Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, Institutes of Brain Science, State Key Laboratory of Medical Neurobiology and Collaborative Innovation Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
Transl Psychiatry. 2021 Jun 8;11(1):353. doi: 10.1038/s41398-021-01468-7.
The purpose of the present study was to investigate whether catalpol exhibited neuroprotective effects in chronic unpredictable mild stress (CUMS) mice through oxidative stress-mediated nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin-domain-containing 3 (NLRP3) inflammasome and neuroinflammation. Deficits in behavioral tests, including open field test (OFT), forced swim test (FST), and elevated plus-maze test (EPM), were ameliorated following catalpol administration. To study the potential mechanism, western blots, quantitative real-time PCR (qRT-PCR) analysis and immunofluorescence imaging were performed on the hippocampus samples. We found that the defects of behavioral tests induced by CUMS could be reversed by the absence of NLRP3 and NLRP3 inflammasome might be involved in the antidepressant effects of catalpol on CUMS mice. Similar to the NLRP3 inflammasome, the expression of interleukin-1 beta (IL-1β), tumor necrosis factor alpha (TNF-α), and inducible nitride oxide synthase (iNOS) were increased after CUMS. The current study demonstrated that catalpol possessed anti-inflammatory effect on CUMS mice and inhibited microglial polarization to the M1 phenotype. In addition, the activity of mitochondrial oxidative stress might be involved in the NLRP3 activation, which was proved by the downregulation of NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC), and cleaved IL-1β, after the administration of mitochondrion-targeted antioxidant peptide SS31. Taken together, we provided evidence that catalpol exhibited antidepressive effects on CUMS mice possibly via the oxidative stress-mediated regulation of NLRP3 and neuroinflammation.
本研究旨在探讨梓醇是否通过氧化应激介导的核苷酸结合寡聚结构域、富含亮氨酸重复序列和吡喃结构域包含蛋白 3（NLRP3）炎症小体和神经炎症对慢性不可预测轻度应激（CUMS）小鼠发挥神经保护作用。梓醇给药后，旷场试验（OFT）、强迫游泳试验（FST）和高架十字迷宫试验（EPM）等行为测试的缺陷得到改善。为了研究潜在机制，我们对海马组织样本进行了 Western blot、定量实时 PCR（qRT-PCR）分析和免疫荧光成像。我们发现，CUMS 诱导的行为测试缺陷可以通过 NLRP3 的缺失得到逆转，NLRP3 炎症小体可能参与了梓醇对 CUMS 小鼠的抗抑郁作用。与 NLRP3 炎症小体相似，IL-1β、TNF-α 和诱导型一氧化氮合酶（iNOS）的表达在 CUMS 后增加。本研究表明，梓醇对 CUMS 小鼠具有抗炎作用，并抑制小胶质细胞向 M1 表型极化。此外，线粒体氧化应激的活性可能参与了 NLRP3 的激活，这一点通过给予线粒体靶向抗氧化肽 SS31 后 NLRP3、凋亡相关斑点样蛋白（ASC）和切割的 IL-1β 的下调得到证实。总之，我们提供的证据表明，梓醇对 CUMS 小鼠具有抗抑郁作用，可能是通过氧化应激介导的 NLRP3 调节和神经炎症。
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