Department of Pharmacy, Peking University Third Hospital, Beijing, China.
National Key Research Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, China.
Neuropharmacology. 2023 Nov 1;238:109673. doi: 10.1016/j.neuropharm.2023.109673. Epub 2023 Jul 28.
Neuropathic pain (NP) is a prevalent clinical problem for which satisfactory treatment options are unavailable. Tetrandrine (TET), a bisbenzylisoquinoline alkaloid extracted from Stephania tetrandra S. Moore, possesses anti-inflammatory and immune-modulatory properties. Chemokine-like factor 1 (CKLF1) is known to play a crucial role in both peripheral and central inflammatory processes. This study aimed to investigate the potential anti-NP effects of TET and the involvement of CKLF1 in the action of TET. A male C57BL/6J mice model of NP caused by spared nerve injury (SNI) was established and mechanical withdrawal thresholds were measured using von Frey filaments. The results showed that TET improved mechanical allodynia in SNI mice and the propofol-induced sleep assay demonstrated that the TET group did not exhibit central inhibition, while the pregabalin (PGB) group showed significant central inhibition. Western blotting and immunofluorescence staining showed that TET significantly inhibited spinal protein expression levels of CKLF1, p-NF-κB/NF-κB, p-IKK/IKK, pro-inflammatory cytokines IL-1β and TNF-α, and increased protein expression levels of the anti-inflammatory cytokine IL-10, while inhibiting the expression levels of microglia and astrocyte markers IBA-1 and GFAP of SNI mice. Moreover, immunofluorescence double-labeling results revealed that CKLF1 was predominantly colocalized with microglia of the spinal cord (SC) in SNI mice. C19 (an antagonism peptide of CKLF1) alleviated SNI-induced mechanical pain hypersensitivity, while C27 (an analog peptide of CKLF1) induced mechanical allodynia in normal mice. TET significantly attenuated mechanical allodynia induced by C27 in mice. TET may effectively alleviate NP by reducing neuroinflammation and decreasing CKLF1.
神经病理性疼痛（NP）是一种普遍存在的临床问题，目前尚无满意的治疗方法。汉防己甲素（TET）是从粉防己 Stephania tetrandra S. Moore 中提取的一种双苄基异喹啉生物碱，具有抗炎和免疫调节作用。趋化因子样因子 1（CKLF1）已知在周围和中枢炎症过程中发挥关键作用。本研究旨在探讨 TET 对 NP 的潜在治疗作用及其在 TET 作用中的 CKLF1 参与情况。建立了由 spared nerve injury（SNI）引起的雄性 C57BL/6J 小鼠 NP 模型，并使用 von Frey 细丝测量机械撤回阈值。结果表明，TET 改善了 SNI 小鼠的机械性痛觉过敏，而丙泊酚诱导的睡眠试验表明，TET 组没有表现出中枢抑制作用，而普瑞巴林（PGB）组则表现出明显的中枢抑制作用。Western blot 和免疫荧光染色显示，TET 显著抑制了脊髓 CKLF1、p-NF-κB/NF-κB、p-IKK/IKK、促炎细胞因子 IL-1β 和 TNF-α 的蛋白表达水平，并增加了抗炎细胞因子 IL-10 的蛋白表达水平，同时抑制了 SNI 小鼠小胶质细胞和星形胶质细胞标志物 IBA-1 和 GFAP 的表达水平。此外，免疫荧光双重标记结果显示，CKLF1 在 SNI 小鼠脊髓中主要与小胶质细胞共定位。C19（CKLF1 的拮抗肽）减轻了 SNI 引起的机械性痛觉过敏，而 C27（CKLF1 的模拟肽）在正常小鼠中引起机械性痛觉过敏。TET 显著减轻了 C27 诱导的小鼠机械性痛觉过敏。TET 可能通过减轻神经炎症和减少 CKLF1 来有效缓解 NP。
