Idebenone Mitigates Traumatic-Brain-Injury-Triggered Gene Expression Changes to Ephrin-A and Dopamine Signaling Pathways While Increasing Microglial Genes
Traumatic brain injury (TBI) leads to persistent pro-inflammatory microglial activation implicated in neurodegeneration. Idebenone, a coenzyme Q10 analogue that interacts with both mitochondria and the tyrosine kinase adaptor SHC1, inhibits aspects of microglial activation in vitro. We used the Nano...
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2025-06-01
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| author | Hyehyun Hwang Chinmoy Sarkar Boris Piskoun Naibo Zhang Apurva Borcar Courtney L. Robertson Marta M. Lipinski Nagendra Yadava Molly J. Goodfellow Brian M. Polster |
| author_facet | Hyehyun Hwang Chinmoy Sarkar Boris Piskoun Naibo Zhang Apurva Borcar Courtney L. Robertson Marta M. Lipinski Nagendra Yadava Molly J. Goodfellow Brian M. Polster |
| author_sort | Hyehyun Hwang |
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| description | Traumatic brain injury (TBI) leads to persistent pro-inflammatory microglial activation implicated in neurodegeneration. Idebenone, a coenzyme Q10 analogue that interacts with both mitochondria and the tyrosine kinase adaptor SHC1, inhibits aspects of microglial activation in vitro. We used the NanoString Neuropathology Panel to test the hypothesis that idebenone post-treatment mitigates TBI-pathology-associated acute gene expression changes by moderating the pro-inflammatory microglial response to injury. Controlled cortical impact to adult male mice increased the microglial activation signature in the peri-lesional cortex at 24 h post-TBI. Unexpectedly, several microglial signature genes upregulated by TBI were further increased by post-injury idebenone administration. However, idebenone significantly attenuated TBI-mediated perturbations to gene expression associated with behavior, particularly in the gene ontology–biological process (GO:BP) pathways “ephrin receptor signaling” and “dopamine metabolic process”. Gene co-expression analysis correlated levels of microglial complement component 1q (<i>C1q</i>) and the neurotrophin receptor gene <i>Ntrk1</i> to large (>3-fold) TBI-induced decreases in dopamine receptor genes <i>Drd1</i> and <i>Drd2</i> that were mitigated by idebenone treatment. Bioinformatics analysis identified SUZ12 as a candidate transcriptional regulator of idebenone-modified gene expression changes. Overall, the results suggest that idebenone may enhance TBI-induced microglial number within the first 24 h of TBI and identify ephrin-A and dopamine signaling as novel idebenone targets. |
| format | Article |
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| issn | 2073-4409 |
| language | English |
| publishDate | 2025-06-01 |
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| spelling | doaj-art-5acce437365d43beb3a0a53c5c83fdf22025-08-20T02:32:52ZengMDPI AGCells2073-44092025-06-01141182410.3390/cells14110824Idebenone Mitigates Traumatic-Brain-Injury-Triggered Gene Expression Changes to Ephrin-A and Dopamine Signaling Pathways While Increasing Microglial GenesHyehyun Hwang0Chinmoy Sarkar1Boris Piskoun2Naibo Zhang3Apurva Borcar4Courtney L. Robertson5Marta M. Lipinski6Nagendra Yadava7Molly J. Goodfellow8Brian M. Polster9Department of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, MD 21201, USADepartment of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, MD 21201, USADepartment of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, MD 21201, USADepartment of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, MD 21201, USADepartment of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, MD 21201, USADepartment of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD 21287, USADepartment of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, MD 21201, USADepartment of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, MD 21201, USADepartment of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, MD 21201, USADepartment of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, MD 21201, USATraumatic brain injury (TBI) leads to persistent pro-inflammatory microglial activation implicated in neurodegeneration. Idebenone, a coenzyme Q10 analogue that interacts with both mitochondria and the tyrosine kinase adaptor SHC1, inhibits aspects of microglial activation in vitro. We used the NanoString Neuropathology Panel to test the hypothesis that idebenone post-treatment mitigates TBI-pathology-associated acute gene expression changes by moderating the pro-inflammatory microglial response to injury. Controlled cortical impact to adult male mice increased the microglial activation signature in the peri-lesional cortex at 24 h post-TBI. Unexpectedly, several microglial signature genes upregulated by TBI were further increased by post-injury idebenone administration. However, idebenone significantly attenuated TBI-mediated perturbations to gene expression associated with behavior, particularly in the gene ontology–biological process (GO:BP) pathways “ephrin receptor signaling” and “dopamine metabolic process”. Gene co-expression analysis correlated levels of microglial complement component 1q (<i>C1q</i>) and the neurotrophin receptor gene <i>Ntrk1</i> to large (>3-fold) TBI-induced decreases in dopamine receptor genes <i>Drd1</i> and <i>Drd2</i> that were mitigated by idebenone treatment. Bioinformatics analysis identified SUZ12 as a candidate transcriptional regulator of idebenone-modified gene expression changes. Overall, the results suggest that idebenone may enhance TBI-induced microglial number within the first 24 h of TBI and identify ephrin-A and dopamine signaling as novel idebenone targets.https://www.mdpi.com/2073-4409/14/11/824C1QCCIEFNAEPHAmitochondrianeuroinflammation |
| spellingShingle | Hyehyun Hwang Chinmoy Sarkar Boris Piskoun Naibo Zhang Apurva Borcar Courtney L. Robertson Marta M. Lipinski Nagendra Yadava Molly J. Goodfellow Brian M. Polster Idebenone Mitigates Traumatic-Brain-Injury-Triggered Gene Expression Changes to Ephrin-A and Dopamine Signaling Pathways While Increasing Microglial Genes Cells C1Q CCI EFNA EPHA mitochondria neuroinflammation |
| title | Idebenone Mitigates Traumatic-Brain-Injury-Triggered Gene Expression Changes to Ephrin-A and Dopamine Signaling Pathways While Increasing Microglial Genes |
| title_full | Idebenone Mitigates Traumatic-Brain-Injury-Triggered Gene Expression Changes to Ephrin-A and Dopamine Signaling Pathways While Increasing Microglial Genes |
| title_fullStr | Idebenone Mitigates Traumatic-Brain-Injury-Triggered Gene Expression Changes to Ephrin-A and Dopamine Signaling Pathways While Increasing Microglial Genes |
| title_full_unstemmed | Idebenone Mitigates Traumatic-Brain-Injury-Triggered Gene Expression Changes to Ephrin-A and Dopamine Signaling Pathways While Increasing Microglial Genes |
| title_short | Idebenone Mitigates Traumatic-Brain-Injury-Triggered Gene Expression Changes to Ephrin-A and Dopamine Signaling Pathways While Increasing Microglial Genes |
| title_sort | idebenone mitigates traumatic brain injury triggered gene expression changes to ephrin a and dopamine signaling pathways while increasing microglial genes |
| topic | C1Q CCI EFNA EPHA mitochondria neuroinflammation |
| url | https://www.mdpi.com/2073-4409/14/11/824 |
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