Pinocembrin protects hemorrhagic brain primarily by inhibiting toll-like receptor 4 and reducing M1 phenotype microglia.
Pinocembrin protects hemorrhagic brain primarily by inhibiting toll-like receptor 4 and reducing M1 phenotype microglia.
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DOI：
10.1016/j.bbi.2016.12.012
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发表时间：
2017-03
期刊：
影响因子：
--
通讯作者：
Wang J
中科院分区：
文献类型：
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作者：
Lan X;Han X;Li Q;Li Q;Gao Y;Cheng T;Wan J;Zhu W;Wang J
神经炎症是脑出血（ICH）进展的主要因素，但目前没有药物可以减少这种反应并防止ICH诱导的损伤。最近，天然产物松属素已被证明可以改善神经炎症，并正在进行缺血性中风治疗的II期临床试验。在这项研究中，我们检查了松属素在ICH模型中的功效，并进一步检查了其对小胶质细胞活化和极化的影响。在体内，松属素剂量依赖性地减少了47.5%的病变体积，并减少了72小时后胶原酶诱导的ICH小鼠的神经功能缺损。最佳剂量的松属素（5 mg/kg）抑制了小胶质细胞活化，表现为CD 68阳性小胶质细胞减少和促炎细胞因子肿瘤坏死因子（TNF）-α、白细胞介素（IL）-1β和IL-6减少。松属素还减少了典型激活的M1样小胶质细胞的数量，而不影响病灶周围区域的M2样小胶质细胞。此外，松属素降低了Toll样受体（TLR）4及其下游靶蛋白TRIF和MyD 88的表达。在小胶质细胞耗竭小鼠和TLR 4lps-del小鼠中，松属素的保护作用丧失，并且松属素未能减少TLR 4lps-del小鼠中M1样小胶质细胞的数量。在脂多糖刺激的BV-2细胞或原代小胶质细胞中，松属素降低M1相关细胞因子和标志物（IL-1β、IL-6、TNF-α和iNOS）、NF-κB活化和TLR 4表达，但不干扰TLR 4/MyD 88和TLR 4/TRIF相互作用或影响红细胞的小胶质细胞吞噬作用。抑制TLR 4信号通路和减少M1样小胶质细胞极化可能是松属素保护出血性脑的主要机制。具有抗炎特性的松属素可能是治疗ICH和其他急性脑损伤的有希望的新候选药物。
Neuroinflammation is a major contributor to intracerebral hemorrhage (ICH) progression, but no drug is currently available to reduce this response and protect against ICH-induced injury. Recently, the natural product pinocembrin has been shown to ameliorate neuroinflammation and is undergoing a phase II clinical trial for ischemic stroke treatment. In this study, we examined the efficacy of pinocembrin in an ICH model, and further examined its effect on microglial activation and polarization. In vivo, pinocembrin dose-dependently reduced lesion volume by 47.5% and reduced neurologic deficits of mice at 72 h after collagenase-induced ICH. The optimal dose of pinocembrin (5 mg/kg) suppressed microglial activation as evidenced by decreases in CD68-positive microglia and reduced proinflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6. Pinocembrin also reduced the number of classically activated M1-like microglia without affecting M2-like microglia in the perilesional region. Additionally, pinocembrin decreased the expression of toll-like receptor (TLR)4 and its downstream target proteins TRIF and MyD88. The protection by pinocembrin was lost in microglia-depleted mice and in TLR4lps-del mice, and pinocembrin failed to decrease the number of M1-like microglia in TLR4lps-del mice. In lipopolysaccharide-stimulated BV-2 cells or primary microglia, pinocembrin decreased M1-related cytokines and markers (IL-1β, IL-6, TNF-α, and iNOS), NF-κB activation, and TLR4 expression, but it did not interfere with TLR4/MyD88 and TLR4/TRIF interactions or affect microglial phagocytosis of red blood cells. Inhibition of the TLR4 signaling pathway and reduction in M1-like microglial polarization might be the major mechanism by which pinocembrin protects hemorrhagic brain. With anti-inflammatory properties, pinocembrin could be a promising new drug candidate for treating ICH and other acute brain injuries.