The organophosphate nerve agent model of epilepsy and disease mitigation by saracatinib
Date
2022-05
Authors
Gage, Meghan
Major Professor
Advisor
Thippeswamy, Thimmasettappa
Greenlee, M. Heather
Underbakke, Eric
Mochel, Jonathan
McGrail, Maura
Committee Member
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Abstract
Organophosphate nerve agents (OPNAs) induce cholinergic crisis through the irreversible inhibition of acetylcholinesterase. These agents have previously been used in chemical warfare scenarios and pose threats to military and civilian populations. OPNA intoxication can initiate status epilepticus (SE), resulting in long-term neurotoxicity, including spontaneous recurrent seizures, changes in cognition and mood, gliosis, and neurodegeneration. The purposes of the studies in this dissertation were to further characterize the rat OP model and evaluate saracatinib, a src family tyrosine kinase inhibitor, as a disease modifier. We challenged male and female adult (7-8 weeks) rats with the OPs diisopropropylflourophosphate (DFP) or soman. We first found that females, compared to males, were more resistant to DFP-induced seizures and that there is evidence of a relationship between the female estrous cycle and DFP-induced neurotoxicity. Second, we are the first to characterize cortical glial scars following DFP-induced neurotoxicity. These scars were like those described after spinal cord injury in which many hypertrophic astrocytes surrounded a core of activated microglia. Third, we demonstrated that the initial severity and duration of SE determines the localization and extent of gliosis and neurodegeneration. When SE was limited to 20 minutes, the damage was localized to the amygdala and piriform cortex, while when SE was longer (>30 minutes), the damage was more widespread. We also tested various dosing regimens of saracatinib following DFP intoxication. 20mg/kg saracatinib daily for seven days was tolerable for animals following OP intoxication. Higher and more frequent dosing led to dramatic weight loss and mortality. Following DFP intoxication and about 20 minutes of SE, early saracatinib administration reduced gliosis and neurodegeneration both 8 days and 10 weeks post-intoxication. We then tested this dosing regimen in soman-intoxicated animals with >30 minutes SE. We observed soman-induced changes in neurobehavior on the horizontal bar test, rotarod, zero maze, and fear conditioning apparatus with minimal evidence of mitigation by saracatinib. Regardless of treatment with saracatinib, soman-treated animals had spontaneous seizures, gliosis, and neurodegeneration. Overall, saracatinib’s efficacy and toxicity are dependent on the initial SE severity and dosing regimen. Future studies with saracatinib will aim to optimize the dosing regimen (longer duration of treatment), explore other administration routes, and test the addition of other possible therapeutic agents.
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dissertation