Neuropharmacology Laboratory of Physiology Department, Medical School of Nanchang University, Nanchang, 330006, People's Republic of China.
Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease, Nanchang, Jiangxi, 330006, People's Republic of China.
Mol Neurobiol. 2022 Dec;59(12):7119-7133. doi: 10.1007/s12035-022-03023-x. Epub 2022 Sep 10.
Neuroinflammation is critical to the comorbidity of chronic pain and depression. Pyroptosis is an inflammatory cell death that is different from apoptosis. Activation of the P2X4 receptor leads to inflammation and is involved in chronic pain and depression. Pinocembrin (5,7-dihydroxyflavanone) is a natural flavonoid compound with anti-inflammatory, antioxidant and neuroprotective effects. In this study, an animal model of chronic pain and depression comorbidity was used to explore the therapeutic effect of pinocembrin in P2X4-mediated pyroptosis. The results showed that nociceptive behaviours and depression-like behaviours were obvious in the model rats induced by chronic constrictive injury (CCI) and chronic unpredictable mild stimulus (CUMS). In the model rats, the mRNA and protein levels of the P2X4 receptor in the hippocampus were increased, and the coexpression of P2X4 and the astrocyte marker glial fibrillary acidic protein (GFAP) in the hippocampus was increased. The protein content of connexion 43 (Cx43), NOD-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and caspase-1 was increased. The serum content of IL-1β and the mRNA and protein expression of IL-1β were increased. The protein content of p-P38MAPK was increased. After treatment with pinocembrin in the model rats, these behavioural changes were improved, and the mRNA and protein levels of the above indicators were decreased. The results of molecular docking confirmed that the affinity of pinocembrin and the P2X4 receptor was - 7.8 (kcal/mol). At the same time, pinocembrin inhibited the ATP release and Ca signal release in primary astrocytes and ATP-activated current of HEK293 cells transfected with the pcDNA3.0-EGFP-hP2X4 plasmid. Therefore, pinocembrin relieved nociceptive and depression-like behaviours in rats with chronic pain and depression comorbidity by inhibiting P2X4 receptor-mediated pyroptosis in the hippocampus. The mechanism of pinocembrin in treating rats with chronic pain and depression comorbidity. GJ stands for gap junction, and Cx43 is mainly expressed in astrocytes.
神经炎症是慢性疼痛和抑郁共病的关键。细胞焦亡是一种不同于细胞凋亡的炎症细胞死亡。P2X4 受体的激活导致炎症，并与慢性疼痛和抑郁有关。白杨素（5,7-二羟基黄酮）是一种具有抗炎、抗氧化和神经保护作用的天然黄酮类化合物。在这项研究中，使用慢性疼痛和抑郁共病动物模型来探讨白杨素在 P2X4 介导的细胞焦亡中的治疗作用。结果表明，慢性缩窄性损伤（CCI）和慢性不可预测轻度刺激（CUMS）诱导的模型大鼠出现明显的痛觉行为和抑郁样行为。在模型大鼠中，海马 P2X4 受体的 mRNA 和蛋白水平增加，海马 P2X4 与星形胶质细胞标志物胶质纤维酸性蛋白（GFAP）的共表达增加。连接蛋白 43（Cx43）、NOD 样受体蛋白 3（NLRP3）、凋亡相关斑点样蛋白含有半胱氨酸蛋白酶募集域（ASC）和半胱氨酸蛋白酶-1 的蛋白含量增加。血清白细胞介素 1β（IL-1β）含量及 IL-1β 的 mRNA 和蛋白表达增加。p-P38MAPK 蛋白含量增加。白杨素治疗模型大鼠后，这些行为变化得到改善，上述指标的 mRNA 和蛋白水平降低。分子对接结果证实白杨素与 P2X4 受体的亲和力为-7.8（千卡/摩尔）。同时，白杨素抑制原代星形胶质细胞中 ATP 的释放和 Ca 信号释放以及 pcDNA3.0-EGFP-hP2X4 质粒转染的 HEK293 细胞中 ATP 激活的电流。因此，白杨素通过抑制海马 P2X4 受体介导的细胞焦亡，缓解慢性疼痛和抑郁共病大鼠的痛觉和抑郁样行为。白杨素治疗慢性疼痛和抑郁共病大鼠的机制。GJ 代表缝隙连接，Cx43 主要在星形胶质细胞中表达。
