Preface: Discovery and development of better medical countermeasures for chemical threats targeting the nervous system

Historically, research on developing better antidotes and treatments for chemical poisonings has not been a mainstream topic in neuroscience research, but the advent of the 9/11 terrorist attacks raised the question of whether the nation is prepared for such an event involving the use of chemical weapons and weaponized toxic chemicals. Whether this could happen is not in question given the well-studied examples in Japan that occurred several years ago (Jett and Spriggs, 2018). More recent assassinations and deliberate poisonings using nerve agents also call for more medical preparedness. Beyond the need to be better prepared for the use of toxic chemicals for nefarious purposes, these same chemicals are occupational hazards and can be released in large-scale industrial accidents.

Many of the most toxic chemicals target the nervous system and cause acute lethal effects, as well as long-term neurological sequelae. Many of the effects of neurotoxic chemical threat agents are similar to what we see affecting individuals with neurological disease and disorders. This provides an opportunity to adapt some of the existing treatments for these illnesses to mass casualty chemical poisoning events, and importantly, to engage the general neuroscience research community in areas such as epilepsy and stroke to contribute to medical countermeasure research.

In this issue, research supported by the National Institutes of Health (NIH) Countermeasures Against Chemical Threats (CounterACT) program is presented with a focus on chemical agents that cause acute and long-term neurological effects. Most of the research has been with organophosphorus (OP) chemical warfare agents or toxic pesticides. The acute effects of OP agents are largely controlled by the standard of care (atropine sulfate, 2 mg IM; prolidoxime chloride 600 mg IM, midazolam, 10 mg IM). There are some weaknesses in the standard of care for acute exposure to OP agents (Jett and Spriggs, 2018) including the need for a more effective acetylcholinesterase (AChE) reactivator than pralidoxime. Centrally acting oximes that are more effective after aging of the AChE-OP complex have been the holy grail of OP medical countermeasures research for many years. Aging has been a particularly intractable problem. This process causes the loss of an alkyl side chain and much further stabilization of the overall complex. Novel centrally acting compounds based on substituted phenoxyalkyl oximes show promise in rat models using sarin and VX surrogates (Chambers and Meek, 2019). Reactivation of AChE is a complex problem and translational research in the neurological effects part of the NIH CounterACT program is supported by studies of the mechanisms of chemical agent toxicity and how antidotes work in animal models. For example, molecular events can now be studied by dynamic imaging in living systems with positron-emission tomography (Thompson and Gerdes, 2019).

In certain age groups during OP poisoning after the acute cholinergic crisis, status epilepticus (SE) becomes refractory to benzodiazepine treatment usingconventional doses, and eventually spontaneous recurring seizures may emerge. This sequence of events usually is observed in rodents older than 21 days of age. Recent work suggests that this refractory SE may be controlled with a polytherapy approach targeting multiple neurotransmitter systems, rather than midazolam alone (Niquet et al., 2019). Likewise, the glutamate receptor antagonist LY293558 has shown significant promise as a new treatment for recurring seizures and behavioral effects caused by soman, and this is potentiated with the addition of caramiphen (Aroniadou-Anderjaska et al., 2019).

There is also substantial evidence from human and animal studies that lasting effects including epilepsy and cognitive impairment may occur in people who survive the acute lethal effects of OP agents (National Toxicology Program, 2019). Diisopropylfluorophosphate (DFP) is a potent OP pesticide now routinely used as a research tool and it has been shown that the prostaglandin-E₂ receptor is a potential target for attenuating DFP-induced hippocampal degeneration when a receptor antagonist is delivered well after status epilepticus has ended (Rojas et al., 2019). Inducible nitric oxide synthase (iNOS) inhibitors prevent some long-term effects after DFP exposure in a rat model and it is a promising follow-on therapy after the standard of care (Putra et al., 2019).

One proposed mechanism for the longer-term effects observed after OP exposure is the disruption of calcium homeostasis, and blockade of calcium release with antagonists seem to ameliorate the observed effects (Deshpande and DeLorenzo, 2019). Neuroinflammation and oxidative stress are also likely involved, and persistent histopathological damage in several brain regions after DFP exposure support this hypothesis (Guignet et al., 2019). Long-term behavioral deficits are correlated with the histopathological data in this study. Oxidative stress brought on by OP-induced seizures may cause some of the long-term effects, but there is also the possibility of direct effects of the OP agents causing oxidative damage, and drug candidates like AEOL 10150 are being looked at as potential general antioxidants that could be used for OP and other chemical threats (Pearson-Smith and Patel, 2019).

Some chemical threats under study cause devastating neurological effects but are not OP compounds. Tetramine or TETS is a potent rodenticide that is a GABA_A receptor channel antagonist and causes seizures similar, but not identical to the OP agents. The natural history of tetramine toxicity is being studied; for example it is much more potent to juvenile rats than adults (Laukova et al., 2019), and allopregnanolone and ganaxolone are effective in the treatment of TETS-induced SE when administered by the intramuscular route (Zolkowska et al., 2018). Hydrogen sulfide is of major concern, and it has been shown that this compound produces lesions in the brain and the redox agent methylene blue may be an effective antidote (Haouzi et al., 2019).

Articles in this special issue represent an example of a diverse effort of basic, translational, and pre-clinical research aimed at understanding the neurological toxicities of chemical threat agents and using this knowledge to develop safer, more effective treatments for exposures to highly toxic chemicals. A more complete description and bibliography for the NIH CounterACT Research Network can be found at https://www.ninds.nih.gov/Current-Research/Trans-Agency-Activities/CounterACT.