Saracatinib, a Src Tyrosine Kinase Inhibitor, as a Disease Modifier in the Rat DFP Model: Sex Differences, Neurobehavior, Gliosis, Neurodegeneration, and Nitro-Oxidative Stress

Gage, Meghan; Putra, Marson; Wachter, Logan; Dishman, Kylie; Gard, Megan; Gomez-Estrada, Crystal; Thippeswamy, Thimmasettappa

doi:10.3390/antiox11010061

Open AccessArticle

Saracatinib, a Src Tyrosine Kinase Inhibitor, as a Disease Modifier in the Rat DFP Model: Sex Differences, Neurobehavior, Gliosis, Neurodegeneration, and Nitro-Oxidative Stress

by

Meghan Gage

,

Marson Putra

,

Logan Wachter

,

Kylie Dishman

,

Megan Gard

,

Crystal Gomez-Estrada

and

Thimmasettappa Thippeswamy

^*

Department of Biomedical Sciences and Interdepartmental Neuroscience Program, Iowa State University, Ames, IA 50011, USA

^*

Author to whom correspondence should be addressed.

Antioxidants 2022, 11(1), 61; https://doi.org/10.3390/antiox11010061

Submission received: 7 November 2021 / Revised: 17 December 2021 / Accepted: 23 December 2021 / Published: 28 December 2021

(This article belongs to the Special Issue Natural or Synthetic Antioxidants for Neurodegenerative Diseases and Brain Health)

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Abstract

Diisopropylfluorophosphate (DFP), an organophosphate nerve agent (OPNA), exposure causes status epilepticus (SE) and epileptogenesis. In this study, we tested the protective effects of saracatinib (AZD0530), a Src kinase inhibitor, in mixed-sex or male-only Sprague Dawley rats exposed to 4–5 mg/kg DFP followed by 2 mg/kg atropine and 25 mg/kg 2-pralidoxime. Midazolam (3 mg/kg) was given to the mixed-sex cohort (1 h post-DFP) and male-only cohort (~30 min post-DFP). Saracatinib (20 mg/kg, oral, daily for 7 days) or vehicle was given two hours later and euthanized eight days or ten weeks post-DFP. Brain immunohistochemistry (IHC) showed increased microgliosis, astrogliosis, and neurodegeneration in DFP-treated animals. In the 10-week post-DFP male-only group, there were no significant differences between groups in the novel object recognition, Morris water maze, rotarod, or forced swim test. Brain IHC revealed significant mitigation by saracatinib in contrast to vehicle-treated DFP animals in microgliosis, astrogliosis, neurodegeneration, and nitro-oxidative stressors, such as inducible nitric oxide synthase, GP91^phox, and 3-Nitrotyrosine. These findings suggest the protective effects of saracatinib on brain pathology seem to depend on the initial SE severity. Further studies on dose optimization, including extended treatment regimen depending on the SE severity, are required to determine its disease-modifying potential in OPNA models.

Keywords: diisopropylfluorophosphate; saracatinib; Src family kinase; neuroinflammation; neurodegeneration; nitro-oxidative stressors; epilepsy; behavioral comorbidities

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MDPI and ACS Style

Gage, M.; Putra, M.; Wachter, L.; Dishman, K.; Gard, M.; Gomez-Estrada, C.; Thippeswamy, T. Saracatinib, a Src Tyrosine Kinase Inhibitor, as a Disease Modifier in the Rat DFP Model: Sex Differences, Neurobehavior, Gliosis, Neurodegeneration, and Nitro-Oxidative Stress. Antioxidants 2022, 11, 61. https://doi.org/10.3390/antiox11010061

AMA Style

Gage M, Putra M, Wachter L, Dishman K, Gard M, Gomez-Estrada C, Thippeswamy T. Saracatinib, a Src Tyrosine Kinase Inhibitor, as a Disease Modifier in the Rat DFP Model: Sex Differences, Neurobehavior, Gliosis, Neurodegeneration, and Nitro-Oxidative Stress. Antioxidants. 2022; 11(1):61. https://doi.org/10.3390/antiox11010061

Chicago/Turabian Style

Gage, Meghan, Marson Putra, Logan Wachter, Kylie Dishman, Megan Gard, Crystal Gomez-Estrada, and Thimmasettappa Thippeswamy. 2022. "Saracatinib, a Src Tyrosine Kinase Inhibitor, as a Disease Modifier in the Rat DFP Model: Sex Differences, Neurobehavior, Gliosis, Neurodegeneration, and Nitro-Oxidative Stress" Antioxidants 11, no. 1: 61. https://doi.org/10.3390/antiox11010061

APA Style

Gage, M., Putra, M., Wachter, L., Dishman, K., Gard, M., Gomez-Estrada, C., & Thippeswamy, T. (2022). Saracatinib, a Src Tyrosine Kinase Inhibitor, as a Disease Modifier in the Rat DFP Model: Sex Differences, Neurobehavior, Gliosis, Neurodegeneration, and Nitro-Oxidative Stress. Antioxidants, 11(1), 61. https://doi.org/10.3390/antiox11010061

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Saracatinib, a Src Tyrosine Kinase Inhibitor, as a Disease Modifier in the Rat DFP Model: Sex Differences, Neurobehavior, Gliosis, Neurodegeneration, and Nitro-Oxidative Stress

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