Vitamin D3 Attenuates Neuropathic Pain via Suppression of Mitochondria-Associated Ferroptosis by Inhibiting PKCα/NOX4 Signaling Pathway

IF 4.8 1区医学 Q1 NEUROSCIENCES CNS Neuroscience & Therapeutics Pub Date : 2024-09-27 DOI:10.1111/cns.70067

Wencui Zhang, Shangchen Yu, Bo Jiao, Caixia Zhang, Kaiwen Zhang, Baowen Liu, Xianwei Zhang

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Abstract

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.

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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

目的由于神经病理性疼痛的机制难以捉摸，因此它仍然是一项尚未解决的重大医学挑战。最近的临床观察表明，维生素 D（VitD）有望缓解疼痛，但其确切的作用机制仍不清楚。本研究探讨了维生素 D3 在幸免神经损伤（SNI）诱导的神经病理性疼痛大鼠模型中的治疗作用和潜在机制。方法评估 VitD3 在神经损伤大鼠模型和幼稚大鼠模型中的镇痛效果和潜在机制。采用 Von Frey 试验评估机械异感。采用 Western 印迹、免疫荧光、生化检测和透射电子显微镜（TEM）研究 VitD3 的分子和细胞效应。结果在SNI后脊髓中观察到铁突变。鞘内注射 VitD3（VitD 的活性形式）可激活维生素 D 受体 (VDR)、抑制铁蛋白沉积并减轻机械痛觉行为。VitD3治疗可保留脊髓GABA能中间神经元，其神经保护作用被铁变态反应诱导剂RSL3所消除。此外，VitD3还能缓解脊髓线粒体形态和氧化代谢的异常。从机制上讲，VitD3 可抑制 SNI 诱导的脊髓 PKCα/NOX4 信号激活。抑制PKCα/NOX4信号传导缓解了SNI大鼠的机械痛觉过敏性，同时降低了铁变态反应和线粒体功能障碍。相反，PKCα/NOX4 信号在幼稚大鼠中的激活会诱发脊髓痛觉减退、铁突变、GABA 能中间神经元缺失和线粒体功能障碍，VitD3 治疗可逆转所有这些症状。结论我们的研究结果提供了证据，证明 VitD3 可能通过激活 VDR，通过抑制 PKCα/NOX4 信号介导的线粒体相关铁凋亡，保护脊髓 GABA 能中间神经元，从而减轻神经性疼痛。VitD单独或与现有镇痛药联合使用，为神经病理性疼痛提供了一条创新的治疗途径。

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来源期刊

CNS Neuroscience & Therapeutics 医学-神经科学

CiteScore

7.30

自引率

12.70%

发文量

240

审稿时长

2 months

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.