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Screening for Efficacious Anticonvulsants and Neuroprotectants in Delayed Treatment Models of Organophosphate-induced
Bryan S Barker1, Jay Spampanato2, Hilary S McCarren1
1Medical Toxicology Research Division, Neuroscience Department, U.S. Army Medical Research Institute of Chemical Defense, 8350 Ricketts Point Rd, Aberdeen Proving Ground, MD 21010, USA.
Abstract:
Organophosphorus (OP) compounds are deadly chemicals that exert their intoxicating effects through the irreversible inhibition of acetylcholinesterase (AChE). In addition to an excess of peripheral ailments, OP intoxication induces status epilepticus (SE) which if left untreated may lead to permanent brain damage or death. Benzodiazepines are typically the primary therapies for OP-induced SE, but these drugs lose efficacy as treatment time is delayed. The CounterACT Neurotherapeutic Screening (CNS) Program was therefore established by the National Institutes of Health (NIH) to discover novel treatments that may be administered adjunctively with the currently approved medical countermeasures for OP-induced SE in a delayed treatment scenario. The CNS program utilizes in vivo EEG recordings and Fluoro-JadeB (FJB) histopathology in two established rat models of OP-induced SE, soman (GD) and diisopropylfluorophosphate (DFP), to evaluate the anticonvulsant and neuroprotectant efficacy of novel adjunct therapies when administered at 20 or 60 min after the induction of OP-induced SE. Here we report the results of multiple compounds that have previously shown anticonvulsant or neuroprotectant efficacy in other models of epilepsy or trauma. Drugs tested were ganaxolone, diazoxide, bumetanide, propylparaben, citicoline, MDL-28170, and chloroquine. EEG analysis revealed that ganaxolone demonstrated the most robust anticonvulsant activity, whereas all other drugs failed to attenuate ictal activity in both models of OP-induced SE. FJB staining demonstrated that none of the tested drugs had widespread neuroprotective abilities. Overall these data suggest that neurosteroids may represent the most promising anticonvulsant option for OP-induced SE out of the seven unique mechanisms tested here. Additionally, these results suggest that drugs that provide significant neuroprotection from OP-induced SE without some degree of anticonvulsant activity are elusive, which further highlights the necessity to continue screening novel adjunct treatments through the CNS program.
Insights
Ganaxolone showed the best anticonvulsant effects against organophosphorus (OP) poisoning-induced seizures in rats. However, none of the tested drugs provided significant neuroprotection, highlighting the need for new treatments for OP intoxication.
Area of Science:
- Neuroscience
- Pharmacology
- Toxicology
Background:
- Organophosphorus (OP) compounds inhibit acetylcholinesterase (AChE), causing intoxication and potentially status epilepticus (SE).
- Current treatments for OP-induced SE, like benzodiazepines, lose efficacy with delayed administration.
- The NIH CounterACT Neurotherapeutic Screening (CNS) Program seeks novel adjunct therapies for delayed OP-induced SE treatment.
Purpose of the Study:
- To evaluate the anticonvulsant and neuroprotective efficacy of seven compounds as adjunct therapies for OP-induced SE.
- To assess efficacy when administered 20 or 60 minutes after OP exposure in rat models.
- To identify promising candidates for treating delayed OP intoxication.
Main Methods:
- Utilized in vivo electroencephalogram (EEG) recordings in rat models of soman (GD) and diisopropylfluorophosphate (DFP)-induced SE.
- Employed Fluoro-JadeB (FJB) histopathology to assess neuroprotection.
- Tested ganaxolone, diazoxide, bumetanide, propylparaben, citicoline, MDL-28170, and chloroquine.
Main Results:
- Ganaxolone demonstrated the most significant anticonvulsant activity against OP-induced SE.
- All other tested compounds failed to attenuate seizure activity in both GD and DFP models.
- No tested drug exhibited widespread neuroprotective effects as indicated by FJB staining.
Conclusions:
- Neurosteroids, like ganaxolone, show promise as anticonvulsant treatments for OP-induced SE.
- Developing effective neuroprotective agents for OP-induced SE that also possess anticonvulsant activity remains challenging.
- Continued screening of novel adjunct treatments is crucial for improving outcomes in OP intoxication.
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