title: Combined diazepam and MK-801 therapy provides synergistic protection from tetramethylenedisulfotetramine-induced tonic-clonic seizures and lethality in mice.
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-801 displayed synergistic protection against tonic-clonic seizures and 24 h lethality as determined by isobolographic analysis. Clonic seizures, however, remained poorly controlled. A modification of the treatment regimen, where DZP was followed 10 min later by MK-801, yielded a reduction in both types of seizures and improved overall outcome. Simultaneous monitoring of subjects via EEG and videography confirmed effectiveness of this sequential regimen. We conclude that TMDT blockage at GABAA receptors involves early activation of NMDA receptors, which contribute to persistent ictogenic activity. Our data predict that a sequential combination treatment with DZP followed by MK-801 will be superior to either individual therapy with, or simultaneous administration of, these two agents in treating TMDT poisoning.
authors.affiliation: Department of Environmental Health Science, School of Health Sciences and Practice, Institute of Public Health, New York Medical College, Valhalla, NY 10595, United States; Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY 10595, United States; Department of Medicine, Division of Pulmonary and Critical Care Medicine, UMDNJ-Robert Wood Johnson Medical School, Piscataway, NJ 08854, United States. Electronic address: michael_shakarjian@nymc.edu.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Shakarjian
authors.affiliation: Department of Environmental Health Science, School of Health Sciences and Practice, Institute of Public Health, New York Medical College, Valhalla, NY 10595, United States. Electronic address: mahils17@gmail.com.
authors.forename: Mahil S
authors.initials: MS
authors.lastname: Ali
authors.affiliation: Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY 10595, United States; Department of Obstetrics and Gynecology, New York Medical College, Valhalla, NY 10595, United States; Department of Neurology, New York Medical College, Valhalla, NY 10595, United States. Electronic address: jana_veliskova@nymc.edu.
authors.forename: Jana
authors.initials: J
authors.lastname: Velíšková
authors.affiliation: Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY 10595, United States; Department of Neurology, New York Medical College, Valhalla, NY 10595, United States. Electronic address: patric_stanton@nymc.edu.
authors.forename: Patric K
authors.initials: PK
authors.lastname: Stanton
authors.affiliation: Department of Environmental Health Science, School of Health Sciences and Practice, Institute of Public Health, New York Medical College, Valhalla, NY 10595, United States. Electronic address: diane_heck@nymc.edu.
authors.forename: Diane E
authors.initials: DE
authors.lastname: Heck
authors.affiliation: Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY 10595, United States; Department of Neurology, New York Medical College, Valhalla, NY 10595, United States; Department of Pediatrics, New York Medical College, Valhalla, NY 10595, United States. Electronic address: libor_velisek@nymc.edu.
authors.forename: Libor
authors.initials: L
authors.lastname: Velíšek
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D058256:Brain Waves / Q000187:drug effects; D001952:Bridged-Ring Compounds / Q000633:toxicity*; D002490:Central Nervous System / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D003975:Diazepam / Q000494:pharmacology*; D018450:Disease Progression; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004569:Electroencephalography; D004830:Epilepsy, Tonic-Clonic / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D018756:GABA Antagonists / Q000633:toxicity*; D018698:Glutamic Acid / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism; D013226:Status Epilepticus / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D013997:Time Factors; D014741:Video Recording; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D000927:Anticonvulsants; D001952:Bridged-Ring Compounds; D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D016291:Dizocilpine Maleate; C010349:tetramethylenedisulfotetramine; D003975:Diazepam
keywords: GABA; Isobologram; NMDA; Seizures; Tetramethylenedisulfotetramine