Saracatinib, a Src Tyrosine Kinase Inhibitor, as a Disease Modifier in the Rat DFP Model: Sex Differences, Neurobehavior, Gliosis, Neurodegeneration, and Nitro-Oxidative Stress
Abstract
:1. Introduction
2. Materials and Methods
2.1. Animal Source, Care and Ethics
2.2. Chemicals and Reagents
2.3. Exposure to Diisopropylflourophosphate (DFP)
2.4. Modified Irwin Scoring for Morbidity Analysis
2.5. Behavioral Evaluation
2.5.1. Novel Object Recognition
2.5.2. Horizontal Bar Test
2.5.3. Rotarod
2.5.4. Morris Water Maze (MWM)
2.5.5. Forced Swim Test
2.6. Immunohistochemistry
2.7. Western Blotting
2.8. Experimental Design, Methodological Rigor, and Statistics
3. Results
3.1. Impact of DFP and SAR Treatment: SE Severity, Weight Loss, SRS, and Mortality
3.2. Impact of DFP Toxicity and SAR Treatment on Short-Term (8 Days) Gliosis and Neurodegeneration
3.2.1. Microgliosis
3.2.2. Astrogliosis
3.2.3. Neurodegeneration
3.3. DFP and SAR Effects in Animals with ~20 min of Continuous CS (SE): Weight Loss, Mortality, SRS, and Morbidity
3.4. Impact of DFP and SAR on Behavioral Comorbidities
3.4.1. Impact of DFP and SAR on Learning and Memory
3.4.2. Impact of DFP and SAR on Anxiety, Depression and Motor Activity
3.5. Long Term Impact of DFP and Mitigation by SAR on Gliosis and Neurodegeneration in Animals with ~20 min of Continuous CS during SE
3.5.1. Microgliosis
3.5.2. Astrogliosis
3.5.3. Neurodegeneration
3.6. SAR Mitigates DFP-Induced Toxicity as an Antioxidant
3.6.1. SAR Mitigates DFP-Induced iNOS
3.6.2. SAR Mitigates DFP-Induced 3NT
3.6.3. Impact of DFP and SAR on GP91phox
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Timepoint | Midazolam Administration | PBS + VEH | PBS + SAR | DFP + VEH | DFP + SAR |
---|---|---|---|---|---|
8 days Males | One hour post DFP | 5 | 0 | 7 | 10 (20%) |
8 days Females | One hour post DFP | 5 | 0 | 8 | 8 (25%) |
10 weeks Males | After 20 min CS | 14 | 14 | 16 | 16 (6%) |
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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
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 StyleGage, 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 StyleGage, 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