Hwang Hyehyun, Sarkar Chinmoy, Piskoun Boris, Zhang Naibo, Borcar Apurva, Robertson Courtney L, Lipinski Marta M, Yadava Nagendra, Goodfellow Molly J, Polster Brian M
Department of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, 600 North Wolfe Street, Blalock 1404, Baltimore, MD 21287, USA.
bioRxiv. 2025 May 11:2025.05.06.652467. doi: 10.1101/2025.05.06.652467.
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 . 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 () and the neurotrophin receptor gene to large (>3-fold) TBI-induced decreases in dopamine receptor genes and 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.
创伤性脑损伤（TBI）会导致持续的促炎性小胶质细胞活化，这与神经退行性变有关。艾地苯醌是一种与线粒体和酪氨酸激酶衔接蛋白SHC1都相互作用的辅酶Q10类似物，可抑制小胶质细胞活化的某些方面。我们使用NanoString神经病理学检测板来检验这一假设，即艾地苯醌在损伤后治疗通过调节小胶质细胞对损伤的促炎反应来减轻与TBI病理相关的急性基因表达变化。对成年雄性小鼠进行控制性皮质撞击，会在TBI后24小时增加损伤周围皮质中的小胶质细胞活化特征。出乎意料的是，TBI上调的几个小胶质细胞特征基因在损伤后给予艾地苯醌时会进一步增加。然而，艾地苯醌显著减轻了TBI介导的与行为相关的基因表达扰动，特别是在基因本体论：生物学过程（GO:BP）途径“ Ephrin受体信号传导”和“多巴胺代谢过程”中。基因共表达分析将小胶质细胞补体成分1q（）和神经营养因子受体基因的水平与TBI诱导的多巴胺受体基因和的大幅（> 3倍）下降相关联，而艾地苯醌治疗可减轻这种下降。生物信息学分析确定SUZ12是艾地苯醌修饰的基因表达变化的候选转录调节因子。总体而言，结果表明艾地苯醌在TBI的最初24小时内增强了TBI诱导的小胶质细胞增殖，并确定Ephrin-A和多巴胺信号传导是艾地苯醌的新靶点。
