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The blockade of NMDA receptor ion channels by ketamine is enhanced in developing rat cortical neurons

机译：在显影大鼠皮质神经元中通过氯胺酮阻断NMDA受体离子通道的阻断

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Ketamine is a non-competitive antagonist of NMDA receptors (NMDARs) commonly used as a dissociative anesthetic in many pediatric procedures. Ketamine acts primarily by blocking NMDA ligand-gated channels. Experimental studies indicate that ketamine administration used for inducing clinically relevant anesthesia can lead to neurotoxic effects, such as apoptosis, selectively on immature brain neurons. However, the underlying mechanisms remain unclear. This study used whole-cell patch-clamp recordings in an in vitro preparation of forebrain slices to analyze pharmacologically the differences in the effects of ketamine administration on the NMDAR channel activity between immature and mature neurons. NMDAR channel activity was recorded in the form of evoked NMDAR-mediated excitatory postsynaptic currents (eEPSCs) from the forebrain of both neonatal and adult rats. Results show that ketamine inhibited eEPSCs in a dose-dependent manner in both immature and mature neurons. However, at each concentration of ketamine applied to the brain slice, a more extensive inhibition could be seen in neonatal neurons than in adult neurons. Further, the blocking effect of ketamine on eEPSCs was measured during the period of 1, 3, and 6 h after ketamine washout. Inhibition of eEPSCs in immature neurons was still evident 6 h after washout. In contrast, the blockade of eEPSCs in mature neurons recovered completely from the inhibition by ketamine in a time-dependent manner. These results indicate that ketamine produces a greater and longer blocking effect on NMDAR channels in immature neurons than in mature neurons. This differential effect is likely to be a critical link to the higher vulnerability to ketamine-induced neurotoxicity in neurons of the developing brain.
机译：氯胺酮是NMDA受体（NMDAR）的非竞争性拮抗剂，通常在许多儿科手术中用作解离性麻醉剂。氯胺酮主要通过阻断NMDA配体门控通道起作用。实验研究表明，用于诱导临床相关麻醉的氯胺酮给药可以选择性地对未成熟的大脑神经元产生神经毒性作用，例如凋亡。但是，其潜在机制仍不清楚。这项研究在体外制备前脑切片中使用全细胞膜片钳记录，以药理学分析氯胺酮对未成熟和成熟神经元之间NMDAR通道活性的影响差异。 NMDAR通道的活动以从新生和成年大鼠的前脑诱发的NMDAR介导的兴奋性突触后电流（eEPSC）的形式记录。结果表明，氯胺酮在未成熟和成熟神经元中均以剂量依赖性方式抑制eEPSCs。但是，在氯胺酮的每种浓度下，应用于大脑切片的新生神经元中的抑制作用要比成人神经元中的抑制作用更为广泛。此外，在氯胺酮冲洗后1、3和6小时的时间内测量了氯胺酮对eEPSC的阻断作用。冲洗后6小时仍能明显抑制未成熟神经元中的eEPSCs。相比之下，成熟神经元中对eEPSC的阻滞以时间依赖性方式完全从氯胺酮的抑制作用中恢复。这些结果表明，与成熟神经元相比，氯胺酮对未成熟神经元的NMDAR通道产生更大和更长的阻断作用。这种差异作用很可能是氯胺酮引起的大脑神经元神经毒性更高脆弱性的关键环节。

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