Department of Anesthesiology, the Second Xiangya Hospital, Central South University, Changsha, China; Department of Pain Management, the Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China; Hunan Province Center for Clinical Anesthesia and Anesthesiology, Research Institute of Central South University, Changsha, Hunan Province, China; Clinical Research Center for Pain Medicine in Hunan Province, Changsha, Hunan Province, China.
Department of the Laboratory, the Second Xiangya Hospital, Central South University, Changsha, China.
Brain Behav Immun. 2024 Jul;119:836-850. doi: 10.1016/j.bbi.2024.05.007. Epub 2024 May 10.
During postherpetic neuralgia (PHN), the cerebral spinal fluid (CSF) possesses the capability to trigger glial activation and inflammation, yet the specific changes in its composition remain unclear. Recent findings from our research indicate elevations of central bone morphogenetic protein 4 (BMP4) during neuropathic pain (NP), serving as an independent modulator of glial cells. Herein, the aim of the present study is to test the CSF-BMP4 expressions and its role in the glial modulation in the process of PHN.
CSF samples were collected from both PHN patients and non-painful individuals (Control) to assess BMP4 and its antagonist Noggin levels. Besides, intrathecal administration of both CSF types was conducted in normal rats to evaluate the impact on pain behavior, glial activity, and inflammation.; Additionally, both Noggin and STAT3 antagonist-Stattic were employed to treat the PHN-CSF or exogenous BMP4 challenged cultured astrocytes to explore downstream signals. Finally, microglial depletion was performed prior to the PHN-CSF intervention so as to elucidate the microglia-astrocyte crosstalk.
BMP4 levels were significantly higher in PHN-CSF compared to Control-CSF (P < 0.001), with a positive correlation with pain duration (P < 0.05, r = 0.502). Comparing with the Control-CSF producing moderate paw withdrawal threshold (PWT) decline and microglial activation, PHN-CSF further exacerbated allodynia and triggered both microglial and astrocytic activation (P < 0.05). Moreover, PHN-CSF rather than Control-CSF evoked microglial proliferation and pro-inflammatory transformation, reinforced iron storage, and activated astrocytes possibly through both SMAD159 and STAT3 signaling, which were all mitigated by the Noggin application (P < 0.05). Next, both Noggin and Stattic effectively attenuated BMP4-induced GFAP and IL-6 upregulation, as well as SMAD159 and STAT3 phosphorylation in the cultured astrocytes (P < 0.05). Finally, microglial depletion diminished PHN-CSF induced astrogliosis, inflammation and endogenous BMP4 expression (P < 0.05).
Our study highlights the role of CSF-BMP4 elevation in glial activation and allodynia during PHN, suggesting a potential therapeutic avenue for future exploration.
在带状疱疹后神经痛（PHN）期间，脑脊液（CSF）具有触发神经胶质激活和炎症的能力，但其成分的具体变化尚不清楚。我们最近的研究发现，中枢骨形态发生蛋白 4（BMP4）在神经病理性疼痛（NP）期间升高，作为神经胶质细胞的独立调节剂。本研究旨在检测 PHN 过程中 CSF-BMP4 表达及其在神经胶质调节中的作用。
收集 PHN 患者和无痛个体（对照组）的 CSF 样本，以评估 BMP4 及其拮抗剂 Noggin 的水平。此外，将两种 CSF 类型鞘内给药至正常大鼠，以评估对疼痛行为、神经胶质活性和炎症的影响；此外，还使用 Noggin 和 STAT3 拮抗剂 Stattic 治疗 PHN-CSF 或外源性 BMP4 刺激的培养星形胶质细胞，以探索下游信号。最后，在 PHN-CSF 干预之前进行小胶质细胞耗竭，以阐明小胶质细胞-星形胶质细胞串扰。
PHN-CSF 中的 BMP4 水平明显高于对照组（P<0.001），与疼痛持续时间呈正相关（P<0.05，r=0.502）。与对照组 CSF 产生中度爪回缩阈值（PWT）下降和小胶质细胞激活相比，PHN-CSF 进一步加重了痛觉过敏，并引发了小胶质细胞和星形胶质细胞的激活（P<0.05）。此外，PHN-CSF 而不是对照组 CSF 引起小胶质细胞增殖和促炎转化，增强铁储存，并通过 SMAD159 和 STAT3 信号激活星形胶质细胞，这些都可以通过 Noggin 应用得到缓解（P<0.05）。接下来，Noggin 和 Stattic 有效减弱了 BMP4 诱导的 GFAP 和 IL-6 上调，以及培养的星形胶质细胞中 SMAD159 和 STAT3 磷酸化（P<0.05）。最后，小胶质细胞耗竭减少了 PHN-CSF 诱导的星形胶质细胞增生、炎症和内源性 BMP4 表达（P<0.05）。
我们的研究强调了 CSF-BMP4 升高在 PHN 期间神经胶质激活和痛觉过敏中的作用，提示未来可能有治疗途径。
