Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Canada.
Hotchkiss Brain Institute, Calgary, Canada.
Sci Rep. 2021 Aug 9;11(1):16153. doi: 10.1038/s41598-021-95635-x.
Recent animal studies have drawn concerns regarding most commonly used anesthetics and their long-term cytotoxic effects, specifically on the nervous tissue. It is therefore imperative that the search continues for agents that are non-toxic at both the cellular and behavioural level. One such agent appears to be dexmedetomidine (DEX) which has not only been found to be less neurotoxic but has also been shown to protect neurons from cytotoxicity induced by other anesthetic agents. However, DEX's effects on the growth and synaptic connectivity at the individual neuronal level, and the underlying mechanisms have not yet been fully resolved. Here, we tested DEX for its impact on neuronal growth, synapse formation (in vitro) and learning and memory in a rodent model. Rat cortical neurons were exposed to a range of clinically relevant DEX concentrations (0.05-10 µM) and cellular viability, neurite outgrowth, synaptic assembly and mitochondrial morphology were assessed. We discovered that DEX did not affect neuronal viability when used below 10 µM, whereas significant cell death was noted at higher concentrations. Interestingly, in the presence of DEX, neurons exhibited more neurite branching, albeit with no differences in corresponding synaptic puncta formation. When rat pups were injected subcutaneously with DEX 25 µg/kg on postnatal day 7 and again on postnatal day 8, we discovered that this agent did not affect hippocampal-dependent memory in freely behaving animals. Our data demonstrates, for the first time, the non-neurotoxic nature of DEX both in vitro and in vivo in an animal model providing support for its utility as a safer anesthetic agent. Moreover, this study provides the first direct evidence that although DEX is growth permissive, causes mitochondrial fusion and reduces oxygen reactive species production, it does not affect the total number of synaptic connections between the cortical neurons in vitro.
最近的动物研究引起了人们对最常用的麻醉剂及其长期细胞毒性作用的关注，特别是对神经组织的影响。因此，迫切需要寻找在细胞和行为水平上均无毒的药物。一种这样的药物似乎是右美托咪定（DEX），它不仅被发现神经毒性较小，而且还能保护神经元免受其他麻醉剂引起的细胞毒性。然而，DEX 对单个神经元水平上的生长和突触连接的影响以及潜在的机制尚未完全解决。在这里，我们在啮齿动物模型中测试了 DEX 对神经元生长、突触形成（体外）以及学习和记忆的影响。将大鼠皮质神经元暴露于一系列临床相关的 DEX 浓度（0.05-10 μM），评估细胞活力、神经突生长、突触形成和线粒体形态。我们发现，DEX 在低于 10 μM 时不会影响神经元活力，而在较高浓度时则会出现明显的细胞死亡。有趣的是，在 DEX 的存在下，神经元表现出更多的神经突分支，尽管对应的突触小体形成没有差异。当在出生后第 7 天和第 8 天给新生大鼠皮下注射 DEX 25μg/kg 时，我们发现该药物不会影响自由活动动物的海马依赖性记忆。我们的数据首次证明了 DEX 在体外和体内动物模型中的非神经毒性，为其作为更安全的麻醉剂的应用提供了支持。此外，这项研究首次直接证明，尽管 DEX 促进生长、引起线粒体融合并减少氧反应性物质的产生，但它不会影响体外皮质神经元之间总的突触连接数量。
