Tonabersat inhibits trigeminal ganglion neuronal-satellite glial cell signaling.
Tonabersat inhibits trigeminal ganglion neuronal-satellite glial cell signaling.
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DOI：
10.1111/j.1526-4610.2008.01262.x
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发表时间：
2009-01
期刊：
影响因子：
5
通讯作者：
Durham PL
中科院分区：
文献类型：
--
作者：
Damodaram S;Thalakoti S;Freeman SE;Garrett FG;Durham PL
三叉神经元的敏化和激活与偏头痛、急性鼻窦炎和过敏性鼻炎的潜在病理学有关。提供硬脑膜和鼻粘膜的感觉神经支配的三叉神经神经元的细胞体与卫星神经胶质细胞相关地存在于三叉神经节中，在卫星神经胶质细胞中它们通过间隙连接进行通信。缝隙连接是由连接蛋白形成的通道，在病理条件下调节神经元和胶质细胞的兴奋状态。托那博沙是一种被测试为抗偏头痛药物的化合物，被认为可以阻断间隙连接的活性。研究三叉神经节内可能导致偏头痛和鼻窦炎显著共病的细胞事件，并确定托那博沙对神经元-卫星胶质细胞通讯的影响。使用注射True Blue的Sprague道利大鼠定位神经节中的神经元细胞体，并研究三叉神经节中经由间隙连接的神经元轴突信号传导。染料偶联研究是在基础条件下进行的，并响应于肿瘤坏死因子-α注射到胡须垫和/或辣椒素注射到眉毛。连接蛋白26和活性p38水平的变化通过免疫组织化学测定。此外，研究了在化学刺激之前托那博沙对间隙连接活性以及连接蛋白和活性p38的表达的影响。将肿瘤坏死因子-α（一种与急性鼻窦炎和过敏性鼻炎的病理学有关的细胞因子）注射到V2区，可以降低刺激位于神经节V1区的神经元所需的辣椒素量。虽然单独将肿瘤坏死因子-α注射到胡须垫或将辣椒素注射到眉毛中不会引起染料运动增加，但这两种刺激的组合通过V1和V2区域的间隙连接大大增加了神经元-卫星胶质细胞的通信。间隙连接活性的变化伴随着连接蛋白26和活性p38水平在V1和V2区的神经元和卫星胶质细胞中的表达增加。托那博沙预处理抑制神经元和卫星胶质细胞之间的间隙连接通讯，并阻断连接蛋白26和活性p38水平的增加，以响应肿瘤坏死因子-α（V2）和辣椒素（V1）的注射。我们认为，在急性鼻窦炎和过敏性鼻炎中，肿瘤坏死因子-α水平的增加减少了刺激V1神经元所需的辣椒素的量，从而导致V1和V2区域的细胞变化。本研究中观察到的细胞事件可能有助于部分解释偏头痛和鼻窦炎的显著合并症。此外，我们提供的证据表明，托那博沙可以防止增加的神经元卫星神经胶质细胞信号，因此，可能是有用的治疗偏头痛，急性鼻窦炎，过敏性鼻炎。
Sensitization and activation of trigeminal neurons are implicated in the underlying pathology of migraine, acute sinusitis, and allergic rhinitis. Cell bodies of trigeminal neurons that provide sensory innervation of the dura and nasal mucosa reside in the trigeminal ganglion in association with satellite glial cells where they communicate via gap junctions. Gap junctions, channels formed by connexins, modulate the excitability state of both neurons and glia under pathological conditions. Tonabersat, a compound being tested as an antimigraine drug, is thought to block gap junction activity. To investigate the cellular events within trigeminal ganglia that may account for the significant comorbidity of migraine and rhinosinusitis and determine the effect of tonabersat on neuron-satellite glia communication. Sprague Dawley rats injected with True Blue were used to localize neuronal cell bodies in the ganglion and study neuronglia signaling via gap junctions in the trigeminal ganglion. Dye coupling studies were conducted under basal conditions and in response to tumor necrosis factor-alpha injection into the whisker pad and/or capsaicin injection into the eyebrow. Changes in connexin 26 and active p38 levels were determined by immunohistochemistry. In addition, the effect of tonabersat prior to chemical stimulation on gap junction activity and expression of connexins and active p38 was investigated. Injection of tumor necrosis factor-alpha, a cytokine implicated in the pathology of acute sinusitis and allergic rhinitis, into the V2 region was shown to lower the amount of capsaicin required to stimulate neurons located in the V1 region of the ganglion. While injection of tumor necrosis factor-alpha into the whisker pad or capsaicin injection into the eyebrow alone did not cause increased dye movement, the combination of both stimuli greatly increased neuron-satellite glia communication via gap junctions in both V1 and V2 regions. The change in gap junction activity was accompanied by increased expression of connexin 26 and active p38 levels in both neurons and satellite glia in V1 and V2 regions. Pretreatment with tonabersat inhibited gap junction communication between neurons and satellite glia and blocked the increase in connexin 26 and active p38 levels in response to injection of both tumor necrosis factor-alpha (V2) and capsaicin (V1). We propose that increased levels of tumor necrosis factor-alpha, as reported during acute sinusitis and allergic rhinitis, reduces the amount of capsaicin necessary to stimulate V1 neurons that leads to cellular changes in both V1 and V2 regions. The cellular events observed in this study may help to explain, in part, the significant comorbidity reported with migraine and rhinosinusitis. In addition, we have provided evidence to suggest that tonabersat can prevent increased neuron-satellite glia signaling and, thus, may be useful in the treatment of migraine, acute sinusitis, and allergic rhinitis.