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 hour 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.

The synthetic rodenticide, tetramethylenedisulfotetramine (TMDT), is a persistent and lethal GABAA Cl‐ channel antagonist. Although banned, TMDT is clandestinely produced, remains popular in Mainland China, and is the cause of numerous unintentional and deliberate poisonings worldwide. TMDT has features that make it a likely tool for terrorist activity. We sought to characterize the TMDT syndrome in C57BL/6 mice and explore the best modalities for treatment. At 0.4 mg/kg ip, TMDT produced neurotoxicity consisting of symptoms of twitches, clonic seizures and tonic‐clonic seizures, the latter often ending in death of the subject upon occurrence of status epilepticus. Upon ip administration, the benzodiazepine, diazepam (DZP), effectively prevented all of TMDT symptoms, whereas the NMDA receptor antagonist, dizocilpine (MK‐801), prevented tonic‐clonic seizures more effectively than the less severe, clonic seizures. While both agents protected mice from the short‐term lethal effects of TMDT, MK‐801 better protected animals from delayed death. We hypothesized that although TMDT initiates its toxic action at GABA receptors, NMDA receptors play a key role in the persistent excitotoxic actions of the agent. We examined the effectiveness of joint treatment with both DZP and MK‐801. By applying isobolographic analysis to the data, we demonstrate that a binary mixture of DZP and MK‐801 displays synergy toward tonic‐clonic seizures and 24 hr lethality prevention. Although simultaneous treatment did not result in effective suppression of clonic seizures, DZP administration given 10 min prior to MK‐801 significantly reduced these seizures and improved overall outcome. In summary, TMDT is a potent neurotoxin and potential terrorist weapon. A sequential combination treatment with DZP and MK‐801 is superior to individual therapy with, or simultaneous administration of these two agents. Grant Funding Source: Supported by CURE, NIH NS072966 and NIH U54AR055073