Department of Pharmacology and Laboratory of Cerebrovascular Pharmacology, College of Pharmaceutical Science, Soochow University, Suzhou 215123, China.
Brain Res. 2012 May 15;1454:48-64. doi: 10.1016/j.brainres.2012.03.020. Epub 2012 Mar 15.
Matrine (Mat) and oxymatrine are two major alkaloids of the Chinese herb Sophora flavescens Ait. (Leguminosae). Previous study has demonstrated that Mat reduces brain edema induced by focal cerebral ischemia. More recently, oxymatrine has been reported to produce neuroprotective effects against focal cerebral ischemia via inhibiting the activation of NF-κB in the ischemic brain tissue. In the current study, we investigated whether direct protection on neurons and astrocytes via inhibition of NF-κB signaling pathway is associated with Mat's neuroprotective effects against cerebral ischemia. In a model of permanent middle cerebral artery occlusion (pMCAO), Mat (12.5, 25 and 50 mg/kg) reduced the infarction volume and improved the neurological deficits in a dose-dependent manner, administered 10 min, 3h and even 6h following pMCAO. Mat 50 mg/kg also decreased the hemispheric water content. The number of GFAP-positive cells was markedly decreased in the ischemic cortex at 12h after ischemia. In contrast, Mat increased the number of GFAP-positive cells. Mat 50mg/kg has no effect on the cerebral blood flow (CBF). Primary neuron or astrocyte cultures were exposed to a paradigm of ischemic insult by using an oxygen-glucose deprivation (OGD), Mat (50-200 μM) reduced LDH leakage and the number of neuronal and astrocytic apoptosis, and increased the number of MAP2-positive and GFAP-positive cells. Further observations revealed that Mat increased the protein levels of IκBα, and blocked the translocation of NF-κB p65 from the cytosol to the nucleus in the ischemic cortex and injured neurons and astrocytes induced by in vitro OGD. Moreover, Mat could down-regulate NF-κB p65 downstream pro-apoptotic gene p53 and/or c-Myc in the injured neurons and astrocytes induced by OGD. The present findings suggest that Mat, even when administrated 6h after ischemia, has neuroprotective effects against focal cerebral ischemia and directly protects neurons and astrocytes via inhibition of NF-κB signaling pathway, contributing to matrine's neuroprotection against focal cerebral ischemia.
苦参碱（Mat）和氧化苦参碱是中国草药苦参（豆科）的两种主要生物碱。先前的研究表明 Mat 可减轻局灶性脑缺血引起的脑水肿。最近，据报道氧化苦参碱通过抑制缺血脑组织中 NF-κB 的激活对局灶性脑缺血产生神经保护作用。在本研究中，我们研究了通过抑制 NF-κB 信号通路对神经元和星形胶质细胞的直接保护是否与 Mat 对脑缺血的神经保护作用有关。在永久性大脑中动脉闭塞（pMCAO）模型中，Mat（12.5、25 和 50mg/kg）以剂量依赖性方式减轻梗死体积并改善神经功能缺损，给药时间为 pMCAO 后 10min、3h 甚至 6h。Mat 50mg/kg 还降低了半球含水量。缺血后 12h 缺血皮质中 GFAP 阳性细胞数量明显减少，而 Mat 增加了 GFAP 阳性细胞数量。Mat 50mg/kg 对脑血流（CBF）没有影响。原代神经元或星形胶质细胞培养物暴露于氧葡萄糖剥夺（OGD）的缺血损伤模型中，Mat（50-200μM）减少了 LDH 漏出和神经元和星形胶质细胞凋亡的数量，并增加了 MAP2 阳性和 GFAP 阳性细胞的数量。进一步的观察表明，Mat 增加了 IκBα 的蛋白水平，并阻止了 NF-κB p65 从细胞质向核内的易位，这是在体外 OGD 诱导的缺血皮质和损伤神经元和星形胶质细胞中发生的。此外，Mat 可以下调 OGD 诱导的损伤神经元和星形胶质细胞中 NF-κB p65 下游促凋亡基因 p53 和/或 c-Myc。这些发现表明，Mat 甚至在缺血后 6h 给药，也具有局灶性脑缺血的神经保护作用，并通过抑制 NF-κB 信号通路直接保护神经元和星形胶质细胞，这有助于苦参碱对局灶性脑缺血的神经保护作用。
