Department of Anesthesiology, Surgery and Pain Management, School of Medicine, Zhongda Hospital, Southeast University, No. 87 Dingjiaqiao Road, Nanjing, 210009, China.
Department of Anesthesiology, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Mol Neurobiol. 2023 Sep;60(9):5273-5291. doi: 10.1007/s12035-023-03413-9. Epub 2023 Jun 7.
Repeated neonatal exposures to sevoflurane induce long-term cognitive impairment that has been reported to have sex-dependent differences. Exercise promotes learning and memory by releasing lactate from the muscle. The study tested the hypothesis that lactate may improve long-term cognitive impairment induced by repeated neonatal exposures to sevoflurane through SIRT1-mediated regulation of adult hippocampal neurogenesis and synaptic plasticity. C57BL/6 mice of both genders were exposed to 3% sevoflurane for 2 h daily from postnatal day 6 (P6) to P8. In the intervention experiments, mice received lactate at 1 g/kg intraperitoneally once daily from P21 to P41. Behavioral tests including open field (OF), object location (OL), novel object recognition (NOR), and fear conditioning (FC) tests were performed to assess cognitive function. The number of 5-Bromo-2'- deoxyuridine positive (BrdU) cells and BrdU/DCX (doublecortin) co-labeled cells, expressions of brain-derived neurotrophic factor (BDNF), activity-regulated cytoskeletal-associated protein (Arc), early growth response 1 (Egr-1), SIRT1, PGC-1α and FNDC5, and long-term potentiation (LTP) were evaluated in the hippocampus. Repeated exposures to sevoflurane induced deficits in OL, NOR and contextual FC tests in male but not female mice. Similarly, adult hippocampal neurogenesis, synaptic plasticity-related proteins and hippocampal LTP were impaired after repeated exposures to sevoflurane in male but not female mice, which could rescue by lactate treatment. Our study suggests that repeated neonatal exposures to sevoflurane inhibit adult hippocampal neurogenesis and induce defects of synaptic plasticity in male but not female mice, which may contribute to long-term cognitive impairment. Lactate treatment rescues these abnormalities through activation of SIRT1.
反复的新生期七氟醚暴露会导致长期认知障碍，据报道这种认知障碍存在性别依赖性差异。运动通过从肌肉中释放乳酸来促进学习和记忆。该研究检验了这样一个假设，即通过 SIRT1 介导的调节成年海马神经发生和突触可塑性，乳酸可能改善反复新生期七氟醚暴露引起的长期认知障碍。雄性和雌性 C57BL/6 小鼠在生后第 6 天（P6）至 P8 每天接受 3%七氟醚暴露 2 小时。在干预实验中，从 P21 至 P41 每天腹腔注射 1g/kg 乳酸。通过旷场（OF）、物体位置（OL）、新物体识别（NOR）和恐惧条件反射（FC）测试来评估认知功能。评估海马中 BrdU 阳性（BrdU）细胞和 BrdU/DCX（双皮质素）共标记细胞的数量、脑源性神经营养因子（BDNF）、活性调节细胞骨架相关蛋白（Arc）、早期生长反应 1（Egr-1）、SIRT1、PGC-1α 和 FNDC5 的表达以及长时程增强（LTP）。反复七氟醚暴露导致雄性但不雌性小鼠 OL、NOR 和上下文 FC 测试缺陷。同样，成年海马神经发生、突触可塑性相关蛋白和海马 LTP 在雄性但不雌性小鼠反复暴露于七氟醚后受损，这可以通过乳酸治疗来挽救。我们的研究表明，反复的新生期七氟醚暴露抑制成年海马神经发生，并导致雄性但不雌性小鼠的突触可塑性缺陷，这可能导致长期认知障碍。乳酸治疗通过激活 SIRT1 来挽救这些异常。
