Long-Term Consequences of Acute Organophosphate Intoxication in an Adolescent Rodent Model

University Of California At Davis, Davis CA

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Abstract

Acute organophosphate (OP) intoxication, resulting from chemical warfare, industrial accidents, and intentional exposures, remains a significant global health crisis, leading to substantial morbidity and mortality. Survivors can quickly develop status epilepticus (SE), which may progress to spontaneous recurrent seizures (SRS), cognitive impairments, and chronic neurological dysfunction. Current standard of care (SOC) treatments, including atropine, pralidoxime (2-PAM), and midazolam (MDZ), improve acute survival but often fail to prevent SE progression, the onset of SRS, and long-term impairments. This is especially concerning during adolescence, a critical period of neurodevelopment and evolving seizure susceptibility, yet little is known about how OP intoxication and SOC treatments, including MDZ, affect disease progression. Additionally, while prolonged acetylcholinesterase (AChE) inhibition has been linked to elevated seizure burden in adult models, its recovery trajectory during adolescence remains poorly understood, along with its relationship to seizure development, benzodiazepine efficacy, and cognitive deficits. To address these gaps, we propose a first-of-its-kind longitudinal study investigating acute OP intoxication in adolescent rats (postnatal day 35) using clinically relevant outcome measures. This study will systematically assess the natural history of seizure development, changes to neural oscillatory activity, and cognitive function over an eight-week period following acute diisopropylfluorophosphate (DFP) intoxication, while also evaluating the effects of SOC with and without MDZ. In parallel, we will track AChE suppression and its recovery profile to determine its relationship with SRS development and learning and memory impairments. We hypothesize that DFP intoxication during this developmental period will result in SE, the emergence of SRS, persistent disruptions to network oscillations, and cognitive deficits. Furthermore, we expect that while MDZ treatment will mitigate SE-related mortality, it will have minimal impact on the long-term trajectory of disease progression. Finally, we anticipate that AChE recovery will be prolonged during adolescence, with delayed restoration correlating with greater seizure susceptibility and cognitive deficits, revealing a critical mechanistic link between cholinergic dysfunction and behavioral alterations. This study will establish the first comprehensive model of acute OP intoxication during adolescence, providing key insights into age-dependent vulnerability, treatment efficacy, and long-term sequelae. By aligning this model with previously established adult paradigms, these findings will directly inform more effective treatment strategies, guiding the identification of targeted countermeasures that consider both age and sex as key variables.