The Kynurenine Pathway in Traumatic Brain Injury: Implications for Psychiatric Outcomes.
The Kynurenine Pathway in Traumatic Brain Injury: Implications for Psychiatric Outcomes.
复制标题
犬尿氨酸途径在创伤性脑损伤：精神病学结果的影响。
DOI：
10.1016/j.biopsych.2021.05.021
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发表时间：
2022-03-01
影响因子：
10.6
通讯作者：
Savitz J
中科院分区：
文献类型：
--
作者：
Meier TB;Savitz J
创伤性脑损伤（TBI）是精神疾病，特别是抑郁和焦虑发展的既定危险因素。然而，这种风险背后的机制途径仍然不清楚，限制了治疗选择，并阻碍了临床有用的生物标志物的鉴定。原发性精神障碍和TBI中涉及的一个显著的病理生理过程是炎症。炎症的一个重要后果是色氨酸向犬尿氨酸的分解增加，随后犬尿氨酸代谢成几种神经活性代谢物，包括神经毒性NMDA受体激动剂喹啉酸（QuinA）和神经保护性NMDA受体拮抗剂犬尿氨酸（KynA）。在这里，我们回顾犬尿氨酸途径（KP）在TBI的研究，并探讨其潜在的临床意义。文献的重要性表明，在所有严重程度的TBI中，神经毒性犬尿氨酸（如QuinA）的产生增加，并且脑脊液和血液中QuinA浓度升高是一个负面的预后指标，与死亡、MRI异常、抑郁和焦虑症状增加以及恢复时间延长相关。我们推测，KP代谢的不平衡也是TBI诱导的神经代谢级联反应可能导致精神后遗症发展的一个分子途径。如果这个模型是正确的，KP代谢物可以用来预测谁可能患上精神疾病，而靶向KP的药物可以帮助预防或治疗TBI背景下出现的抑郁和焦虑。
Traumatic brain injury (TBI) is an established risk factor for the development of psychiatric disorders, especially depression and anxiety. Yet the mechanistic pathways underlying this risk remain unclear, limiting treatment options and hindering the identification of clinically-useful biomarkers. One salient pathophysiological process implicated in both primary psychiatric disorders and TBI is inflammation. An important consequence of inflammation is the increased breakdown of tryptophan to kynurenine and, subsequently, the metabolism of kynurenine into several neuroactive metabolites including the neurotoxic NMDA receptor agonist, quinolinic acid (QuinA), and the neuroprotective NMDA receptor antagonist, kynurenic acid (KynA). Here, we review studies of the kynurenine pathway (KP) in TBI and examine their potential clinical implications. The weight of the literature suggests that there is increased production of neurotoxic kynurenines such as QuinA in TBI of all severities, and that elevated QuinA concentrations in both the cerebrospinal fluid and blood are a negative prognostic indicator, being associated with death, MRI abnormalities, increased depressive and anxiety symptoms, and prolonged recovery. We hypothesize that an imbalance in KP metabolism is also one molecular pathway through which the TBI-induced neurometabolic cascade may predispose to the development of psychiatric sequelae. If this model is correct, KP metabolites could serve to predict who is likely to develop psychiatric illness while drugs that target the KP could help to prevent or treat depression and anxiety arising in the context of TBI.
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