Jiangsu Key Laboratory of Drug Target and Drug for Degenerative Diseases, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China; State Key Laboratory of Trauma, Burns and Combined Injury, Shock and Transfusion of Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China.
Jiangsu Key Laboratory of Drug Target and Drug for Degenerative Diseases, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
Phytomedicine. 2023 Mar;111:154673. doi: 10.1016/j.phymed.2023.154673. Epub 2023 Jan 13.
Treatment of paclitaxel (PTX)-induced peripheral neuropathy (PIPN) is full of challenges because of the unclear pathogenesis of PIPN. Herbal folk medicine Khellin (Khe) is a natural compound extracted from Ammi visnaga for treatment of renal colics and muscle spasms.
Here, we aimed to assess the potential of Khe in ameliorating PIPN-like pathology in mice and investigate the underlying mechanisms.
PIPN model mice were conducted by injection of PTX based on the published approach. The capability of Khe in ameliorating the PTX-induced neurological dysfunctions was assayed by detection of nociceptive hypersensitivities including mechanical hyperalgesia, thermal hypersensitivity, and cold allodynia in mice. The underlying mechanisms were investigated by assays against the PIPN mice with MAOB-specific knockdown in spinal cord and dorsal root ganglion (DRG) tissues by injection of adeno-associated virus (AAV)-MAOB-shRNA.
We determined that MAOB not MAOA is highly overexpressed in the spinal cord and DRG tissues of PIPN mice and Khe as a selective MAOB inhibitor improved PIPN-like pathology in mice. Khe promoted neurite outgrowth, alleviated apoptosis, and improved mitochondrial dysfunction of DRG neurons by targeting MAOB. Moreover, Khe inhibited spinal astrocytes activation and suppressed neuroinflammation of spinal astrocytes via MAOB/NF-κB/NLRP3/ASC/Caspase1/IL-1β pathway.
Our work might be the first to report that MAOB not MAOA is selectively overexpressed in the spinal cord and DRG tissues of PIPN mice, and all findings have highly addressed the potency of selective MAOB inhibitor in the amelioration of PIPN-like pathology and highlighted the potential of Khe in treating PTX-induced side effects.
紫杉醇（PTX）诱导的周围神经病（PIPN）的治疗充满了挑战，因为 PIPN 的发病机制尚不清楚。草药民间药物芹菜素（Khe）是从 Ammi visnaga 中提取的天然化合物，用于治疗肾绞痛和肌肉痉挛。
在这里，我们旨在评估 Khe 改善小鼠 PIPN 样病理学的潜力，并研究潜在的机制。
根据已发表的方法，通过注射 PTX 构建 PIPN 模型小鼠。通过检测小鼠的痛觉过敏包括机械性痛觉过敏、热敏性和冷觉过敏，评估 Khe 改善 PTX 诱导的神经功能障碍的能力。通过注射腺相关病毒（AAV）-MAOB-shRNA 来靶向脊髓和背根神经节（DRG）组织中的 MAOB 特异性敲低，对 PIPN 小鼠进行了检测。
我们确定 MAOB 而不是 MAOA 在 PIPN 小鼠的脊髓和 DRG 组织中高度过表达，作为一种选择性 MAOB 抑制剂，Khe 改善了小鼠的 PIPN 样病理。Khe 通过靶向 MAOB 促进 DRG 神经元的轴突生长、减轻凋亡和改善线粒体功能障碍。此外，Khe 通过 MAOB/NF-κB/NLRP3/ASC/Caspase1/IL-1β 通路抑制脊髓星形胶质细胞激活并抑制脊髓星形胶质细胞的神经炎症。
我们的工作可能是首次报道 MAOB 而不是 MAOA 选择性地在 PIPN 小鼠的脊髓和 DRG 组织中过度表达，所有发现都高度说明了选择性 MAOB 抑制剂在改善 PIPN 样病理方面的效力，并突出了 Khe 治疗 PTX 诱导的副作用的潜力。
