BackgroundBrain injury and neurological deficit are consequences of cardiac arrest (CA), leading to high morbidity and mortality. Peripheral activation of the kynurenine pathway (KP), the main catabolic route of tryptophan metabolized at first into kynurenine, predicts poor neurological outcome in patients resuscitated after out‐of‐hospital CA. Here, we investigated KP activation in hippocampus and plasma of rats resuscitated from CA, evaluating the effect of KP modulation in preventing CA‐induced neurological deficit.Methods and ResultsEarly KP activation was first demonstrated in 28 rats subjected to electrically induced CA followed by cardiopulmonary resuscitation. Hippocampal levels of the neuroactive metabolites kynurenine, 3‐hydroxy‐anthranilic acid, and kynurenic acid were higher 2 hours after CA, as in plasma. Further, 36 rats were randomized to receive the inhibitor of the first step of KP, 1‐methyl‐DL‐tryptophan, or vehicle, before CA. No differences were observed in hemodynamics and myocardial function. The CA‐induced KP activation, sustained up to 96 hours in hippocampus (and plasma) of vehicle‐treated rats, was counteracted by the inhibitor as indicated by lower hippocampal (and plasmatic) kynurenine/tryptophan ratio and kynurenine levels. 1‐Methyl‐DL‐tryptophan reduced the CA‐induced neurological deficits, with a significant correlation between the neurological score and the individual kynurenine levels, as well as the kynurenine/tryptophan ratio, in plasma and hippocampus.ConclusionsThese data demonstrate the CA‐induced lasting activation of the first step of the KP in hippocampus, showing that this activation was involved in the evolving neurological deficit. The degree of peripheral activation of KP may predict neurological function after CA.

中文翻译：

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心脏骤停复苏大鼠的脑犬尿氨酸通路和功能结果

背景脑损伤和神经功能缺损是心脏骤停（CA）的后果，导致高发病率和死亡率。犬尿氨酸途径 (KP) 是色氨酸首先代谢为犬尿氨酸的主要分解代谢途径，犬尿氨酸途径 (KP) 的外周激活预示着院外 CA 后复苏的患者神经系统结果不佳。在这里，我们研究了 CA 复苏大鼠海马和血浆中 KP 的激活，评估 KP 调节在预防 CA 诱导的神经功能缺损中的效果。方法和结果首先在 28 只接受电诱导 CA 并随后进行心肺复苏的大鼠中证实了早期 KP 激活。CA 后 2 小时，海马神经活性代谢物犬尿氨酸、3-羟基邻氨基苯甲酸和犬尿酸的水平较高，与血浆中一样。此外，36 只大鼠在 CA 之前随机接受 KP 第一步抑制剂、1-甲基-DL-色氨酸或媒介物。血流动力学和心肌功能没有观察到差异。CA 诱导的 KP 激活在媒介物处理的大鼠的海马（和血浆）中持续长达 96 小时，被抑制剂抵消，如较低的海马（和血浆）犬尿氨酸/色氨酸比率和犬尿氨酸水平所示。1-甲基-DL-色氨酸减少了 CA 诱导的神经功能缺损，神经功能评分与个体犬尿氨酸水平以及血浆和海马中的犬尿氨酸/色氨酸比率之间存在显着相关性。结论这些数据表明 CA 诱导的神经功能缺损海马 KP 第一步的持久激活，表明这种激活与不断发展的神经功能缺损有关。KP 的外周激活程度可以预测 CA 后的神经功能。