Organophosphate Intoxication in Juvenile Rats Results in Spontaneous Recurrent Seizures, Altered Hippocampal Oscillations, and Cognitive Dysfunction
Abstract number :
1.227
Submission category :
2. Translational Research / 2D. Models
Year :
2024
Submission ID :
1347
Source :
www.aesnet.org
Presentation date :
12/7/2024 12:00:00 AM
Published date :
Authors :
Presenting Author: Ali Izadi, PhD – University of California Davis
Maria Munoz, BS – University of California Davis
Jeremy Macmahon, BS – University of California Davis
Peter Andrew, BS – University of California Davis
Izzy Triana, Undergraduate – University of California Davis
Donald Bruun, PhD – University of California Davis
Pamela Lein, PhD – University of California Davis
Gene Gurkoff, PhD – University of California Davis
Rationale: Intoxication with organophosphates (OPs), whether from chemical weaponization or unintentional agro-industrial poisoning, results in hundreds of thousands of deaths globally each year. Acute intoxication causes status epilepticus (SE), the development of spontaneous recurrent seizures (SRS), cognitive impairments, and reduced long-term quality of life. Clinical treatments include immediate pharmacological intervention, however required doses elicit significant side effects and fail to effectively prevent progression to SE and SRS. Moreover, the majority of research has focused on adults, however, exposure events also include a significant number of younger casualties who are particularly susceptible to the neurotoxic effects of OPs. Diisopropylfluorophosphate (DFP) is a well-described adult rodent OP model that predictably induces acute SE, chronic SRS, and long-term pathology comparable to clinical outcomes. However, the effects of DFP intoxication in juvenile rats has not been well investigated; studies to date have not established the development of chronic SRS or long-term comorbidities. In this study, we aimed to establish a juvenile model of DFP intoxication to investigate the development of acute and chronic seizures, altered neural oscillations, and cognitive dysfunction.
Methods: On postnatal day (PND) 23, male Sprague Dawley rats (n=16) were implanted with depth electrodes in the hippocampus, prefrontal cortex, amygdala, and cortical screws over prefrontal and posterior regions. On PND 28, animals were treated with 3.75 mg/kg DFP, and 1 minute later with 0.1 mg/kg atropine-sulfate, and 25 mg/kg pralidoxime. Acute seizures were recorded following DFP, and over the subsequent 21 days, SRS were quantified via continuous video/electrophysiology monitoring. Electrophysiology was also evaluated for changes to oscillatory activity across the 21 days of recordings. Six weeks post DFP, animals underwent novel object (NOR) and Barnes maze (BM) behavioral testing.
Results: Of the 7 rats that exhibited SE following DFP, 6 developed SRS in an average of 5.3 ± 0.7 days. The number of recorded seizures decreased over the 21 days post DFP, whereas seizure length significantly increased. For analysis of hippocampal oscillations, the ratio of theta:delta power was significantly reduced over the 21-day recording period. Critically, reduced theta:delta on day 1 post DFP significantly correlated with the later development of SRS. Finally, animals exhibiting SRS performed worse than controls on both BM and NOR, 6 weeks post DFP.
Conclusions: OP research related to basic mechanisms and consequences, let alone the development of therapeutics in young subjects is limited. These preliminary data work towards establishing a juvenile DFP model, addressing significant gaps in knowledge regarding the pathogenesis of acute seizures, chronic SRS, and long-term functional impairments. A better understanding of these mechanisms during development will allow for the advancement of targeted therapeutics effective across all age groups.
Funding: UC Davis CounterACT Pilot Project U54 NS127758
Translational Research