Sarchielli Paola, Alberti Andrea, Vaianella Luana, Pierguidi Laura, Floridi Alessandro, Mazzotta Giovanni, Floridi Ardesio, Gallai Virgilio
Neurologic Clinic, Department of Neuroscience, Institute of Clinical and Applied Biochemistry, University of Perugia, Italy.
Headache. 2004 Nov-Dec;44(10):961-8. doi: 10.1111/j.1526-4610.2004.04189.x.
To investigate changes in the levels of calcitonin gene-related peptide and its intracellular messenger cyclic adenosine monophosphate in serial samples of internal jugular blood taken from migraine patients without aura assessed during attacks, and to assess their relationship with the levels of IL-8, MCP-1, and RANTES in the same samples.
Calcitonin gene-related peptide, the marker of trigeminovascular activation, is released in both the internal and external jugular venous blood of migraine patients during attacks. Experimental evidence demonstrated that when released from C-type sensory neurons in inflammatory pain models, it differentially induced expression of neutrophil chemotactic chemokine IL-8, but not monocyte chemotactic chemokine MCP-1 or lymphocyte chemotactic chemokine RANTES. These chemokines were never investigated in migraine.
DESIGN/METHODS: Eight migraine without aura patients were admitted to the hospital during the attacks. Internal jugular venous blood samples were taken immediately after catheter insertion, at the 1st, 2nd, and 4th hours after attack onset, and within 2 hours from its cessation. The levels of the sensory neuropeptide calcitonin gene-related peptide and the messenger cyclic adenosine monophosphate were measured by RIA method, and those of IL-8, MCP-1, and RANTES were measured by ELISA method.
Higher calcitonin gene-related peptide levels were found in the internal jugular venous blood of migraine without aura patients compared with the time of catheter insertion (ANOVA: P<.0001) with a peak at the first hour (52.6+/-9.2 ng/mL). A transient increase in IL-8 was observed at the 2nd and 4th hours (P<.01 and P<.002, respectively), whereas no changes in the levels of MCP-1 and RANTES were found at any time of the study. The increase in IL-8 was accompanied by a parallel increase in cyclic adenosine monophosphate.
The present study confirms previous findings of an increase in calcitonin gene-related peptide in internal jugular venous blood of migraine without aura patients during attacks. The transient increase in the levels of IL-8 concurs with the results of recent experimental research showing a calcitonin gene-related peptide-induced activation of IL-8 gene expression, but not RANTES and MCP-1, via the transcriptional factor AP-2, which mediates transduction in response to cyclic adenosine monophosphate. Although IL-8 is transiently increased during migraine attacks, an accumulation of leukocytes secondary to neurogenic inflammation is unlikely, as it is for other inflammatory events, because they are self limiting. Other events, including nitric oxide production, may contribute to counteract meningeal transvascular leukocyte migration during migraine attacks, as suggested by the model of sterile inflammation.
研究无先兆偏头痛患者发作期颈内静脉系列血样中降钙素基因相关肽及其细胞内信使环磷酸腺苷水平的变化，并评估其与同一样本中白细胞介素-8（IL-8）、单核细胞趋化蛋白-1（MCP-1）和调节激活正常T细胞表达和分泌的因子（RANTES）水平的关系。
降钙素基因相关肽作为三叉神经血管激活的标志物，在偏头痛患者发作期的颈内静脉和颈外静脉血中均有释放。实验证据表明，在炎症性疼痛模型中，当降钙素基因相关肽从C型感觉神经元释放时，它可差异性地诱导中性粒细胞趋化因子IL-8的表达，但不诱导单核细胞趋化因子MCP-1或淋巴细胞趋化因子RANTES的表达。这些趋化因子在偏头痛中从未被研究过。
设计/方法：8例无先兆偏头痛患者在发作期入院。在插入导管后立即、发作开始后第1、2和4小时以及发作停止后2小时内采集颈内静脉血样。采用放射免疫分析法测定感觉神经肽降钙素基因相关肽和信使环磷酸腺苷的水平，采用酶联免疫吸附测定法测定IL-8、MCP-1和RANTES的水平。
与插入导管时相比，无先兆偏头痛患者颈内静脉血中降钙素基因相关肽水平更高（方差分析：P<0.0001），在第1小时达到峰值（52.6±9.2 ng/mL）。在第2和4小时观察到IL-8短暂升高（分别为P<0.01和P<0.002），而在研究的任何时间MCP-1和RANTES水平均无变化。IL-8的升高伴随着环磷酸腺苷的平行升高。
本研究证实了先前的发现，即无先兆偏头痛患者发作期颈内静脉血中降钙素基因相关肽增加。IL-8水平的短暂升高与最近的实验研究结果一致，该研究表明降钙素基因相关肽通过转录因子AP-2诱导IL-8基因表达激活，但不诱导RANTES和MCP-1基因表达激活，转录因子AP-2介导对环磷酸腺苷的转导反应。虽然偏头痛发作期间IL-8短暂升高，但与其他炎症事件不同，神经源性炎症继发的白细胞聚集不太可能发生，因为它们是自限性的。如无菌性炎症模型所示，其他事件，包括一氧化氮的产生，可能有助于抵消偏头痛发作期间脑膜跨血管白细胞迁移。
