School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China; Department of Laboratory Medicine, Chengdu Medical College, Chengdu, 610500, China.
School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China; Institute of Innovative Medicine Ingredients of Southwest Specialty Medicinal Materials, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
J Ethnopharmacol. 2019 Jun 12;237:39-46. doi: 10.1016/j.jep.2019.03.026. Epub 2019 Mar 14.
Migraine is a prevalent, complex, painful, and disabling neurovascular disorder that places an enormous social and economic burden on patients. Rhizome Chuanxiong (RCX), the dried rhizomes of Ligusticum striatum DC., has been widely used in the clinic for the treatment of migraine for centuries in China. Total alkaloids (TAs) are considered to be important effective ingredients of L. striatum, especially for cardiovascular and cerebrovascular diseases. However, there has been no study published, to date, reporting the antimigraine effects of TAs from RCX (RCXTAs).
The present study was designed to evaluate the antimigraine effects of RCXTAs and explore the underlying mechanisms in an experimental migraine rat model.
RCXTAs were prepared in accordance with our previous optimized preparation process. A nitroglycerin-induced migraine model in rats and a reserpine-induced migraine model in mice were established to investigate the effects of RCXTAs on monoamine neurotransmitters in brain tissue, including 5-hydroxytryptamine (5-HT) and its metabolite (5-HIAA). Migraine rats or mice were divided into six groups as follows: control; model; zolmitriptan (1.67 mg/kg); and low-, medium-, and high-dose RCXTAs (12.5, 25, and 50 mg/kg, respectively). The levels of 5-HT and 5-HIAA in the brains of rats and mice were determined by using the enzyme-linked immunosorbent assay method. Pathological changes in the brains of migraine rats were examined by immunohistochemistry. The protein expression of 5-HT receptor, c-Fos, and c-Jun in the periaqueductal gray (PAG) of migraine rats was measured by Western blot.
After preventive administration of RCXTAs to the nitroglycerin-induced migraine rats, the levels of 5-HT and 5-HIAA in the brain tissue were generally upregulated in all three RCXTA dose groups, a finding that was similar to that observed in the control group. Additionally, the 5-HT and 5-HIAA levels were significantly increased in the medium- and high-dose RCXTA groups when compared with the model group (p < 0.01). Therapeutical administration of RCXTAs to reserpine-induced migraine mice also inhibited the reduction of 5-HT and 5-HIAA in the brain (p < 0.01). Both immunohistochemistry and Western blot tests showed that RCXTAs pretreatment has significantly upregulated 5-HT receptor expression and downregulated c-Jun expression in the nitroglycerin-induced migraine rats.
RCXTAs exerted significant preventive and therapeutic effects on migraine via increasing the levels of 5-HT and 5-HIAA. Upregulation of the expression of monoamine neurotransmitter 5-HT receptor and downregulation of the expression of c-Jun were the possible mechanisms.
偏头痛是一种普遍存在的、复杂的、疼痛的、致残的神经血管疾病，给患者带来了巨大的社会和经济负担。川芎（RCX），是藁本的干燥根茎，在中国临床上已广泛用于偏头痛的治疗，已有数百年的历史。总生物碱（TAs）被认为是藁本的重要有效成分，特别是对心血管和脑血管疾病。然而，迄今为止，还没有研究报道 RCX 中的 TA（RCXTAs）的抗偏头痛作用。
本研究旨在评估 RCXTAs 的抗偏头痛作用，并在实验性偏头痛大鼠模型中探讨其潜在机制。
按照我们之前优化的制备工艺制备 RCXTAs。建立硝酸甘油诱导的偏头痛大鼠模型和利血平诱导的偏头痛小鼠模型，以研究 RCXTAs 对脑组织中单胺神经递质 5-羟色胺（5-HT）及其代谢产物 5-羟吲哚乙酸（5-HIAA）的影响。偏头痛大鼠或小鼠分为六组：对照组；模型组；佐米曲普坦（1.67mg/kg）；以及低、中、高剂量 RCXTAs（12.5、25 和 50mg/kg）。采用酶联免疫吸附法测定大鼠和小鼠脑内 5-HT 和 5-HIAA 水平。通过免疫组织化学法观察偏头痛大鼠脑组织的病理变化。采用 Western blot 法测定偏头痛大鼠中脑导水管周围灰质（PAG）中 5-HT 受体、c-Fos 和 c-Jun 的蛋白表达。
RCXTAs 预防性给药后，可普遍上调硝酸甘油诱导的偏头痛大鼠脑内 5-HT 和 5-HIAA 水平，与对照组相似。与模型组相比，中、高剂量 RCXTA 组的 5-HT 和 5-HIAA 水平显著升高（p<0.01）。RCXTAs 治疗性给药对利血平诱导的偏头痛小鼠也抑制了脑内 5-HT 和 5-HIAA 的减少（p<0.01）。免疫组织化学和 Western blot 检测均显示，RCXTAs 预处理可显著上调硝酸甘油诱导的偏头痛大鼠 5-HT 受体的表达，下调 c-Jun 的表达。
RCXTAs 通过增加 5-HT 和 5-HIAA 的水平对偏头痛具有显著的预防和治疗作用。上调单胺神经递质 5-HT 受体的表达和下调 c-Jun 的表达可能是其作用机制。
