Department of Anesthesiology, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, China.
Fujian Provincial Key Laboratory of Emergency Medicine, Fuzhou, China.
CNS Neurosci Ther. 2024 Jan;30(1):e14486. doi: 10.1111/cns.14486. Epub 2023 Oct 13.
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.
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.
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.
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.
右美托咪定（DEX）已被报道可减轻新生儿缺氧缺血性脑损伤（HIBD）。本研究旨在探讨 DEX 是否通过促进 BDNF/TrkB/CREB 信号通路介导的海马神经发生来改善 HIBD 新生大鼠的认知障碍。
采用 Rice-Vannucci 法诱导生后 7 天大鼠 HIBD，并在 HIBD 诱导后立即腹腔内给予 DEX（25μg/kg）。通过腹腔内注射 TrkB 受体拮抗剂 ANA-12 或海马内注射腺相关病毒（AAV）-shRNA-BDNF 调节 BDNF/TrkB/CREB 通路。采用 Western blot 法检测 BDNF、TrkB 和 CREB 的水平。免疫荧光染色鉴定海马齿状回星形胶质细胞的极化并评估神经发生水平。尼氏染色和 TTC 染色评估神经元损伤程度。水迷宫试验评估空间学习和记忆能力。
RNA 测序技术显示，HIBD 后新生大鼠海马 BDNF 和神经发生水平明显下降。我们的结果表明，DEX 治疗可有效增加 BDNF 蛋白表达和 TrkB 和 CREB 的磷酸化，促进 HIBD 新生大鼠海马齿状回神经发生。具体而言，DEX 治疗可显著增加 HIBD 新生大鼠海马星形胶质细胞中 BDNF 的表达，同时减少有害 A1 星形胶质细胞的比例，增加有益 A2 星形胶质细胞的比例。此外，使用 ANA-12 或 AAV-shRNA-BDNF 抑制 BDNF/TrkB/CREB 通路，显著拮抗 DEX 对海马神经发生、神经元存活和认知改善的有利作用。
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，促进海马神经发生，减轻 HIBD 新生大鼠的神经元损伤和认知障碍。
