T.C. Health Ministry, Anesthesiology and Reanimation Clinic, University of Health Sciences, Bağcılar Training and Research Hospital, Istanbul, Turkey.
Department of Molecular Biology and Genetics, Institute of Graduate Studies in Sciences, Istanbul University, 34134, Vezneciler-Fatih/Istanbul, Turkey.
Naunyn Schmiedebergs Arch Pharmacol. 2021 Jul;394(7):1553-1567. doi: 10.1007/s00210-021-02077-3. Epub 2021 Mar 27.
Anesthetic-induced toxicity in early life may lead to risk of cognitive decline at later ages. Notably, multiple exposures to isoflurane (ISO) cause acute apoptotic cell death in the developing brain and long-term cognitive dysfunction. This study is the first to investigate whether levosimendan (LVS), known for its protective myocardial properties, can prevent anesthesia-induced apoptotic response in brain cells and learning and memory impairment. Postnatal day (P)7 Wistar albino pups were randomly assigned to groups consisting of an equal number of males and females in this laboratory investigation. We treated rats with LVS (0.8 mg/kg/day) intranasally 30 min before each ISO exposure (1.5%, 3 h) at P7+9+11. We selected DMSO as the drug vehicle. Also, the control group at P7+9+11 received 50% O for 3 h instead of ISO. Neuroprotective activity of LVS against ISO-induced cognitive dysfunction was evaluated by Morris water maze. Expression of apoptotic-related proteins was detected in the whole brain using western blot. LVS pretreatment significantly prevented anesthesia-induced deficit in spatial learning (at P28-32) and memory (at P33, P60, and P90). No sex-dependent difference occurred on any day of the training and probe trial. Intranasal LVS was also found to significantly prevent the ISO-induced apoptosis by reducing Bax and cleaved caspase-3, and by increasing Bcl-2 and Bcl-xL. Our findings support pretreatment with intranasal LVS application as a simple strategy in daily clinical practice in pediatric anesthesia to protect infants and children from the risk of general anesthesia-induced cell death and cognitive declines.
在生命早期，麻醉诱导的毒性可能导致以后年龄认知能力下降的风险。值得注意的是，多次接触异氟醚（ISO）会导致发育中的大脑急性细胞凋亡和长期认知功能障碍。这项研究首次探讨了左西孟旦（LVS）是否可以预防麻醉诱导的脑细胞凋亡反应和学习记忆障碍，左西孟旦以其保护心肌的特性而闻名。在这项实验室研究中，将出生后第 7 天（P）的 Wistar 白化幼鼠随机分为雄性和雌性数量相等的组。我们在 P7+9+11 每天用 LVS（0.8 mg/kg/天）经鼻内给药 30 分钟，然后再用 ISO（1.5%，3 小时）处理大鼠。我们选择 DMSO 作为药物载体。此外，对照组在 P7+9+11 接受 50%O2 3 小时，而不是 ISO。通过 Morris 水迷宫评估 LVS 对 ISO 诱导的认知功能障碍的神经保护活性。使用 Western blot 检测整个大脑中与凋亡相关的蛋白质表达。LVS 预处理可显著预防麻醉诱导的空间学习（P28-32）和记忆（P33、P60 和 P90）障碍。在训练和探针试验的任何一天都没有出现性别依赖性差异。经鼻内 LVS 还可通过减少 Bax 和切割的 caspase-3，同时增加 Bcl-2 和 Bcl-xL，显著预防 ISO 诱导的凋亡。我们的研究结果支持在儿科麻醉的日常临床实践中，使用经鼻内 LVS 预处理作为一种简单的策略，以保护婴儿和儿童免受全身麻醉诱导的细胞死亡和认知下降的风险。
