Missouri State University, Springfield, MO 65806, USA.
Headache. 2012 Jan;52(1):80-9. doi: 10.1111/j.1526-4610.2011.02048.x. Epub 2011 Dec 8.
The goal of this study was to use protein array analysis to investigate temporal regulation of stimulated cytokine expression in trigeminal ganglia and the spinal trigeminal nucleus in response to co-treatment of sumatriptan and naproxen sodium or individual drug.
Activation of neurons and glia in trigeminal ganglia and the spinal trigeminal nucleus leads to increased levels of cytokines that promote peripheral and central sensitization, which are key events in migraine pathology. While recent clinical studies have provided evidence that a combination of sumatriptan and naproxen sodium is more efficacious in treating migraine than either drug alone, it is not well understood why the combination therapy is superior to monotherapy.
Male Sprague-Dawley rats were left untreated (control), injected with capsaicin, or pretreated with sumatriptan/naproxen, sumatriptan, or naproxen for 1 hour prior to capsaicin. Trigeminal ganglia and the spinal trigeminal nucleus were isolated 2 and 24 hours after capsaicin or drug treatment, and levels of 90 proteins were determined using a RayBio® Label-Based Rat Antibody Array (RayBiotech, Norcross, GA, USA).
Capsaicin stimulated a >3-fold increase in expression of the majority of cytokines in trigeminal ganglia at 2 hours that was sustained at 24 hours. Significantly, treatment with sumatriptan/naproxen almost completely abolished the stimulatory effects of capsaicin at 2 and 24 hours. Capsaicin stimulated >3-fold expression of more proteins in the spinal trigeminal nucleus at 24 hours when compared to 2 hours. Similarly, sumatriptan/naproxen abolished capsaicin stimulation of proteins in the spinal trigeminal nucleus at 2 hours and greatly suppressed protein expression 24 hours post-capsaicin injection. Interestingly, treatment with sumatriptan alone suppressed expression of different cytokines in trigeminal ganglia and the spinal trigeminal nucleus than repressed by naproxen sodium.
We found that the combination of sumatriptan/naproxen was effective in blocking capsaicin stimulation of pro-inflammatory proteins implicated in the development of peripheral and central sensitization in response to capsaicin activation of trigeminal neurons. Based on our findings that sumatriptan and naproxen regulate expression of different proteins in trigeminal ganglia and the spinal trigeminal nucleus, we propose that these drugs function on therapeutically distinct cellular targets to suppress inflammation and pain associated with migraine.
本研究旨在使用蛋白质芯片分析来研究舒马曲坦和萘普生钠联合治疗或单独用药时三叉神经节和三叉神经脊束核中受刺激的细胞因子表达的时间调节。
三叉神经节和三叉神经脊束核中神经元和神经胶质的激活导致细胞因子水平升高，促进外周和中枢敏化，这是偏头痛发病机制中的关键事件。虽然最近的临床研究提供了证据表明舒马曲坦和萘普生钠联合治疗偏头痛比单独使用任何一种药物更有效，但尚不清楚为什么联合治疗优于单药治疗。
雄性 Sprague-Dawley 大鼠未治疗（对照）、注射辣椒素或预先用舒马曲坦/萘普生、舒马曲坦或萘普生处理 1 小时后用辣椒素处理。辣椒素或药物处理后 2 和 24 小时分离三叉神经节和三叉神经脊束核，使用 RayBio® Label-Based Rat Antibody Array（RayBiotech，美国佐治亚州诺克罗斯）测定 90 种蛋白质的水平。
辣椒素在 2 小时内刺激三叉神经节中大多数细胞因子的表达增加了 3 倍以上，24 小时时仍持续增加。值得注意的是，舒马曲坦/萘普生治疗几乎完全消除了辣椒素在 2 和 24 小时的刺激作用。与 2 小时相比，辣椒素在 24 小时内刺激了更多蛋白质在三叉神经脊束核中的表达增加了 3 倍以上。同样，舒马曲坦/萘普生在 2 小时时消除了辣椒素对蛋白质的刺激，并大大抑制了辣椒素注射后 24 小时的蛋白质表达。有趣的是，舒马曲坦单独治疗抑制了三叉神经节和三叉神经脊束核中不同细胞因子的表达，而不是由萘普生钠抑制。
我们发现，舒马曲坦/萘普生联合治疗可有效阻断辣椒素刺激三叉神经神经元激活后外周和中枢敏化发展所涉及的促炎蛋白。基于我们的发现，舒马曲坦和萘普生调节三叉神经节和三叉神经脊束核中不同蛋白质的表达，我们提出这些药物作用于治疗上不同的细胞靶点，以抑制与偏头痛相关的炎症和疼痛。
