Combined diazepam and MK-801 therapy provides synergistic protection from tetramethylenedisulfotetramine-induced tonic-clonic seizures and lethality in mice

Neurotoxicology
Michael P ShakarjianLibor Velíšek

Abstract

The synthetic rodenticide, tetramethylenedisulfotetramine (TMDT), is a persistent and highly lethal GABA-gated Cl(-) channel blocker. TMDT is clandestinely produced, remains popular in mainland China, and causes numerous unintentional and deliberate poisonings worldwide. TMDT is odorless, tasteless, and easy to manufacture, features that make it a potential weapon of terrorism. There is no effective treatment. We previously characterized the effects of TMDT in C57BL/6 mice and surveyed efficacies of GABAergic and glutamatergic anticonvulsant treatments. At 0.4 mg/kg i.p., TMDT produced neurotoxic symptomatology consisting of twitches, clonic and tonic-clonic seizures, often progressing to status epilepticus and death. If administered immediately after the occurrence of the first clonic seizure, the benzodiazepine diazepam (DZP) effectively prevented all subsequent seizure symptoms, whereas the NMDA receptor antagonist dizocilpine (MK-801) primarily prevented tonic-clonic seizures. The latter agent, however, appeared to be more effective at preventing delayed death. The present study further explored these phenomena, and characterized the therapeutic actions of DZP and MK-801 as combinations. Joint treatment with both DZP and MK...Continue Reading

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Citations

Jul 16, 2015·British Journal of Clinical Pharmacology·Hsien-Yi ChenKent R Olson
Jul 8, 2016·Annals of the New York Academy of Sciences·Michael P ShakarjianLibor Velíšek
Jul 29, 2016·Annals of the New York Academy of Sciences·Isaac N PessahPamela J Lein
Feb 8, 2018·Developmental Neurobiology·Marcela LaukováMichael P Shakarjian
Nov 19, 2019·Frontiers in Pharmacology·Ruo-Yue HuangHualin Fu
Jan 24, 2021·Toxicological Sciences : an Official Journal of the Society of Toxicology·Shane AntrobusIsaac N Pessah

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