Kargı-Gemici Ezgi, Şengelen Aslıhan, Aksüt Yunus, Akyol Onat, Şengiz-Erhan Selma, Bay Mehmet, Önay-Uçar Evren, Selcan Ayşin, Demirgan Serdar
Clinic of Anesthesiology and Reanimation, University of Health Sciences, Bağcılar Training and Research Hospital, Istanbul, Turkiye.
Department of Molecular Biology and Genetics, Faculty of Science, Istanbul University, Istanbul, Turkiye.
Neurotoxicology. 2024 Dec;105:82-93. doi: 10.1016/j.neuro.2024.08.005. Epub 2024 Aug 30.
General anesthetics exposure, particularly prolonged or repeated exposure, is a crucial cause of neurological injuries. Notably, isoflurane (ISO), used in pediatric anesthesia practice, is toxic to the developing brain. The relatively weak antioxidant system at early ages needs antioxidant support to protect the brain against anesthesia. Cerium oxide nanoparticles (CeO-NPs, nanoceria) are nano-antioxidants and stand out due to their unique surface chemistry, high stability, and biocompatibility. Although CeO-NPs have been shown to exhibit neuroprotective and cognitive function-facilitating effects, there are no reports on their protective effects against anesthesia-induced neurotoxicity and cognitive impairments. Herein, Wistar albino rat pups were exposed to ISO (1.5 %, 3-h) at postnatal day (P)7+P9+P11, and the protective properties of CeO-NP pretreatment (0.5 mg/kg, intraperitoneal route) were investigated for the first time. The control group at P7+9+11 received 50 % O (3-h) instead of ISO. Exposure to nanoceria one-hour before ISO protected hippocampal neurons of the developing rat brain against apoptosis [determined by hematoxylin-eosin (HE) staining, immunohistochemistry (IHC) analysis with caspase-3, and immunoblotting with Bax/Bcl2, cleaved caspase-3 and PARP1] oxidative stress, and inflammation [determined by immunoblotting with 4-hydroxynonenal (4HNE), nuclear factor kappa-B (NF-κB), and tumor necrosis factor-alpha (TNF-α)]. CeO-NP pretreatment also reduced ISO-induced learning (at P28-32) and memory (at P33) deficits evaluated by Morris Water Maze. However, memory deficits and thigmotactic behaviors were detected in the agent-control group; elimination of these harmful effects will be possible with dose studies, thus providing evidence supporting safer use. Overall, our findings support pretreatment with nanoceria application as a simple strategy that might be used for pediatric anesthesia practice to protect infants and children from ISO-induced cell death and learning and memory deficits.
全身麻醉暴露，尤其是长期或反复暴露，是神经损伤的一个关键原因。值得注意的是，用于儿科麻醉实践的异氟烷（ISO）对发育中的大脑有毒性。早期相对较弱的抗氧化系统需要抗氧化支持来保护大脑免受麻醉影响。氧化铈纳米颗粒（CeO-NPs，纳米氧化铈）是纳米抗氧化剂，因其独特的表面化学性质、高稳定性和生物相容性而脱颖而出。尽管CeO-NPs已被证明具有神经保护和促进认知功能的作用，但尚无关于其对麻醉诱导的神经毒性和认知障碍的保护作用的报道。在此，Wistar白化大鼠幼崽在出生后第7天+第9天+第11天暴露于ISO（1.5%，3小时），首次研究了CeO-NP预处理（0.5mg/kg，腹腔注射途径）的保护特性。出生后第7天+第9天+第11天的对照组接受50%氧气（3小时）而非ISO。在ISO暴露前1小时给予纳米氧化铈可保护发育中大鼠大脑的海马神经元免受凋亡[通过苏木精-伊红（HE）染色、用半胱天冬酶-3进行免疫组织化学（IHC）分析以及用Bax/Bcl2、裂解的半胱天冬酶-3和PARP1进行免疫印迹法测定]、氧化应激和炎症[通过用4-羟基壬烯醛（4HNE）、核因子κB（NF-κB）和肿瘤坏死因子-α（TNF-α）进行免疫印迹法测定]。CeO-NP预处理还减少了通过莫里斯水迷宫评估的ISO诱导的学习（在出生后第28 - 32天）和记忆（在出生后第33天）缺陷。然而，在药物对照组中检测到记忆缺陷和趋触行为；通过剂量研究有可能消除这些有害影响，从而提供支持更安全使用的证据。总体而言，我们的研究结果支持将纳米氧化铈预处理作为一种简单策略，可用于儿科麻醉实践，以保护婴幼儿免受ISO诱导的细胞死亡以及学习和记忆缺陷。
