次黄嘌呤通过抑制血清和海马体中的炎症迅速产生抗抑郁作用

IF 4.1 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY ACS Chemical Neuroscience Pub Date : 2024-11-06 Epub Date: 2024-10-23 DOI:10.1021/acschemneuro.4c00345
Lei Wu, Jianhuai Chen, Qiao Yu, Chao Lu, Yachun Shu
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引用次数: 0

摘要

抑郁症的发生和发展与大脑和外周物质的紊乱密切相关。血液中代谢物异常会影响神经中枢的信号调节功能,是抑郁症发作的关键因素之一。本研究主要关注血清中的代谢物及其在海马中的抗抑郁机制。本研究采用代谢组学技术对抑郁症患者的血清代谢物进行了筛查。研究还使用了多种抑郁小鼠模型和行为测试来评估其抗抑郁作用。通过 Western 印迹、ELISA 和免疫荧光检测了炎症信号的表达。我们发现,抑郁症患者血清中的代谢物次黄嘌呤含量明显降低,在慢性不可预测轻度应激(CUMS)和社会挫败应激(SD)等两种抑郁症小鼠模型中也发现了同样的结果。通过给予不同剂量的次黄嘌呤(5、10、15毫克/千克),我们发现只有15毫克/千克的次黄嘌呤能够明显减少新奇抑制性进食试验(NSF)的潜伏期并增加食物消耗量,而且在2小时后单次给药还能逆转CUMS模型小鼠的抑郁表型。次黄嘌呤明显降低了CUMS小鼠血清中炎症的表达,并下调了海马中MAPK和NLRP3相关通路的表达。此外,次黄嘌呤还抑制了海马CA1、CA3和齿状回(DG)神经胶质细胞(包括GFAP和IBA-1)的活化。总之,次黄嘌呤通过调节MAPK、NLRP3相关通路和神经胶质细胞,抑制外周和海马炎症,从而发挥抗抑郁作用。这是我们首次在抑郁症患者体内发现一种紊乱的代谢物,并进一步系统地证明了其抗抑郁的功效和潜在机制,为抗抑郁药物的研发提供了新思路。
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Hypoxanthine Produces Rapid Antidepressant Effects by Suppressing Inflammation in Serum and Hippocampus.

The occurrence and development of depression are closely related to disorders of the brain and peripheral substances. Abnormal metabolites in the blood affect the signal regulation function of the nerve center, which is one of the key factors for depression episodes. This study was focused on metabolites in serum and the mechanism of its antidepressant in the hippocampus. In the present study, serum metabolites in patients with depression were screened by metabolomic techniques. Various depressive mouse models and behavioral tests were used to assess its antidepressant effects. The expressions of inflammatory signaling were detected by using Western blot, ELISA, and immunofluorescence. We found that the metabolite hypoxanthine in the serum of patients with depression was significantly reduced, and the same result was also found in two mouse models of depression such as chronic unpredictable mild stress (CUMS) and social defeat stress (SD). By administering different doses of hypoxanthine (5, 10, 15 mg/kg), we found that only 15 mg/kg was able to significantly reduce the latency and increase food consumption in the novelty suppressed-feeding test (NSF), which was also able to reverse the depressive phenotypes of mice in the CUMS model after a single administration at 2 h later. Hypoxanthine obviously reduced the expressions of inflammation in serum and downregulated the expressions of MAPK and NLRP3-related pathways in the hippocampus in CUMS mice. Moreover, hypoxanthine also suppressed the activations of glial cells including GFAP and IBA-1 in hippocampal CA1, CA3, and dentate gyrus (DG). To sum up, hypoxanthine exerted antidepressant effect relying on the inhibition of peripheral and hippocampal inflammations by regulating MAPK, NLRP3-related pathways, and glial cells. This was the first time that we have found a disordered metabolite in patients with depression and further systematically demonstrated its efficacy and potential mechanism of antidepressants, providing new ideas for antidepressant drug development.

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来源期刊
ACS Chemical Neuroscience
ACS Chemical Neuroscience BIOCHEMISTRY & MOLECULAR BIOLOGY-CHEMISTRY, MEDICINAL
CiteScore
9.20
自引率
4.00%
发文量
323
审稿时长
1 months
期刊介绍: ACS Chemical Neuroscience publishes high-quality research articles and reviews that showcase chemical, quantitative biological, biophysical and bioengineering approaches to the understanding of the nervous system and to the development of new treatments for neurological disorders. Research in the journal focuses on aspects of chemical neurobiology and bio-neurochemistry such as the following: Neurotransmitters and receptors Neuropharmaceuticals and therapeutics Neural development—Plasticity, and degeneration Chemical, physical, and computational methods in neuroscience Neuronal diseases—basis, detection, and treatment Mechanism of aging, learning, memory and behavior Pain and sensory processing Neurotoxins Neuroscience-inspired bioengineering Development of methods in chemical neurobiology Neuroimaging agents and technologies Animal models for central nervous system diseases Behavioral research
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