UC Davis

Organophosphorus cholinesterase inhibitors (OPs) are a class of toxic chemicals that includes both pesticides and nerve agent chemical weapons. Every year accidental or intentional exposure to OPs accounts for millions of poisonings globally. Current standard of care (SOC) for treatment of acute OP intoxication improves survival if administered promptly following intoxication but does not prevent development of chronic neuropathology or neurological sequelae in survivors of such intoxications. While acute OP-induced status epilepticus (SE) is known to be a critical driver of subsequent neuropathology and adverse neurological consequences following intoxication, treatment of acute OP intoxication is likely to be delayed beyond the optimal therapeutic window for SOC intervention. This dissertation addresses two limitations in the treatment of acute OP intoxication: 1) identification of biomarkers for identification of populations at-risk of chronic neurological outcomes, and 2) assessment and targeting of the downstream process of neuroinflammation to mitigate adverse neurological consequences following OP poisoning. In Chapter 2, we identify acute and delayed electrophysiologic signatures following acute intoxication with the OP pesticide diisopropylfluorophosphate (DFP) that correlate with the frequency of spontaneous recurrent seizures (SRS). These findings present novel and translatable electrophysiologic biomarkers with potential to assist in triage following a mass casualty OP exposure incident. Chapter 3 characterizes the microglial and astrocytic neuroinflammatory responses following acute DFP intoxication, providing novel information regarding the spatiotemporal progression of glial phenotypes up to 28 days post exposure (DPE). These data point to early targeting of pro-inflammatory microglial activation as a potential strategy to improve outcomes following acute DFP intoxication. Chapter 4 builds upon the findings of Chapter 3 through transient depletion of microglia via administration of the colony stimulating factor 1 receptor (CSF1R) inhibitor PLX5622 to female rats following acute DFP intoxication. We identify a time-dependent anti-epileptogenic effect of CSF1R inhibition post-DFP intoxication; PLX5622 administration 1-3 DPE prevented the development of SRS while PLX5622 from 4-6 DPE did not reduce the incidence of SRS relative to animals intoxicated with DFP and not provided PLX5622. Animals treated with PLX5622 1-3 DPE displayed attenuated chronic microglial and astrocytic activation and a greater density of neurons at 28 DPE. Collectively, Chapters 3 and 4 provide a natural history of glial inflammatory responses and identify the time-dependent epileptogenic effect of microglial activation following acute DFP intoxication. In Chapter 5, we assess the pleiotropic anti-seizure/anti-inflammatory neurosteroid allopregnanolone (ALLO) in a translatable model of acute soman intoxication. ALLO provides dose-dependent control of soman-induced seizures and mitigates acute neurodegeneration and neuroinflammation following soman intoxication. The findings of this dissertation offer tangible, clinically relevant improvements to acute and delayed treatment of OP poisoning, while also highlighting the time-dependency of microglial-targeted anti-inflammatory interventions post-intoxication.