Idebenone Enhances the Early Microglial Response to Traumatic Brain Injury and Mitigates Acute Gene Expression Changes to Ephrin-A and Dopamine Signaling Pathways

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 peri-lesional cortex at 24 hours 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 ( C1q ) and the neurotrophin receptor gene Ntrk1 to large (>3-fold) TBI-induced decreases in dopamine receptor genes Drd1 and Drd2 that were mitigated by idebenone treatment. Bioinformatics analysis identified SUZ12 as a candidate transcriptional regulator of idebenone-modified gene expression changes. Overall, results suggest that idebenone enhances TBI-induced microglial proliferation within the first 24 hours of TBI and identify Ephrin-A and dopamine signaling as novel idebenone targets.