IDO-Kynurenine通路介导NLRP3炎症小体激活诱导的老年小鼠术后认知障碍。

IF 1.7 4区医学 Q4 NEUROSCIENCES International Journal of Neuroscience Pub Date : 2024-11-01 Epub Date: 2023-10-26 DOI:10.1080/00207454.2023.2262741

Jian Lu, Ye Zhang, Qian Hao, Hongmei Zhou, Youming Zong

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引用次数: 0

摘要

术后认知功能障碍（POCD）是一种常见的术后并发症，尤其是老年患者。它延长了住院时间，增加了死亡率，给家庭和社会带来了沉重负担。越来越多的研究表明，pyrin结构域蛋白3（NLRP3）炎症小体的过度激活与POCD有关。NLRP3炎症小体在激活促炎细胞因子方面起着关键作用。根据现有研究，吲哚胺2，3-双加氧酶（IDO）被炎症因子有效上调，脑内色氨酸主要由IDO催化生成犬尿氨酸（KYN），IDO-kynurenine代谢可能导致抑郁障碍和记忆缺陷的发展。因此，本研究阐明了IDO-Kynurenine通路是否介导NLRP3炎症小体激活诱导的老年小鼠术后认知障碍。采用异氟烷麻醉下剖腹探查法在C57BL/6J老龄小鼠中建立POCD模型。采用Morris水迷宫（MWM）评价学习记忆能力。我们发现，麻醉和手术后，海马IDO和犬尿氨酸氨基转移酶II（KAT-II）mRNA上调，NLRP3、ASC、IL-1β和IDO过表达，KYN水平升高。此外，我们用NLRP3炎症小体抑制剂（MCC950）处理这些小鼠，以观察其对NLRP3、ASC、IL-1β以及IDO和KYN水平表达的影响。我们发现MCC950逆转了NLRP3、ASC、IL-1β和IDO的过度表达以及KYN水平的升高，表明IDO可能是NLRP3炎症小体的下游介质。为了阐明IDO犬尿氨酸途径在术后认知障碍中的作用，我们用IDO抑制剂1-甲基-色氨酸（1-MT）治疗这些小鼠，观察其对学习记忆能力以及色氨酸、KYN和犬尿烯酸（KYNA）水平的影响。我们发现1-MT降低了麻醉/手术小鼠的KYN和KYNA水平的升高，降低了海马中TRP水平，并提高了学习和记忆能力。最后，IDO过表达导致大脑中KYNA水平的增加和认知障碍。进一步的研究表明，PF-04859989，一种KAT-II（大脑KYNA合成的主要酶）的抑制剂，降低了大脑KYNA水平，并恢复了认知障碍。总之，这些结果表明IDO-Kynurenine通路介导NLRP3炎症小体激活诱导的术后认知障碍。IDO-Kynurenine通路可能是治疗老年患者麻醉和手术引起的认知障碍的新靶点。

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IDO-Kynurenine pathway mediates NLRP3 inflammasome activation-induced postoperative cognitive impairment in aged mice.

Aim: Postoperative cognitive dysfunction (POCD) is a common postoperative complication, especially in elderly patients. It extends hospital stay, increases the mortality rate and are heavy burdens to the family and society. Accumulating research has indicated that overactivation of pyrin domain-containing protein 3 (NLRP3) inflammasomes is related to POCD andplays a critical role in activating pro-inflammatory cytokines. According to existing studies, indoleamine 2,3-dioxygenase (IDO) is potently up-regulated by inflammatory factors, tryptophan in brain is mainly catalyzed by IDO to kynurenine (KYN), KYN metabolism may contribute to the development of depressive disorder and memory deficits. Hence, this study elucidated whether IDO-Kynurenine pathway mediates NLRP3 inflammasome activation-induced postoperative cognitive impairment in aged mice.

Material and methods: POCD model was established in aged C57BL/6J mice by exploratory laparotomy under isoflurane anesthesia. Learning and memory were determined using Morris water maze.

Results: The data showed that IDO and kynurenine aminotransferase-II (KAT-II) mRNA in hippocampus was up-regulated, and NLRP3, caspase recruitment domain (ASC), interleukin-1b (IL-1b) and IDO overexpressed, KYN levels increased after anesthesia and surgery. NLRP3 inflammasome inhibitor (MCC950) reversed NLRP3, ASC, IL-1b and IDO overexpression, and the elevation of KYN levels. To clarify the role of IDO-Kynurenine pathway in postoperative cognitive impairment, IDO inhibitor (1-methyl-Ltryptophan 1-MT) reduced the elevation of KYN and kynurenic acid (KYNA) levels, reduction of tryptophan (TRP), as well as improved learning and memory abilities. Finally, KAT-II inhibitor (PF-04859989) reduced brain KYNA levels and restored the cognitive impairment.

Conclusion: These results reveal that IDO-Kynurenine pathway mediates NLRP3 inflammasome activation-induced postoperative cognitive impairment.

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来源期刊

International Journal of Neuroscience 医学-神经科学

CiteScore

5.10

自引率

0.00%

发文量

132

审稿时长

2 months

期刊介绍： The International Journal of Neuroscience publishes original research articles, reviews, brief scientific reports, case studies, letters to the editor and book reviews concerned with problems of the nervous system and related clinical studies, epidemiology, neuropathology, medical and surgical treatment options and outcomes, neuropsychology and other topics related to the research and care of persons with neurologic disorders. The focus of the journal is clinical and transitional research. Topics covered include but are not limited to: ALS, ataxia, autism, brain tumors, child neurology, demyelinating diseases, epilepsy, genetics, headache, lysosomal storage disease, mitochondrial dysfunction, movement disorders, multiple sclerosis, myopathy, neurodegenerative diseases, neuromuscular disorders, neuropharmacology, neuropsychiatry, neuropsychology, pain, sleep disorders, stroke, and other areas related to the neurosciences.