Chen Andi, Chen Xiaohui, Deng Jianhui, Wei Jianjie, Qian Haitao, Huang Yongxin, Wu Shuyan, Gao Fei, Gong Cansheng, Liao Yanling, Zheng Xiaochun
Department of Anesthesiology, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China.
Fujian Provincial Key Laboratory of Emergency Medicine, Fujian Provincial Key Laboratory of Critical care Medicine, Fujian Provincial Co-Constructed Laboratory of "Belt and Road", Fujian Emergency Medical Center, Fuzhou, China.
Front Pharmacol. 2022 Aug 19;13:983920. doi: 10.3389/fphar.2022.983920. eCollection 2022.
Hypoxic-ischemic brain damage (HIBD) is the main cause of neurological dysfunction in neonates. Olfactory cognitive function is important for feeding, the ability to detect hazardous situations and social relationships. However, only a few studies have investigated olfactory cognitive dysfunction in neonates with HIBD; furthermore, the specific mechanisms involved are yet to be elucidated. It has been reported that neurogenesis in the subventricular zone (SVZ) is linked to olfactory cognitive function. Recently, dexmedetomidine (DEX) has been shown to provide neuroprotection in neonates following HIBD. In the present study, we investigated whether DEX could improve olfactory cognitive dysfunction in neonatal rats following HIBD and attempted to determine the underlying mechanisms. We induced HIBD in rats using the Rice-Vannucci model, and DEX (25 μg/kg, i.p.) was administered immediately after the induction of HIBD. Next, we used triphenyl tetrazolium chloride (TTC) staining and the Zea-longa score to assess the success of modelling. The levels of BDNF, TNF-α, IL-1β and IL-6 were determined by western blotting. Immunofluorescence staining was used to detect microglial activation and microglial M1/M2 polarization as well as to evaluate the extent of neurogenesis in the SVZ. To evaluate the olfactory cognitive function, the rats in each group were raised until post-natal days 28-35; then, we performed the buried food test and the olfactory memory test. Analysis showed that HIBD induced significant brain infarction, neurological deficits, and olfactory cognitive dysfunction. Furthermore, we found that DEX treatment significantly improved olfactory cognitive dysfunction in rat pups with HIBD. DEX treatment also increased the number of newly formed neuroblasts (BrdU/DCX) and neurons (BrdU/NeuN) in the SVZ by increasing the expression of BDNF in rat pups with HIBD. Furthermore, analysis showed that the neurogenic effects of DEX were possibly related to the inhibition of inflammation and the promotion of M1 to M2 conversion in the microglia. Based on the present findings, DEX treatment could improve olfactory cognitive dysfunction in neonatal rats with HIBD by promoting neurogenesis in the SVZ and enhancing the expression of BDNF in the microglia. It was possible associated that DEX inhibited neuroinflammation and promoted M1 to M2 conversion in the microglia.
缺氧缺血性脑损伤（HIBD）是新生儿神经功能障碍的主要原因。嗅觉认知功能对于进食、察觉危险情况的能力以及社会关系都很重要。然而，仅有少数研究调查了HIBD新生儿的嗅觉认知功能障碍；此外，其中涉及的具体机制尚待阐明。据报道，脑室下区（SVZ）的神经发生与嗅觉认知功能有关。最近，右美托咪定（DEX）已被证明可在HIBD后的新生儿中提供神经保护作用。在本研究中，我们调查了DEX是否能改善HIBD后新生大鼠的嗅觉认知功能障碍，并试图确定其潜在机制。我们使用Rice-Vannucci模型在大鼠中诱导HIBD，并在HIBD诱导后立即腹腔注射DEX（25μg/kg）。接下来，我们使用氯化三苯基四氮唑（TTC）染色和Zea-longa评分来评估建模是否成功。通过蛋白质免疫印迹法测定脑源性神经营养因子（BDNF）、肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）和白细胞介素-6（IL-6）的水平。免疫荧光染色用于检测小胶质细胞活化和小胶质细胞M1/M2极化，以及评估SVZ中的神经发生程度。为了评估嗅觉认知功能，将每组大鼠饲养至出生后28 - 35天；然后，我们进行了埋藏食物试验和嗅觉记忆试验。分析表明，HIBD诱导了明显的脑梗死、神经功能缺损和嗅觉认知功能障碍。此外，我们发现DEX治疗显著改善了HIBD幼鼠的嗅觉认知功能障碍。DEX治疗还通过增加HIBD幼鼠中BDNF的表达，增加了SVZ中新形成的神经母细胞（BrdU/DCX）和神经元（BrdU/NeuN）的数量。此外，分析表明DEX的神经发生作用可能与抑制炎症和促进小胶质细胞从M1向M2转化有关。基于目前的研究结果，DEX治疗可通过促进SVZ中的神经发生和增强小胶质细胞中BDNF的表达来改善HIBD新生大鼠的嗅觉认知功能障碍。DEX可能通过抑制神经炎症和促进小胶质细胞从M1向M2转化发挥作用。
