Dexmedetomidine alleviates cognitive impairment by promoting hippocampal neurogenesis via BDNF/TrkB/CREB signaling pathway in hypoxic–ischemic neonatal rats

IF 4.8 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics Pub Date : 2023-10-13 DOI:10.1111/cns.14486

Xiaohui Chen, Andi Chen, Jianjie Wei, Yongxin Huang, Jianhui Deng, Pinzhong Chen, Yanlin Yan, Mingxue Lin, Lifei Chen, Jiuyun Zhang, Zhibin Huang, Xiaoqian Zeng, Cansheng Gong, Xiaochun Zheng

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引用次数: 0

Abstract

Aims

Dexmedetomidine (DEX) has been reported to alleviate hypoxic–ischemic brain damage (HIBD) in neonates. This study aimed to investigate whether DEX improves cognitive impairment by promoting hippocampal neurogenesis via the BDNF/TrkB/CREB signaling pathway in neonatal rats with HIBD.

Methods

HIBD was induced in postnatal day 7 rats using the Rice-Vannucci method, and DEX (25 μg/kg) was administered intraperitoneally immediately after the HIBD induction. The BDNF/TrkB/CREB pathway was regulated by administering the TrkB receptor antagonist ANA-12 through intraperitoneal injection or by delivering adeno-associated virus (AAV)-shRNA-BDNF via intrahippocampal injection. Western blot was performed to measure the levels of BDNF, TrkB, and CREB. Immunofluorescence staining was utilized to identify the polarization of astrocytes and evaluate the levels of neurogenesis in the dentate gyrus of the hippocampus. Nissl and TTC staining were performed to evaluate the extent of neuronal damage. The MWM test was conducted to evaluate spatial learning and memory ability.

Results

The levels of BDNF and neurogenesis exhibited a notable decrease in the hippocampus of neonatal rats after HIBD, as determined by RNA-sequencing technology. Our results demonstrated that treatment with DEX effectively increased the protein expression of BDNF and the phosphorylation of TrkB and CREB, promoting neurogenesis in the dentate gyrus of the hippocampus in neonatal rats with HIBD. Specifically, DEX treatment significantly augmented the expression of BDNF in hippocampal astrocytes, while decreasing the proportion of detrimental A1 astrocytes and increasing the proportion of beneficial A2 astrocytes in neonatal rats with HIBD. Furthermore, inhibiting the BDNF/TrkB/CREB pathway using either ANA-12 or AAV-shRNA-BDNF significantly counteracted the advantageous outcomes of DEX on hippocampal neurogenesis, neuronal survival, and cognitive improvement.

Conclusions

DEX promoted neurogenesis in the hippocampus by activating the BDNF/TrkB/CREB pathway through the induction of polarization of A1 astrocytes toward A2 astrocytes, subsequently mitigating neuronal damage and cognitive impairment in neonates with HIBD.

Abstract Image

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右美托咪定通过BDNF/TrkB/CREB信号通路促进缺氧缺血性新生大鼠海马神经发生，减轻认知障碍。

目的：据报道，地塞米松（DEX）可减轻新生儿缺氧缺血性脑损伤（HIBD）。本研究旨在探讨DEX是否通过BDNF/TrkB/CREB信号通路促进新生HIBD大鼠海马神经发生来改善认知障碍 μg/kg）。通过腹膜内注射TrkB受体拮抗剂ANA-12或通过海马内注射递送腺相关病毒（AAV）-shRNA BDNF来调节BDNF/TrkB/CREB通路。进行蛋白质印迹以测量BDNF、TrkB和CREB的水平。免疫荧光染色用于鉴定星形胶质细胞的极化，并评估海马齿状回的神经发生水平。进行Nissl和TTC染色以评估神经元损伤的程度。MWM测试用于评估空间学习和记忆能力。结果：用RNA测序技术检测新生大鼠HIBD后海马BDNF和神经发生水平显著降低。我们的研究结果表明，DEX治疗可有效增加新生HIBD大鼠BDNF的蛋白表达以及TrkB和CREB的磷酸化，促进海马齿状回的神经发生。具体而言，在患有HIBD的新生大鼠中，DEX治疗显著增加了海马星形胶质细胞中BDNF的表达，同时降低了有害的A1星形胶质细胞的比例，增加了有益的A2星形胶质细胞比例。此外，使用ANA-12或AAV shRNA BDNF抑制BDNF/TrkB/CREB通路显著抵消了DEX对海马神经发生、神经元存活和认知改善的有利结果。结论：DEX通过诱导A1星形胶质细胞向A2星形胶质细胞极化，激活BDNF/TrkB/CREB通路，从而促进海马神经发生，从而减轻HIBD新生儿的神经元损伤和认知障碍。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

CNS Neuroscience & Therapeutics 医学-神经科学

CiteScore

7.30

自引率

12.70%

发文量

240

审稿时长

2 months

期刊介绍： CNS Neuroscience & Therapeutics provides a medium for rapid publication of original clinical, experimental, and translational research papers, timely reviews and reports of novel findings of therapeutic relevance to the central nervous system, as well as papers related to clinical pharmacology, drug development and novel methodologies for drug evaluation. The journal focuses on neurological and psychiatric diseases such as stroke, Parkinson’s disease, Alzheimer’s disease, depression, schizophrenia, epilepsy, and drug abuse.