Department of Pharmacology, Basic Medical Sciences Center, Shanxi Medical University, Taiyuan, China.
Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, China.
CNS Neurosci Ther. 2023 Nov;29(11):3378-3390. doi: 10.1111/cns.14268. Epub 2023 May 19.
Few treatments are available in the subacute phase of traumatic brain injury (TBI) except rehabilitation training. We previously reported that transient CO inhalation applied within minutes after reperfusion has neuroprotective effects against cerebral ischemia/reperfusion injury. In this study, it was hypothesized that delayed CO postconditioning (DCPC) starting at the subacute phase may promote neurological recovery of TBI.
Using a cryogenic TBI (cTBI) model, mice received DCPC daily by inhaling 5%/10%/20% CO for various time-courses (one/two/three cycles of 10-min inhalation/10-min break) at Days 3-7, 3-14 or 7-18 after cTBI. Beam walking and gait tests were used to assess the effect of DCPC. Lesion size, expression of GAP-43 and synaptophysin, amoeboid microglia number and glia scar area were detected. Transcriptome and recombinant interferon regulatory factor 7 (Irf7) adeno-associated virus were applied to investigate the molecular mechanisms.
DCPC significantly promoted recovery of motor function in a concentration and time-course dependent manner with a wide therapeutic time window of at least 7 days after cTBI. The beneficial effects of DCPC were blocked by intracerebroventricular injection of NaHCO . DCPC also increased puncta density of GAP-43 and synaptophysin, and reduced amoeboid microglia number and glial scar formation in the cortex surrounding the lesion. Transcriptome analysis showed many inflammation-related genes and pathways were altered by DCPC, and Irf7 was a hub gene, while overexpression of IRF7 blocked the motor function improvement of DCPC.
We first showed that DCPC promoted functional recovery and brain tissue repair, which opens a new therapeutic time window of postconditioning for TBI. Inhibition of IRF7 is a key molecular mechanism for the beneficial effects of DCPC, and IRF7 may be a potential therapeutic target for rehabilitation after TBI.
创伤性脑损伤（TBI）亚急性期除康复训练外，治疗方法有限。我们之前报道过，再灌注后几分钟内短暂吸入 CO 具有抗脑缺血/再灌注损伤的神经保护作用。在这项研究中，我们假设亚急性期开始的迟发性 CO 后处理（DCPC）可能会促进 TBI 的神经功能恢复。
使用低温 TBI（cTBI）模型，在 cTBI 后第 3-7 天、第 3-14 天或第 7-18 天，通过每天吸入 5%/10%/20% CO 进行一次/两次/三次 10 分钟吸入/10 分钟休息的循环，进行 DCPC。采用走棒试验和步态试验评估 DCPC 的效果。检测损伤大小、GAP-43 和突触素的表达、阿米巴样小胶质细胞数量和神经胶质瘢痕面积。应用转录组和重组干扰素调节因子 7（Irf7）腺相关病毒探讨分子机制。
DCPC 以浓度和时间依赖性方式显著促进运动功能恢复，cTBI 后至少 7 天的治疗时间窗口较宽。脑室注射 NaHCO 阻断了 DCPC 的有益作用。DCPC 还增加了 GAP-43 和突触素的突触点密度，并减少了损伤周围皮质中的阿米巴样小胶质细胞数量和神经胶质瘢痕形成。转录组分析表明，DCPC 改变了许多炎症相关基因和通路，Irf7 是一个枢纽基因，而 IRF7 的过表达阻断了 DCPC 的运动功能改善。
我们首次表明，DCPC 促进了功能恢复和脑组织修复，为 TBI 的后处理治疗开辟了新的治疗时间窗口。抑制 IRF7 是 DCPC 有益作用的关键分子机制，IRF7 可能是 TBI 后康复治疗的潜在靶点。
