Multiple lines of evidence have shown that neuroinflammation and autophagy are highly involved in the process of depression. Nobiletin (NOB) displays neuroprotective effects and anti-depressant-like effects. Given the evidence that NOB exerts anti-inflammatory effects and regulates autophagy, we investigate the anti-neuroinflammatory properties and the effect of regulating the autophagy of NOB and subsequently uncover the potential anti-depressant mechanisms of NOB. The behavioral changes of rats were observed after prolonged lipopolysaccharide (LPS) treatment and NOB administration. Rat hippocampus and BV2 cells treated by LPS and NOB were evaluated. The methods of real-time PCR analysis, Western blot, immunostaining, and adenovirus transfection were employed to determine neuroinflammation, autophagic markers, and nucleotide-binding oligomerization domain-like receptor 3 (NLRP3) activation. Our study showed LPS enhanced the expression of pro-inflammatory cytokines and NLRP3 inflammasome activation but inhibited autophagy in both rat hippocampus and BV2 cells. NOB significantly improved the behavioral deficits and ameliorated the neuroinflammation induced by LPS in rats. Furthermore, NOB promoted autophagy and attenuated NLRP3 inflammasome activation induced by LPS, involving in the process the adenosine monophosphate–activated protein kinase (AMPK) pathway. Neuroprotective and anti-depressant actions of NOB relied on its effects of promoting autophagy and suppressing the activation of NLRP3, in which process of AMPK pathway may be involved.

多条证据表明，神经炎症和自噬与抑郁症的发病过程密切相关。Nobiletin（NOB）具有神经保护作用和抗抑郁样作用。给定NOB发挥抗炎作用并调节自噬的证据，我们研究了NOB的抗神经炎症特性和调节自噬的作用，随后揭示了NOB的潜在抗抑郁机制。长期脂多糖（LPS）处理和NOB给药后，观察到大鼠的行为变化。对LPS和NOB处理的大鼠海马和BV2细胞进行了评估。采用实时PCR分析，蛋白质印迹，免疫染色和腺病毒转染的方法确定神经炎症，自噬标记，和核苷酸结合低聚域样受体3（NLRP3）激活。我们的研究表明，LPS增强了大鼠海马和BV2细胞中促炎性细胞因子的表达和NLRP3炎性体的激活，但抑制了自噬。NOB明显改善了行为缺陷并改善了LPS诱导的大鼠神经炎症。此外，NOB促进了LPS诱导的自噬并减弱了NLRP3炎性小体的激活，该过程涉及腺苷单磷酸激活的蛋白激酶（AMPK）途径。NOB的神经保护和抗抑郁作用取决于其促进自噬和抑制NLRP3活化的作用，其中可能涉及AMPK通路的过程。我们的研究表明，LPS增强了大鼠海马和BV2细胞中促炎性细胞因子的表达和NLRP3炎性体的激活，但抑制了自噬。NOB明显改善了行为缺陷并改善了LPS诱导的大鼠神经炎症。此外，NOB促进了LPS诱导的自噬并减弱了NLRP3炎性小体的激活，该过程涉及腺苷单磷酸激活的蛋白激酶（AMPK）途径。NOB的神经保护和抗抑郁作用取决于其促进自噬和抑制NLRP3活化的作用，其中可能涉及AMPK通路的过程。我们的研究表明，LPS增强了大鼠海马和BV2细胞中促炎性细胞因子的表达和NLRP3炎性体的激活，但抑制了自噬。NOB明显改善了行为缺陷并改善了LPS诱导的大鼠神经炎症。此外，NOB促进了LPS诱导的自噬并减弱了NLRP3炎性小体的激活，该过程涉及腺苷单磷酸激活的蛋白激酶（AMPK）途径。NOB的神经保护和抗抑郁作用取决于其促进自噬和抑制NLRP3活化的作用，其中可能涉及AMPK通路的过程。NOB明显改善了行为缺陷并改善了LPS诱导的大鼠神经炎症。此外，NOB促进了LPS诱导的自噬并减弱了NLRP3炎性小体的激活，该过程涉及腺苷单磷酸激活的蛋白激酶（AMPK）途径。NOB的神经保护和抗抑郁作用取决于其促进自噬和抑制NLRP3活化的作用，其中可能涉及AMPK通路的过程。NOB明显改善了行为缺陷并改善了LPS诱导的大鼠神经炎症。此外，NOB促进了LPS诱导的自噬并减弱了NLRP3炎性小体的激活，该过程涉及腺苷单磷酸激活的蛋白激酶（AMPK）途径。NOB的神经保护和抗抑郁作用取决于其促进自噬和抑制NLRP3活化的作用，其中可能涉及AMPK通路的过程。