{"title":"维生素 D3 通过抑制 PKCα/NOX4 信号通路抑制线粒体相关铁凋亡减轻神经性疼痛","authors":"Wencui Zhang, Shangchen Yu, Bo Jiao, Caixia Zhang, Kaiwen Zhang, Baowen Liu, Xianwei Zhang","doi":"10.1111/cns.70067","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Aims</h3>\n \n <p>Neuropathic pain remains a significant unmet medical challenge due to its elusive mechanisms. Recent clinical observations suggest that vitamin D (VitD) holds promise in pain relief, yet its precise mechanism of action is still unclear. This study explores the therapeutical role and potential mechanism of VitD<sub>3</sub> in spared nerve injury (SNI)-induced neuropathic pain rat model.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>The analgesic effects and underlying mechanisms of VitD<sub>3</sub> were evaluated in SNI and naïve rat models. Mechanical allodynia was assessed using the Von Frey test. Western blotting, immunofluorescence, biochemical assay, and transmission electron microscope (TEM) were employed to investigate the molecular and cellular effects of VitD<sub>3</sub>.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>Ferroptosis was observed in the spinal cord following SNI. Intrathecal administration of VitD<sub>3</sub>, the active form of VitD, activated the vitamin D receptor (VDR), suppressed ferroptosis, and alleviated mechanical nociceptive behaviors. VitD<sub>3</sub> treatment preserved spinal GABAergic interneurons, and its neuroprotective effects were eliminated by the ferroptosis inducer RSL3. Additionally, VitD<sub>3</sub> mitigated aberrant mitochondrial morphology and oxidative metabolism in the spinal cord. Mechanistically, VitD<sub>3</sub> inhibited SNI-induced activation of spinal PKCα/NOX4 signaling. Inhibition of PKCα/NOX4 signaling alleviated mechanical pain hypersensitivity, accompanied by reduced ferroptosis and mitochondrial dysfunction in SNI rats. Conversely, activation of PKCα/NOX4 signaling in naïve rats induced hyperalgesia, ferroptosis, loss of GABAergic interneurons, and mitochondrial dysfunction in the spinal cord, all of which were reversed by VitD<sub>3</sub> treatment.</p>\n </section>\n \n <section>\n \n <h3> Conclusions</h3>\n \n <p>Our findings provide evidence that VitD<sub>3</sub> attenuates neuropathic pain by preserving spinal GABAergic interneurons through the suppression of mitochondria-associated ferroptosis mediated by PKCα/NOX4 signaling, probably via VDR activation. VitD, alone or in combination with existing analgesics, presents an innovative therapeutic avenue for neuropathic pain.</p>\n </section>\n </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"30 9","pages":""},"PeriodicalIF":4.8000,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70067","citationCount":"0","resultStr":"{\"title\":\"Vitamin D3 Attenuates Neuropathic Pain via Suppression of Mitochondria-Associated Ferroptosis by Inhibiting PKCα/NOX4 Signaling Pathway\",\"authors\":\"Wencui Zhang, Shangchen Yu, Bo Jiao, Caixia Zhang, Kaiwen Zhang, Baowen Liu, Xianwei Zhang\",\"doi\":\"10.1111/cns.70067\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n \\n <section>\\n \\n <h3> Aims</h3>\\n \\n <p>Neuropathic pain remains a significant unmet medical challenge due to its elusive mechanisms. Recent clinical observations suggest that vitamin D (VitD) holds promise in pain relief, yet its precise mechanism of action is still unclear. This study explores the therapeutical role and potential mechanism of VitD<sub>3</sub> in spared nerve injury (SNI)-induced neuropathic pain rat model.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Methods</h3>\\n \\n <p>The analgesic effects and underlying mechanisms of VitD<sub>3</sub> were evaluated in SNI and naïve rat models. Mechanical allodynia was assessed using the Von Frey test. Western blotting, immunofluorescence, biochemical assay, and transmission electron microscope (TEM) were employed to investigate the molecular and cellular effects of VitD<sub>3</sub>.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Results</h3>\\n \\n <p>Ferroptosis was observed in the spinal cord following SNI. Intrathecal administration of VitD<sub>3</sub>, the active form of VitD, activated the vitamin D receptor (VDR), suppressed ferroptosis, and alleviated mechanical nociceptive behaviors. VitD<sub>3</sub> treatment preserved spinal GABAergic interneurons, and its neuroprotective effects were eliminated by the ferroptosis inducer RSL3. Additionally, VitD<sub>3</sub> mitigated aberrant mitochondrial morphology and oxidative metabolism in the spinal cord. Mechanistically, VitD<sub>3</sub> inhibited SNI-induced activation of spinal PKCα/NOX4 signaling. Inhibition of PKCα/NOX4 signaling alleviated mechanical pain hypersensitivity, accompanied by reduced ferroptosis and mitochondrial dysfunction in SNI rats. Conversely, activation of PKCα/NOX4 signaling in naïve rats induced hyperalgesia, ferroptosis, loss of GABAergic interneurons, and mitochondrial dysfunction in the spinal cord, all of which were reversed by VitD<sub>3</sub> treatment.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Conclusions</h3>\\n \\n <p>Our findings provide evidence that VitD<sub>3</sub> attenuates neuropathic pain by preserving spinal GABAergic interneurons through the suppression of mitochondria-associated ferroptosis mediated by PKCα/NOX4 signaling, probably via VDR activation. VitD, alone or in combination with existing analgesics, presents an innovative therapeutic avenue for neuropathic pain.</p>\\n </section>\\n </div>\",\"PeriodicalId\":154,\"journal\":{\"name\":\"CNS Neuroscience & Therapeutics\",\"volume\":\"30 9\",\"pages\":\"\"},\"PeriodicalIF\":4.8000,\"publicationDate\":\"2024-09-27\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70067\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"CNS Neuroscience & Therapeutics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1111/cns.70067\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"NEUROSCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"CNS Neuroscience & Therapeutics","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/cns.70067","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
Vitamin D3 Attenuates Neuropathic Pain via Suppression of Mitochondria-Associated Ferroptosis by Inhibiting PKCα/NOX4 Signaling Pathway
Aims
Neuropathic pain remains a significant unmet medical challenge due to its elusive mechanisms. Recent clinical observations suggest that vitamin D (VitD) holds promise in pain relief, yet its precise mechanism of action is still unclear. This study explores the therapeutical role and potential mechanism of VitD3 in spared nerve injury (SNI)-induced neuropathic pain rat model.
Methods
The analgesic effects and underlying mechanisms of VitD3 were evaluated in SNI and naïve rat models. Mechanical allodynia was assessed using the Von Frey test. Western blotting, immunofluorescence, biochemical assay, and transmission electron microscope (TEM) were employed to investigate the molecular and cellular effects of VitD3.
Results
Ferroptosis was observed in the spinal cord following SNI. Intrathecal administration of VitD3, the active form of VitD, activated the vitamin D receptor (VDR), suppressed ferroptosis, and alleviated mechanical nociceptive behaviors. VitD3 treatment preserved spinal GABAergic interneurons, and its neuroprotective effects were eliminated by the ferroptosis inducer RSL3. Additionally, VitD3 mitigated aberrant mitochondrial morphology and oxidative metabolism in the spinal cord. Mechanistically, VitD3 inhibited SNI-induced activation of spinal PKCα/NOX4 signaling. Inhibition of PKCα/NOX4 signaling alleviated mechanical pain hypersensitivity, accompanied by reduced ferroptosis and mitochondrial dysfunction in SNI rats. Conversely, activation of PKCα/NOX4 signaling in naïve rats induced hyperalgesia, ferroptosis, loss of GABAergic interneurons, and mitochondrial dysfunction in the spinal cord, all of which were reversed by VitD3 treatment.
Conclusions
Our findings provide evidence that VitD3 attenuates neuropathic pain by preserving spinal GABAergic interneurons through the suppression of mitochondria-associated ferroptosis mediated by PKCα/NOX4 signaling, probably via VDR activation. VitD, alone or in combination with existing analgesics, presents an innovative therapeutic avenue for neuropathic pain.
期刊介绍：
CNS Neuroscience & Therapeutics provides a medium for rapid publication of original clinical, experimental, and translational research papers, timely reviews and reports of novel findings of therapeutic relevance to the central nervous system, as well as papers related to clinical pharmacology, drug development and novel methodologies for drug evaluation. The journal focuses on neurological and psychiatric diseases such as stroke, Parkinson’s disease, Alzheimer’s disease, depression, schizophrenia, epilepsy, and drug abuse.
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