Idebenone Mitigates Traumatic-Brain-Injury-Triggered Gene Expression Changes to Ephrin-A and Dopamine Signaling Pathways While Increasing Microglial Genes
Abstract
:1. Introduction
2. Materials and Methods
2.1. Controlled Cortical Impact (CCI) Mouse Model and RNA Extraction
2.2. Gene Set Enrichment Analyses
2.3. Development of the Microglia Gene Signature
3. Results
3.1. Idebenone Reverses TBI-Induced Gene Expression Changes Related to Tissue Integrity, Transmitter Synthesis and Storage, and Axon and Dendrite Structure Without Broadly Inhibiting the TBI Neuropathology Gene Signature or Cytokine Response
3.2. Idebenone Enhances Expression of Microglia Signature Genes Following TBI
3.3. “Ephrin Receptor Signaling” and “Dopamine Metabolic Process” Are Top Gene Ontology Pathways Affected by Idebenone Treatment
3.4. Idebenone Mitigates Widespread TBI-Induced Perturbations to Ephrin-A Signaling Genes
3.5. Idebenone’s Ability to Rescue the Gene Expression Levels of Select GO:BP Dopamine Metabolic Process Genes Following TBI Reveals an Idebenone Partial Responder
3.6. Complement Component 1q (C1q) and Homeostatic Microglial Gene Expression Levels Correlate with Expression of a GO:BP “Behavior” Gene Subgroup Following TBI
3.7. Idebenone Alters Expression of Many Genes Encoding SHC1-Interacting Tyrosine Kinase Receptors
3.8. Expression of TRKA-Encoding Ntrk1, but Not That of Idebenone-Altered Growth Factor Genes, Correlates with Drd2-Related “Behavior” Gene Subgroup Changes Following TBI
3.9. Bioinformatics Analysis Identifies Additional Co-Regulated Genes and the Transcriptional Regulator SUZ12 as Candidate Mediators of Idebenone-Modified TBI-Induced Gene Expression Changes
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Name | Description | Fold Change | p-Value |
---|---|---|---|
Drd2 | dopamine receptor D2 | 6.19 | 0.040 |
Cd4 | CD4 antigen | 5.30 | 0.011 |
Slc18a3 | solute carrier family 18 (vesicular monoamine), member 3 | 3.94 | 0.037 |
Drd1 | dopamine receptor D1 | 2.58 | 0.049 |
Ang | angiogenin, ribonuclease, RNase A family, 5 | 1.94 | 0.044 |
Dgkb | diacylglycerol kinase, beta | 1.61 | 0.002 |
Tlr2 | toll-like receptor 2 | 1.45 | 0.027 |
Ccr5 | chemokine (C-C motif) receptor 5 | 1.37 | 0.038 |
Efna5 | ephrin A5 | 1.33 | 0.011 |
Calb1 | calbindin 1 | 1.31 | 0.029 |
Hgf | hepatocyte growth factor | 1.31 | 0.043 |
Itpr1 | inositol 1,4,5-trisphosphate receptor 1 | 1.31 | 0.013 |
Stab1 | stabilin 1 | 1.30 | 0.036 |
Hpgds | hematopoietic prostaglandin D synthase | 1.28 | 0.009 |
Camk4 | calcium/calmodulin-dependent protein kinase IV | 1.25 | 0.027 |
Fgf14 | fibroblast growth factor 14 | 1.25 | 0.048 |
Negr1 | neuronal growth regulator 1 | 1.24 | 0.009 |
Bcl2 | B cell leukemia/lymphoma 2 | 1.23 | 0.025 |
Fcrls | Fc receptor-like S, scavenger receptor | 1.21 | 0.001 |
Gusb | glucuronidase, beta | 1.20 | 0.009 |
C1qb | complement component 1, q subcomponent, beta polypeptide | 1.18 | 0.043 |
Lrrk2 | leucine-rich repeat kinase 2 | 1.18 | 0.047 |
Grn | granulin | 1.18 | 0.011 |
Gucy1b3 | guanylate cyclase 1, soluble, beta 3 | 1.17 | 0.041 |
Amph | amphiphysin | 1.16 | 0.013 |
Comt | catechol-O-methyltransferase | 1.16 | 0.000 |
Cntn4 | contactin 4 | 1.15 | 0.015 |
Ap1s1 | adaptor protein complex AP-1, sigma 1 | 1.14 | 0.028 |
Nptn | neuroplastin | 1.14 | 0.029 |
Tnr | tenascin R | 1.12 | 0.033 |
U2af2 | U2 small nuclear ribonucleoprotein auxiliary factor (U2AF) 2 | 1.12 | 0.008 |
Gsr | glutathione reductase | 1.09 | 0.011 |
Cycs | cytochrome c, somatic | −1.27 | 0.030 |
Efna1 | ephrin A1 | −1.28 | 0.022 |
Epha5 | Eph receptor A5 | −1.28 | 0.001 |
Tenm2 | teneurin transmembrane protein 2 | −1.33 | 0.003 |
Npy | neuropeptide Y | −1.33 | 0.020 |
Grm2 | glutamate receptor, metabotropic 2 | −1.38 | 0.038 |
Epha6 | Eph receptor A6 | −1.39 | 0.007 |
Epha7 | Eph receptor A7 | −1.39 | 0.005 |
Htr1a | 5-hydroxytryptamine (serotonin) receptor 1A | −1.85 | 0.002 |
Ntf3 | neurotrophin 3 | −2.90 | 0.035 |
Term | Significance Score | Genes Altered |
---|---|---|
Tissue Integrity | 1.8404 | Cd4, Efna1, Efna5, Epha3, Epha5, Epha6, Epha7, Negr1 |
Transmitter Synthesis and Storage | 1.4634 | Comt, Drd1, Drd2, Htra1a, Pde1b, Slc18A3 |
Axon and Dendrite Structure | 1.4395 | Ap1s1, Calb1, Cntn4, Comt, Drd1, Drd2, Efna5, Epha7, Grm2, Lrrk2, Nptn, Tenm2 |
Transmitter Release | 1.3826 | Adcy5, Adora2a, Bcl-2, Camk4, Comt, Drd1, Drd2, Grm2, Htra1a, Itpr1, Pde1b |
Neural Connectivity | 1.3675 | Amph, Ap1s1, Calb1, Comt, Drd1, Drd2, Epha7, Grm2, Itpr1, Lrrk2, Nptn, Slc18a3, Tenm2 |
Trophic Factors | 1.3475 | Bcl-2, Camk4, Ntf3, Ntrk1 |
Transmitter Response and Reuptake | 1.3387 | Adcy5, Adora2a, Camk4, Drd1, Drd2, Grm2, Gucy1b3, Itpr1, Nptn, Npy |
Growth Factor Signaling | 1.2998 | Bcl2, Drd2, Efna1, Efna5, Epha3, Epha5, Epha6, Fgf14, Hgf, Ntf3, Ntrk1 |
Vesicle Trafficking | 1.2817 | Amph, Calb1, Cntn4 Drd1, Drd2, Fgf14, Grm2, Lrrk2, Nptn, Npy, Ntf3, Ntrk1, Slc18a3, Tnr |
Activated Microglia | 1.2704 | Bcl-2, C1qb, Ccr5, Fcrls, Grn, Gusb, Tlr2 |
Name | Description | Fold Change | p-Value |
---|---|---|---|
Adora2a | adenosine A2a receptor | 4.23 | 0.057 |
Ntrk1 | neurotrophic tyrosine kinase, receptor, type 1 | 2.12 | 0.062 |
Adcy5 | adenylate cyclase 5 | 1.82 | 0.057 |
Pde1b | phosphodiesterase 1B, Ca2+-calmodulin dependent | 1.66 | 0.068 |
Epha3 | Eph receptor A3 | −1.71 | 0.078 |
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Hwang, H.; Sarkar, C.; Piskoun, B.; Zhang, N.; Borcar, A.; Robertson, C.L.; Lipinski, M.M.; Yadava, N.; Goodfellow, M.J.; Polster, B.M. Idebenone Mitigates Traumatic-Brain-Injury-Triggered Gene Expression Changes to Ephrin-A and Dopamine Signaling Pathways While Increasing Microglial Genes. Cells 2025, 14, 824. https://doi.org/10.3390/cells14110824
Hwang H, Sarkar C, Piskoun B, Zhang N, Borcar A, Robertson CL, Lipinski MM, Yadava N, Goodfellow MJ, Polster BM. Idebenone Mitigates Traumatic-Brain-Injury-Triggered Gene Expression Changes to Ephrin-A and Dopamine Signaling Pathways While Increasing Microglial Genes. Cells. 2025; 14(11):824. https://doi.org/10.3390/cells14110824
Chicago/Turabian StyleHwang, Hyehyun, Chinmoy Sarkar, Boris Piskoun, Naibo Zhang, Apurva Borcar, Courtney L. Robertson, Marta M. Lipinski, Nagendra Yadava, Molly J. Goodfellow, and Brian M. Polster. 2025. "Idebenone Mitigates Traumatic-Brain-Injury-Triggered Gene Expression Changes to Ephrin-A and Dopamine Signaling Pathways While Increasing Microglial Genes" Cells 14, no. 11: 824. https://doi.org/10.3390/cells14110824
APA StyleHwang, H., Sarkar, C., Piskoun, B., Zhang, N., Borcar, A., Robertson, C. L., Lipinski, M. M., Yadava, N., Goodfellow, M. J., & Polster, B. M. (2025). Idebenone Mitigates Traumatic-Brain-Injury-Triggered Gene Expression Changes to Ephrin-A and Dopamine Signaling Pathways While Increasing Microglial Genes. Cells, 14(11), 824. https://doi.org/10.3390/cells14110824