Journal Article
Central toxic effects of an antitumoral bufadienolide: In silico targets and in vivo findings
Rayran Walter Ramos de Sousa; Antonia Amanda Cardoso de Almeida; Gabriel da Silva Fernandes; Rita de Cassia de Lima Sousa; Railson Pereira Souza; Layana Karine Farias Lima; Francisco das Chagas Pereira de Andrade; Anderson Nogueira Mendes; Evaldo dos Santos Monção Filho; Mariana Helena Chaves; Gerardo Magela Vieira Junior; Domingos de Jesus Rodrigues; Dalton Dittz; Chistiane Mendes Feitosa; Paulo Michel Pinheiro Ferreira
Naunyn-Schmiedeberg's Archives of Pharmacology · Vol. 399, Issue 11 · pp. 17693-17713 · 2026
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.