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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| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-06-01
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| Series: | Cells |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2073-4409/14/11/824 |
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| Summary: | 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. |
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| ISSN: | 2073-4409 |