Protective effects of palmatine on substance P-induced pyroptosis via down-regulation of P2X4 receptor in neuron-like PC12 cells

Wenhao Shen^a,d,e, Lijuan Liu^a, Jiawen Xiong^a, Yufeng Song^a, Yuqing Wen^b, Ruoyu Huang^a,d,e, Ting Zhan^b, Junpei Du^b, Yue Zuo^a, Min Zhou^a, Yun Gao^b,c, Wei Xiong^a,d,e,*

ABSTRACT: Palmatine has a wide range of medical applications due to its anti-inflammatory, antiviral, and neuroprotective effects. The P2X4 receptor is a potential therapeutic target for chronic neuropathic pain. This study aimed to investigate whether palmatine could prevent pyroptosis induced by substance P (SP) in rat pheochromocytoma-derived PC12 cells through P2X4 receptor. The PC12 cells were cultured with a medium containing SP in the presence or absence of palmatine. Subsequently, the cytotoxicity and protective effects of palmatine were assessed using CCK8 assays. Expression of the P2X4 receptor in PC12 cells was determined by Western blot analysis, RT-PCR, and immunofluorescence staining. The analyses showed that P2X4 expression was up-regulated in PC12 cells cultured with SP and co-localized with brain-derived neurotrophic factor (BDNF). The enhanced P2X4 expression in PC12 cells may lead to a release of neuronal BDNF, which cannot protect the PC12 cells from SP-induced damage but promotes damage. Furthermore, our work indicated that SP-induced cell pyroptosis was via the up-regulation of NLRP3, caspase-1, TNF-?, IL-1?, IL-18, and intracellular free Ca2+ levels. These detrimental effects were ameliorated by treatment with either palmatine or P2X4 shRNA. These findings suggest that palmatine may be an effective drug candidate for the treatment of chronic pain since it can protect PC12 cells from SP-induced pyroptosis by inhibiting the expression of P2X4 receptor

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^a	The Affiliated Stomatological Hospital, Jiangxi Medical College, Nanchang University, Jiangxi 330006 China
^b	Department of Physiology, School of Basic Medical Science, Nanchang University, Jiangxi 330006 China
^c	Jiangxi Provincial Key Laboratory of Autonomic Nervous Function and Disease, Jiangxi 330006 China
^d	Jiangxi Provincial Key Laboratory of Oral Biomedicine, Jiangxi 330006 China
^e	Jiangxi Province Clinical Research Center for Oral Diseases, Jiangxi 330006 China

* Corresponding author, E-mail: xiongwei96@163.com

Received 8 Oct 2023, Accepted 5 May 2024

Protective effects of palmatine on substance P-induced pyroptosis via down-regulation of P2X4 receptor in neuron-like PC12 cells

Wenhao Shena,d,e, Lijuan Liua, Jiawen Xionga, Yufeng Songa, Yuqing Wenb, Ruoyu Huanga,d,e, Ting Zhanb, Junpei Dub, Yue Zuoa, Min Zhoua, Yun Gaob,c, Wei Xionga,d,e,*

Wenhao Shen^a,d,e, Lijuan Liu^a, Jiawen Xiong^a, Yufeng Song^a, Yuqing Wen^b, Ruoyu Huang^a,d,e, Ting Zhan^b, Junpei Du^b, Yue Zuo^a, Min Zhou^a, Yun Gao^b,c, Wei Xiong^a,d,e,*