长链非编码 RNA H19 敲低通过 Nrf2/HO-1 轴促进创伤性脑损伤后的神经病理和功能恢复。

LncRNA H19 knockdown promotes neuropathologic and functional recovery via the Nrf2/HO-1 axis after traumatic brain injury.

机构信息

Department of Neurosurgery of Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, China.

出版信息

CNS Neurosci Ther. 2024 Jul;30(7):e14870. doi: 10.1111/cns.14870.

DOI:10.1111/cns.14870

PMID:39049714

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11269889/

Abstract

AIMS

Traumatic brain injury (TBI) stands as a significant concern in public health, frequently leading to enduring neurological deficits. Long non-coding RNA H19 (lncRNA H19) exerts a potential regulator role in the pathology of brain injury. This study investigates the effects of lncRNA H19 knockdown (H19-KD) on the pathophysiology of TBI and its potential neuroprotective mechanisms.

METHODS

Controlled cortical impact was employed to establish a stable TBI mouse model. The expression levels of various genes in perilesional cortex and striatum tissue after TBI was detected by RT-qPCR. AAV9-shRNA-H19 was injected into the lateral ventricle of mice to knockdown the expression of lncRNA H19. Various behavioral tests were performed to evaluate sensorimotor and cognitive functions after TBI. Immunofluorescence and Nissl staining were performed to assess brain tissue damage and neuroinflammation. The Nrf2 and HO-1 expression was performed by Western blot.

RESULTS

After TBI, the expression of lncRNA H19 was elevated in perilesional tissue and gradually reverted to baseline. Behavioral tests demonstrated that H19-KD significantly promoted the recovery of sensorimotor and cognitive functions after TBI. Besides, H19-KD reduced brain tissue loss, preserved neuronal integrity, and ameliorated white matter damage at the histological level. In addition, H19-KD restrained the pro-inflammatory and facilitated anti-inflammatory phenotypes of microglia/macrophages, attenuating the neuroinflammatory response after TBI. Furthermore, H19-KD promoted activation of the Nrf2/HO-1 axis after TBI, while suppression of Nrf2 partially abolished the neuroprotective effect.

CONCLUSION

H19-KD exerts neuroprotective effects after TBI in mice, partially mediated by the activation of the Nrf2/HO-1 axis.

摘要

目的

外伤性脑损伤（TBI）是公共卫生领域的一个重大关注点，常导致持久的神经功能缺损。长链非编码 RNA H19（lncRNA H19）在外伤性脑损伤的病理中发挥潜在的调节作用。本研究旨在探讨 lncRNA H19 敲低（H19-KD）对 TBI 病理生理学的影响及其潜在的神经保护机制。

方法

采用皮质撞击法建立稳定的 TBI 小鼠模型。通过 RT-qPCR 检测 TBI 后损伤皮层和纹状体组织中各种基因的表达水平。将 AAV9-shRNA-H19 注射到小鼠侧脑室以敲低 lncRNA H19 的表达。通过各种行为测试评估 TBI 后感觉运动和认知功能的恢复情况。免疫荧光和尼氏染色评估脑组织损伤和神经炎症。通过 Western blot 检测 Nrf2 和 HO-1 的表达。

结果

TBI 后，损伤周围组织中 lncRNA H19 的表达升高，逐渐恢复至基线水平。行为学测试表明，H19-KD 显著促进了 TBI 后感觉运动和认知功能的恢复。此外，H19-KD 减少了脑组织丢失，保护了神经元的完整性，并改善了组织学水平的白质损伤。此外，H19-KD 抑制了小胶质细胞/巨噬细胞的促炎表型，促进了抗炎表型，减轻了 TBI 后的神经炎症反应。此外，H19-KD 促进了 TBI 后 Nrf2/HO-1 轴的激活，而 Nrf2 的抑制部分消除了神经保护作用。