Melatonin pretreatment alleviates the long-term synaptic toxicity and dysmyelination induced by neonatal Sevoflurane exposure via MT1 receptor-mediated Wnt signaling modulation.
Melatonin pretreatment alleviates the long-term synaptic toxicity and dysmyelination induced by neonatal Sevoflurane exposure via MT1 receptor-mediated Wnt signaling modulation.
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褪黑激素预处理通过MT1受体介导的Wnt信号调节来减轻新生儿七氟硫富烷诱导的长期突触毒性和致命性。
DOI：
10.1111/jpi.12771
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发表时间：
2021-12
影响因子：
10.3
通讯作者：
中科院分区：
文献类型：
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作者：
七氟醚（Sev）是应用最广泛的小儿麻醉药之一。新生儿反复使用Sev的主要问题是其潜在的认知和学习/记忆的长期损害，目前仍缺乏有效的治疗方法。在细胞水平上，Sev在多个方面发挥毒性作用，使其难以受到有效干扰。褪黑素是生理状态下受生物节律调节和反馈的一种松果体激素。最近的研究表明，外源性褪黑素或其激动剂在各种病理条件下具有显著的神经保护作用。褪黑素是否能够预防Sev的长期毒性仍然是一个谜。在这里，我们报告了新生儿反复暴露于Sev上调海马神经元和少突胶质细胞中的MT1受体。褪黑素预处理可显著缓解Sev诱导的突触缺陷、髓鞘发育障碍和长期学习障碍。MT1‐shRNA和MT1敲除均可有效阻断褪黑素对突触发育、髓鞘形成和行为表现的保护作用。有趣的是，在新生儿暴露于Sev后，在海马神经元和少突胶质细胞中观察到Wnt信号的长期抑制，而不是cAMP/PKA信号。药理学激活Wnt信号可以挽救Sev诱导的长期突触缺陷和髓鞘发育障碍。进一步分析表明，MT1受体与β - catenin和Axin2共表达良好，并通过其C端与β - catenin结合。褪黑素预处理有效地恢复了Sev诱导的Wnt抑制。Wnt信号抑制剂XAV939显著削弱褪黑素的保护作用。综上所述，我们的数据证明了褪黑素预处理对新生儿Sev暴露引起的长期突触损伤和髓鞘发育障碍的有益作用，以及褪黑素与典型Wnt信号之间MT1受体介导的新型相互作用，表明褪黑素可能在临床应用于提高儿科Sev麻醉的安全性。
Sevoflurane (Sev) is one of the most widely used pediatric anesthetics. The major concern of neonatal repeated application of Sev is its potential long‐term impairment of cognition and learning/memory, for which there still lacks effective treatment. At the cellular level, Sev exerts toxic effects in multiple aspects, making it difficult for effective interference. Melatonin is a pineal hormone regulated by and feedbacks to biological rhythm at physiological condition. Recent studies have revealed significant neuroprotective effects of exogenous melatonin or its agonists under various pathological conditions. Whether melatonin could prevent the long‐term toxicity of Sev remains elusive. Here, we report that neonatal repeated Sev exposure up‐regulated MT1 receptor in hippocampal neurons and oligodendrocytes. Pretreatment with melatonin significantly alleviated Sev‐induced synaptic deficiency, dysmyelination, and long‐term learning impairment. Both MT1‐shRNA and MT1 knockout effectively blocked the protective effects of melatonin on synaptic development, myelination, and behavior performance. Interestingly, long‐lasting suppression of Wnt signaling, instead of cAMP/PKA signaling, was observed in hippocampal neurons and oligodendrocytes after neonatal Sev exposure. Pharmacologically activating Wnt signaling rescued both the long‐term synaptic deficits and dysmyelination induced by Sev. Further analysis showed that MT1 receptor co‐expressed well with β‐catenin and Axin2 and bound to β‐catenin by its C‐terminal. Melatonin pretreatment effectively rescued Sev‐induced Wnt suppression. Wnt signaling inhibitor XAV939 significantly compromised the protective effects of melatonin. Taken together, our data demonstrated a beneficial effect of melatonin pretreatment on the long‐term synaptic impairment and dysmyelination induced by neonatal Sev exposure, and a novel MT1 receptor‐mediated interaction between melatonin and canonical Wnt signaling, indicating that melatonin may be clinically applied for improving the safety of pediatric Sev anesthesia.
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影响因子：
1
作者：
Abbasivash, Rahman;Salimi, Sohrab;Sane, Shahryar
通讯作者：
Sane, Shahryar
影响因子：
10.3
作者：
Lin, MT;Chuang, JI
通讯作者：
Chuang, JI
影响因子：
5.7
作者：
Budnik V;Salinas PC
通讯作者：
Salinas PC
DOI：
10.1111/j.1749-6632.2009.04435.x
发表时间：
2009-01-01
期刊：
TRENDS IN COMPARATIVE ENDOCRINOLOGY AND NEUROBIOLOGY
影响因子：
--
作者：
Falcon, Jack;Besseau, Laurence;Boeuf, Gilles
通讯作者：
Boeuf, Gilles
影响因子：
5.9
作者：
Huang, Hei-Jen;Chen, Shu-Ling;Hsieh-Li, Hsiu Mei
通讯作者：
Hsieh-Li, Hsiu Mei