Tetramethylenedisulfotetramine Neurotoxicity: In Vivo Validation of In Vitro Screen to Identify Potential Countermeasures

Tetramethylenedisulfotetramine (TMDT), a synthetic neurotoxin, induces a seizure syndrome by blocking Cl- influx through the GABAA channel. This process leads to uncontrolled depolarization followed by excessive Ca2+ entry into neurons and potential excitotoxicity. No standardized, effective treatment for TMDT poisoning currently exists. Primary neuronal cultures were used to screen candidate countermeasures for alleviation of TMDT-provoked hyperexcitability by monitoring changes in intracellular Ca2+ levels ([Ca2+]i). Agents antagonizing NMDA or β-adrenergic receptors reversed TMDT-induced increases in [Ca2+]i and displayed the best counteracting potential. We have commenced testing these in vitro leads in vivo. Adult male mice were injected with 0.25 mg/kg TMDT subcutaneously followed by intraperitoneal monotherapy immediately after the first clonic seizure observed. They were continuously monitored over 1 hr, for the occurrence and severity of clonic and tonic-clonic seizures, and for 24-hr mortality. Our current results indicate that MK-801 is superior, completely eliminating tonic-clonic seizures and 24-hr mortality. At 40 mg/kg, memantine decreased mortality by 75%, however delayed tonic-clonic seizures were observed. Although both procyclidine and ketamine prevented tonic-clonic seizures at higher doses (60 and 70 mg/kg, respectively), they were not as effective in preventing TMDT-induced lethality. Propranolol was the least effective at reducing seizure severity and mortality rate. Altogether, our in vitro assay provides a useful screen to identify potential countermeasures against TMDT neurotoxicity. Positive leads are being tested and show activity in vivo, supporting utility of the screen

Mechanisms of Oxidant Generation by Catalase

The enzyme catalase converts solar radiation into reactive oxidant species (ROS). In this study, we report that several bacterial catalases (hydroperoxidases, HP), including Escherichia coli HP-I and HP-II also generate reactive oxidants in response to ultraviolet B light (UVB). HP-I and HP-II are identical except for the presence of NADPH. We found that only one of the catalases, HPI, produces oxidants in response to UVB light, indicating a potential role for the nucleotide in ROS production. This prompts us to speculate that NADPH may act as a cofactor regulating ROS generation by mammalian catalases. Structural analysis of the NADPH domains of several mammalian catalases revealed that the nucleotide is bound in a constrained conformation and that UVB irradiation induces NADPH oxidation and positional changes. Biochemical and kinetic analysis indicate that ROS formation by the enzyme is enhanced by oxidation of the cofactor. Conformational changes following absorption of UVB light by catalase NADPH have the potential to facilitate ROS production by the enzyme

Tetramethylenedisulfotetramine Neurotoxicity: What Have We Learned in the Past 70 Years?

Tetramethylenedisulfotetramine (tetramine, TETS, TMDT) is a seizure-producing neurotoxic chemical formed by the condensation of sulfamide and formaldehyde. Serendipitously discovered through an occupational exposure in 1949, it was promoted as a rodenticide but later banned worldwide due to its danger to human health. However, exceptional activity of the agent against rodent pests resulted in its clandestine manufacture with large numbers of inadvertent, intentional, and mass poisonings, which continue to this day. Facile synthesis, extreme potency, persistence, lack of odor, color, and taste identify it as an effective food adulterant and potential chemical agent of terror. No known antidote or targeted treatment is currently available. In this review we examine the origins of tetramethylenedisulfotetramine, from its identification as a neurotoxicant 70 years ago, through early research, to the most recent findings including the risk it poses in the post-911 world. Included is the information known regarding its in vitro pharmacology as a GABAA receptor channel antagonist, the toxic syndrome it produces in vivo, and its effect upon vulnerable populations. We also summarize the available information about potential therapeutic countermeasures and treatment strategies as well as the contribution of clinical development of TMDT poisoning to our understanding of epileptogenesis. Finally we identify gaps in our knowledge and suggest potentially fruitful directions for continued research on this dangerous, yet intriguing compound

Mouse Model of Human Poisonings with Tetramethylenedisulfotetramine: Characterization of the Effect of Exposure Route on Syndrome Outcomes

Tetramethylenedisulfotetramine (TMDT) is a synthetic neurotoxic rodenticide and potential chemical threat agent. Signs of TMDT poisoning include convulsions which can progress into status epilepticus and death. Although clinical reports clearly show that poisoning via food and drink is the main route of exposure, experimental studies have primarily utilized parenteral routes. Here we used two different modes of oral administration of TMDT and compared the toxic outcomes with two different parenteral routes. Adult male mice were given various doses of TMDT either perorally in peanut butter or cereal pellets, or injected intraperitoneally (i.p.) or subcutaneously (s.c.). All routes produced the complete TMDT syndrome including twitches, clonic and tonic-clonic seizures and death. However potencies varied with the following rank order: i.p. \u3e s.c. \u3e oral (cereal)\u3e\u3eoral (peanut butter). Our data clearly show that ingestion of TMDT with peanut butter markedly reduces the overall syndrome severity relative to oral exposure via cereals. No significant differences were observed by substituting peanut oil for water as a vehicle for i.p. administered TMDT. In conclusion, high vs low fat food can differentially affect TMDT onset of action, probably due to differences in availability from the gastrointestinal tract. These results should be considered when searching for effective treatments for TMDT poisoning

Walking and Hiking: A guide to places near Cuba, New Mexico

We hope this guide will provide all the information you need to enjoy walking and hiking near Cuba. We have included maps and descriptions of nine walking places that vary in distance and variety of landscape. For each you will find information on parking, distance, difficulty, suitability for dogs, and what you may expect to see. If a medical practitioner or other health professional has recommended walking for your health, you may wish to view your prescription on the inside of the front cover. We have also provided a checklist of things to take with you on the back cover. Enjoy your walks