Mechanisms of disease-modifying effect of saracatinib (AZD0530), a Src/Fyn tyrosine kinase inhibitor, in the rat kainate model of temporal lobe epilepsy
We have recently demonstrated the role of the Fyn-PKCδ signaling pathway in status epilepticus (SE)-induced neuroinflammation and epileptogenesis in experimental models of temporal lobe epilepsy (TLE). In this study, we show a significant disease-modifying effect and the mechanisms of a Fyn/Src tyro...
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| Format: | Article |
| Language: | English |
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Elsevier
2021-08-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996121001595 |
| _version_ | 1818666419631423488 |
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| author | Shaunik Sharma Steven Carlson Adriana Gregory-Flores Andy Hinojo-Perez Ashley Olson Thimmasettappa Thippeswamy |
| author_facet | Shaunik Sharma Steven Carlson Adriana Gregory-Flores Andy Hinojo-Perez Ashley Olson Thimmasettappa Thippeswamy |
| author_sort | Shaunik Sharma |
| collection | DOAJ |
| description | We have recently demonstrated the role of the Fyn-PKCδ signaling pathway in status epilepticus (SE)-induced neuroinflammation and epileptogenesis in experimental models of temporal lobe epilepsy (TLE). In this study, we show a significant disease-modifying effect and the mechanisms of a Fyn/Src tyrosine kinase inhibitor, saracatinib (SAR, also known as AZD0530), in the rat kainate (KA) model of TLE. SAR treatment for a week, starting the first dose (25 mg/kg, oral) 4 h after the onset of SE, significantly reduced spontaneously recurring seizures and epileptiform spikes during the four months of continuous video-EEG monitoring. Immunohistochemistry of brain sections and Western blot analyses of hippocampal lysates at 8-day (8d) and 4-month post-SE revealed a significant reduction of SE-induced astrogliosis, microgliosis, neurodegeneration, phosphorylated Fyn/Src-419 and PKCδ-tyr311, in SAR-treated group when compared with the vehicle control. We also found the suppression of nitroxidative stress markers such as iNOS, 3-NT, 4-HNE, and gp91phox in the hippocampus, and nitrite and ROS levels in the serum of the SAR-treated group at 8d post-SE. The qRT-PCR (hippocampus) and ELISA (serum) revealed a significant reduction of key proinflammatory cytokines TNFα and IL-1β mRNA in the hippocampus and their protein levels in serum, in addition to IL-6 and IL-12, in the SAR-treated group at 8d in contrast to the vehicle-treated group. These findings suggest that SAR targets some of the key biomarkers of epileptogenesis and modulates neuroinflammatory and nitroxidative pathways that mediate the development of epilepsy. Therefore, SAR can be developed as a potential disease-modifying agent to prevent the development and progression of TLE. |
| first_indexed | 2024-12-17T06:04:14Z |
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| id | doaj.art-ff73065c40994bddaf6b38a0e5731cae |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-17T06:04:14Z |
| publishDate | 2021-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-ff73065c40994bddaf6b38a0e5731cae2022-12-21T22:00:47ZengElsevierNeurobiology of Disease1095-953X2021-08-01156105410Mechanisms of disease-modifying effect of saracatinib (AZD0530), a Src/Fyn tyrosine kinase inhibitor, in the rat kainate model of temporal lobe epilepsyShaunik Sharma0Steven Carlson1Adriana Gregory-Flores2Andy Hinojo-Perez3Ashley Olson4Thimmasettappa Thippeswamy5Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames 50011, USADepartment of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames 50011, USADepartment of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames 50011, USADepartment of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames 50011, USADepartment of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames 50011, USACorresponding author at: Epilepsy Research Laboratory, Department of Biomedical Science, 2036 College of Veterinary Medicine, Iowa State University, Ames, Iowa 50011, USA.; Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames 50011, USAWe have recently demonstrated the role of the Fyn-PKCδ signaling pathway in status epilepticus (SE)-induced neuroinflammation and epileptogenesis in experimental models of temporal lobe epilepsy (TLE). In this study, we show a significant disease-modifying effect and the mechanisms of a Fyn/Src tyrosine kinase inhibitor, saracatinib (SAR, also known as AZD0530), in the rat kainate (KA) model of TLE. SAR treatment for a week, starting the first dose (25 mg/kg, oral) 4 h after the onset of SE, significantly reduced spontaneously recurring seizures and epileptiform spikes during the four months of continuous video-EEG monitoring. Immunohistochemistry of brain sections and Western blot analyses of hippocampal lysates at 8-day (8d) and 4-month post-SE revealed a significant reduction of SE-induced astrogliosis, microgliosis, neurodegeneration, phosphorylated Fyn/Src-419 and PKCδ-tyr311, in SAR-treated group when compared with the vehicle control. We also found the suppression of nitroxidative stress markers such as iNOS, 3-NT, 4-HNE, and gp91phox in the hippocampus, and nitrite and ROS levels in the serum of the SAR-treated group at 8d post-SE. The qRT-PCR (hippocampus) and ELISA (serum) revealed a significant reduction of key proinflammatory cytokines TNFα and IL-1β mRNA in the hippocampus and their protein levels in serum, in addition to IL-6 and IL-12, in the SAR-treated group at 8d in contrast to the vehicle-treated group. These findings suggest that SAR targets some of the key biomarkers of epileptogenesis and modulates neuroinflammatory and nitroxidative pathways that mediate the development of epilepsy. Therefore, SAR can be developed as a potential disease-modifying agent to prevent the development and progression of TLE.http://www.sciencedirect.com/science/article/pii/S0969996121001595Fyn/Src tyrosine kinaseEpileptogenesisNitroxidative stressNeuroinflammationProinflammatory cytokinesSpontaneous seizures |
| spellingShingle | Shaunik Sharma Steven Carlson Adriana Gregory-Flores Andy Hinojo-Perez Ashley Olson Thimmasettappa Thippeswamy Mechanisms of disease-modifying effect of saracatinib (AZD0530), a Src/Fyn tyrosine kinase inhibitor, in the rat kainate model of temporal lobe epilepsy Neurobiology of Disease Fyn/Src tyrosine kinase Epileptogenesis Nitroxidative stress Neuroinflammation Proinflammatory cytokines Spontaneous seizures |
| title | Mechanisms of disease-modifying effect of saracatinib (AZD0530), a Src/Fyn tyrosine kinase inhibitor, in the rat kainate model of temporal lobe epilepsy |
| title_full | Mechanisms of disease-modifying effect of saracatinib (AZD0530), a Src/Fyn tyrosine kinase inhibitor, in the rat kainate model of temporal lobe epilepsy |
| title_fullStr | Mechanisms of disease-modifying effect of saracatinib (AZD0530), a Src/Fyn tyrosine kinase inhibitor, in the rat kainate model of temporal lobe epilepsy |
| title_full_unstemmed | Mechanisms of disease-modifying effect of saracatinib (AZD0530), a Src/Fyn tyrosine kinase inhibitor, in the rat kainate model of temporal lobe epilepsy |
| title_short | Mechanisms of disease-modifying effect of saracatinib (AZD0530), a Src/Fyn tyrosine kinase inhibitor, in the rat kainate model of temporal lobe epilepsy |
| title_sort | mechanisms of disease modifying effect of saracatinib azd0530 a src fyn tyrosine kinase inhibitor in the rat kainate model of temporal lobe epilepsy |
| topic | Fyn/Src tyrosine kinase Epileptogenesis Nitroxidative stress Neuroinflammation Proinflammatory cytokines Spontaneous seizures |
| url | http://www.sciencedirect.com/science/article/pii/S0969996121001595 |
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