Department of Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai 200025, China.
Department of Anesthesiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, China.
Eur J Pharmacol. 2019 Jul 5;854:128-138. doi: 10.1016/j.ejphar.2019.03.008. Epub 2019 Mar 7.
Protocatechuic acid (PCA) has been well studied for its neuroprotection value in several diseases, but the effect in intracerebral haemorrhage (ICH) has not been reported. Here we verified the protection of PCA in ICH, and investigated the relative mechanisms. ICH model mice were established by injection of collagenase IV. The mice were treated with PCA once per day for 3 days, starting immediately after operation. The modified neurological severity score (mNSS) of mice at 1st, 3rd and 7th day after operation were recorded. And some of mice were euthanized at 3rd day to compare brain water content, pro-inflammatory cytokines expression, and cell apoptosis in perihematomal tissue. Additionally, SH-SY5Y cells were treated hemin to mimic secondary injury of ICH. Cells were incubated with PCA for treatment. The cell viability, ROS, apoptosis rate and protein expression of apoptosis-relative protein and MAPKs and NF-κB were detected and analysed. The results revealed PCA alleviated the cerebral oedema at 3rd post ICH, and significantly improved neurological functions. PCA also attenuated the protein and gene expression of TNF-а, IL-1β and IL-6 vivo. PCA dose-dependently decreased the generation of ROS and apoptosis rate. Furthermore, PCA treatment dose-dependently decreased the expression of bax, cleaved caspase-3, increased bcl-2 expression; PCA downregulated P38/JNK-NF-κB pathway. In conclusion, PCA effectively improves prognosis of ICH mice by inhibiting oxidative stress, inflammation and apoptosis. The mechanism possibly results of downregulating of P38/JNK-NF-κB pathway, and PCA can be a potential therapeutic agent for ICH.
原儿茶酸（PCA）在几种疾病中的神经保护价值已得到充分研究，但在脑出血（ICH）中的作用尚未报道。在这里，我们验证了 PCA 在 ICH 中的保护作用，并研究了相关机制。通过注射 IV 型胶原酶建立 ICH 模型小鼠。术后立即每天用 PCA 处理一次，持续 3 天。记录术后第 1、3 和 7 天小鼠的改良神经功能缺损评分（mNSS）。部分小鼠于第 3 天处死，比较血肿周围组织的脑含水量、促炎细胞因子表达和细胞凋亡。此外，用血红素处理 SH-SY5Y 细胞模拟 ICH 的继发性损伤。用 PCA 孵育细胞进行处理。检测和分析细胞活力、ROS、细胞凋亡率以及凋亡相关蛋白和 MAPKs 和 NF-κB 的蛋白表达。结果表明，PCA 减轻了 ICH 后第 3 天的脑水肿，并显著改善了神经功能。PCA 还减轻了 TNF-а、IL-1β 和 IL-6 的蛋白和基因表达。PCA 呈剂量依赖性降低 ROS 的产生和细胞凋亡率。此外，PCA 处理呈剂量依赖性降低 bax、cleaved caspase-3 的表达，增加 bcl-2 的表达；PCA 下调了 P38/JNK-NF-κB 通路。总之，PCA 通过抑制氧化应激、炎症和细胞凋亡，有效改善 ICH 小鼠的预后。其机制可能是通过下调 P38/JNK-NF-κB 通路，PCA 可能成为 ICH 的潜在治疗药物。
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