Environmental Health Science
Cell Biology and Anatomy
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.
Laukova, M., Pervez, S., Sannoh, F., Veliskova, J., Velisek, L., & Shakarjian, M. (2017). Tetramethylenedisulfotetramine Neurotoxicity: In Vivo Validation of In Vitro Screen to Identify Potential Countermeasures. Retrieved from https://touroscholar.touro.edu/cgi/viewcontent.cgi?article=1013&context=nymc_fac_posters