylcholinesterase activity.
Characterized the impact of MBG on seizure activity and neuronal excitability in vivo.
MBG significantly reduced seizure incidence in pre-treated animals with NMDA receptor blockers, with a strong affinity for excitatory targets.
Interaction with GABA A receptors was associated with lethality, revealing the dual action of MBG on excitatory and inhibitory pathways.
In silico docking confirmed MBG’s binding to crucial neuronal targets, contributing to seizure onset.

Abstract

Abstract Marinobufagin (MBG), a cardiotonic steroid from Rhinella toads, exhibits potent antitumor activity. However, their involvement in the mammalian neurotoxicity remains unclear. Therefore, this study evaluated the systemic (neuro)toxicological action of MBG to understand its central effects, particularly those associated with seizure-inducing activity. Initially, physicochemical, pharmacokinetic, and drug-likeness profiles and molecular docking with receptors/channels were investigated by in silico platforms. Next, the pro-convulsive action of MBG was investigated using pharmacological modulators for specific neurotransmission pathways and in vitro inhibitory activity of acetylcholinesterase was quantified. MBG has intestinal absorption and capacity to cross the blood–brain barrier (BBB), binds strongly to plasma proteins, and acts as an inhibitory substrate for the CYP3A4 enzyme. It was classified as a drug-like molecule according to Lipinski’s rule and ineligible according to the Lead-like and World Drug Index criteria. Molecular docking emphasized the interaction of MBG with ictogenesis-related targets, confirmed by reduction of in vivo seizures and death of pretreated animals with pharmacological blockers for dopamine D2 and glutamate NMDA receptors and Na v 1.2 channels, mainly. It was shown that affinity of MBG for excitatory targets is essential for neuronal excitability and onset of seizures and that interaction with GABA A receptors is involved in bufadienolide-induced lethality. The findings also suggest that MBG-induced seizures may involve in silico binding to NMDA receptors and interactions with key excitatory (Na v 1.2 channels and NMDA receptor) and inhibitory (GABA A and D2 receptors) neuronal targets, contributing to altered neuronal excitability. Notably, it is the first report that characterized MBG-induced seizures and proposes it as a promising chemical option to understand ictogenesis and mechanism(s) of new anticonvulsive agents.

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