Saracatinib, a Src Tyrosine Kinase Inhibitor, as a Disease Modifier in the Rat DFP Model: Sex Differences, Neurobehavior, Gliosis, Neurodegeneration, and Nitro-Oxidative Stress
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 D...
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MDPI AG
2021-12-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/11/1/61 |
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| author | Meghan Gage Marson Putra Logan Wachter Kylie Dishman Megan Gard Crystal Gomez-Estrada Thimmasettappa Thippeswamy |
| author_facet | Meghan Gage Marson Putra Logan Wachter Kylie Dishman Megan Gard Crystal Gomez-Estrada Thimmasettappa Thippeswamy |
| author_sort | Meghan Gage |
| collection | DOAJ |
| description | 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<sup>phox</sup>, 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. |
| first_indexed | 2024-03-10T03:01:03Z |
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| language | English |
| last_indexed | 2024-03-10T03:01:03Z |
| publishDate | 2021-12-01 |
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| series | Antioxidants |
| spelling | doaj.art-b173e9d9b119403fb5059d593f6e9aa92023-11-23T12:46:45ZengMDPI AGAntioxidants2076-39212021-12-011116110.3390/antiox11010061Saracatinib, a Src Tyrosine Kinase Inhibitor, as a Disease Modifier in the Rat DFP Model: Sex Differences, Neurobehavior, Gliosis, Neurodegeneration, and Nitro-Oxidative StressMeghan Gage0Marson Putra1Logan Wachter2Kylie Dishman3Megan Gard4Crystal Gomez-Estrada5Thimmasettappa Thippeswamy6Department of Biomedical Sciences and Interdepartmental Neuroscience Program, Iowa State University, Ames, IA 50011, USADepartment of Biomedical Sciences and Interdepartmental Neuroscience Program, Iowa State University, Ames, IA 50011, USADepartment of Biomedical Sciences and Interdepartmental Neuroscience Program, Iowa State University, Ames, IA 50011, USADepartment of Biomedical Sciences and Interdepartmental Neuroscience Program, Iowa State University, Ames, IA 50011, USADepartment of Biomedical Sciences and Interdepartmental Neuroscience Program, Iowa State University, Ames, IA 50011, USADepartment of Biomedical Sciences and Interdepartmental Neuroscience Program, Iowa State University, Ames, IA 50011, USADepartment of Biomedical Sciences and Interdepartmental Neuroscience Program, Iowa State University, Ames, IA 50011, USADiisopropylfluorophosphate (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<sup>phox</sup>, 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.https://www.mdpi.com/2076-3921/11/1/61diisopropylfluorophosphatesaracatinibSrc family kinaseneuroinflammationneurodegenerationnitro-oxidative stressors |
| spellingShingle | Meghan Gage Marson Putra Logan Wachter Kylie Dishman Megan Gard Crystal Gomez-Estrada Thimmasettappa Thippeswamy 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 diisopropylfluorophosphate saracatinib Src family kinase neuroinflammation neurodegeneration nitro-oxidative stressors |
| title | Saracatinib, a Src Tyrosine Kinase Inhibitor, as a Disease Modifier in the Rat DFP Model: Sex Differences, Neurobehavior, Gliosis, Neurodegeneration, and Nitro-Oxidative Stress |
| title_full | Saracatinib, a Src Tyrosine Kinase Inhibitor, as a Disease Modifier in the Rat DFP Model: Sex Differences, Neurobehavior, Gliosis, Neurodegeneration, and Nitro-Oxidative Stress |
| title_fullStr | Saracatinib, a Src Tyrosine Kinase Inhibitor, as a Disease Modifier in the Rat DFP Model: Sex Differences, Neurobehavior, Gliosis, Neurodegeneration, and Nitro-Oxidative Stress |
| title_full_unstemmed | Saracatinib, a Src Tyrosine Kinase Inhibitor, as a Disease Modifier in the Rat DFP Model: Sex Differences, Neurobehavior, Gliosis, Neurodegeneration, and Nitro-Oxidative Stress |
| title_short | Saracatinib, a Src Tyrosine Kinase Inhibitor, as a Disease Modifier in the Rat DFP Model: Sex Differences, Neurobehavior, Gliosis, Neurodegeneration, and Nitro-Oxidative Stress |
| title_sort | saracatinib a src tyrosine kinase inhibitor as a disease modifier in the rat dfp model sex differences neurobehavior gliosis neurodegeneration and nitro oxidative stress |
| topic | diisopropylfluorophosphate saracatinib Src family kinase neuroinflammation neurodegeneration nitro-oxidative stressors |
| url | https://www.mdpi.com/2076-3921/11/1/61 |
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