Neuroprotective Drug Discovery Key Laboratory of Nanjing Medical University, Department of Pharmacology, Nanjing Medical University, Nanjing, 211166, Jiangsu, China.
Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, 210029, China.
J Neuroinflammation. 2018 Jun 21;15(1):187. doi: 10.1186/s12974-018-1182-9.
Management of neuropathic pain is a real clinical challenge. Despite intense investigation, the mechanisms of neuropathic pain remain substantially unidentified. Matrix metalloproteinase (MMP)-9 and MMP-2 have been reported to contribute to the development and maintenance of neuropathic pain. Therefore, inhibition of MMP-9/2 may provide a novel therapeutic approach for the treatment of neuropathic pain. In this study, we aim to investigate the effect of procyanidins (PC), clinically used health product, on MMP-9/2 in neuropathic pain.
The nociception was assessed by measuring the incidence of foot withdrawal in response to mechanical indentation in mice. Cell signaling was assayed using gelatin zymography, western blotting, and immunohistochemistry. The BV2 cells were cultured to investigate the effects of PC on microglia.
Both in vitro and in vivo administration of PC significantly suppresses the activity of MMP-9/2. Oral administration of PC relieves neuropathic pain behaviors induced by chronic constriction sciatic nerve injury (CCI) in mice. Additionally, PC blocks the maturation of interleukin-1β, which is a critical substrate of MMPs, and markedly suppresses CCI-induced MAPK phosphorylation and neuronal and microglia activation, including the reduced phosphorylation of protein kinase C γ and NMDAR1. Furthermore, PC decreases the phosphorylation of p38 mitogen-activated protein kinase and inhibits the translocation of nuclear factor-κB (NF-κB) in microglia.
PC is an effective and safe approach to alleviate neuropathic pain via a powerful inhibition on the activation of MMP-9/2.
神经病理性疼痛的治疗是一个临床挑战。尽管进行了深入的研究，但神经病理性疼痛的发病机制仍未得到充分阐明。基质金属蛋白酶（MMP）-9 和 MMP-2 被报道有助于神经病理性疼痛的发展和维持。因此，抑制 MMP-9/2 可能为治疗神经病理性疼痛提供一种新的治疗方法。在这项研究中，我们旨在研究原花青素（PC），一种临床应用的保健品，对神经病理性疼痛中 MMP-9/2 的影响。
通过测量小鼠对机械压迫的足部退缩反应来评估痛觉。使用明胶酶谱法、western blot 和免疫组织化学法检测细胞信号转导。培养 BV2 细胞以研究 PC 对小胶质细胞的影响。
PC 的体内和体外给药均显著抑制 MMP-9/2 的活性。PC 的口服给药可缓解慢性缩窄性坐骨神经损伤（CCI）诱导的小鼠神经病理性疼痛行为。此外，PC 阻断了白细胞介素-1β的成熟，白细胞介素-1β是 MMPs 的关键底物，并显著抑制 CCI 诱导的 MAPK 磷酸化和神经元及小胶质细胞激活，包括蛋白激酶 C γ和 NMDAR1 的磷酸化减少。此外，PC 降低了 p38 丝裂原活化蛋白激酶的磷酸化，并抑制了小胶质细胞中核因子-κB（NF-κB）的易位。
PC 是一种通过有效抑制 MMP-9/2 的激活来缓解神经病理性疼痛的有效且安全的方法。
