Combined treatment with diazepam and MK‐801 provide enhanced protection from tetramethylenedisulfotetramine‐induced seizures and lethality (1143.14)

Abstract

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