Tumor necrosis factor-α increases brain-derived neurotrophic factor expression in trigeminal ganglion neurons in an activity-dependent manner.

Many chronic trigeminal pain conditions, such as migraine or temporo-mandibular disorders, are associated with inflammation within peripheral endings of trigeminal ganglion (TG) sensory neurons. A critical role in mechanisms of neuroinflammation is attributed to proinflammatory cytokines, such as interleukin-1β and tumor necrosis factor-α (TNFα) that also contribute to mechanisms of persistent neuropathic pain resulting from nerve injury. However, the mechanisms of cytokine-mediated synaptic plasticity and nociceptor sensitization are not completely understood. In the present study, we examined the effects of TNFα on neuronal expression of brain-derived neurotrophic factor (BDNF), whose role in synaptic plasticity and sensitization of nociceptive pathways is well documented. We show that 4- and 24-hr treatment with TNFα increases BDNF mRNA and protein, respectively, in neuron-enriched dissociated cultures of rat TG. TNFα increases the phosphorylated form of the cyclic adenosine monophosphate-responsive element binding protein (CREB), a transcription factor involved in regulation of BDNF expression in neurons, and activates transcription of BDNF exon IV (former exon III) and, to a lesser extent, exon VI (former exon IV), but not exon I. TNFα-mediated increase in BDNF expression was accompanied by increase in calcitonin gene-related peptide (CGRP), which is consistent with previously published studies, and indicates that both peptides are similarly regulated in TG neurons by inflammatory mediators. The effect of TNFα on BDNF expression is dependent on sodium influx through TTX-sensitive channels and on p38-mitogen-activated protein kinase. Moreover, electrical stimulation and forskolin, known to increase intracellular cAMP, potentiate the TNFα-mediated upregulation of BDNF expression. This study provides new evidence for a direct action of proinflammatory cytokines on TG primary sensory neurons, and reveals a mechanism through which TNFα stimulates de novo synthesis of BDNF in these neurons. Thus, TNFα should be considered in mechanisms of BDNF-dependent neuronal plasticity.

许多慢性三叉神经痛病症，如偏头痛或颞下颌关节紊乱，与三叉神经节（TG）感觉神经元外周末梢的炎症有关。促炎细胞因子在神经炎症机制中起着关键作用，例如白细胞介素 -1β和肿瘤坏死因子 -α（TNFα），它们也参与了神经损伤导致的持续性神经病理性疼痛的机制。然而，细胞因子介导的突触可塑性和伤害感受器敏化的机制尚未完全清楚。在本研究中，我们检测了TNFα对脑源性神经营养因子（BDNF）神经元表达的影响，BDNF在突触可塑性和伤害性通路敏化中的作用已有充分记载。我们发现，用TNFα处理4小时和24小时分别增加了大鼠TG富含神经元的离散培养物中BDNF的mRNA和蛋白质水平。TNFα增加了环磷酸腺苷反应元件结合蛋白（CREB）的磷酸化形式，CREB是一种参与调节神经元中BDNF表达的转录因子，并激活了BDNF外显子IV（原外显子III）的转录，在较小程度上激活了外显子VI（原外显子IV），但不激活外显子I。TNFα介导的BDNF表达增加伴随着降钙素基因相关肽（CGRP）的增加，这与先前发表的研究一致，表明这两种肽在TG神经元中受炎症介质的类似调节。TNFα对BDNF表达的影响依赖于通过河豚毒素敏感通道的钠内流以及p38丝裂原活化蛋白激酶。此外，电刺激和毛喉素（已知可增加细胞内cAMP）增强了TNFα介导的BDNF表达上调。这项研究为促炎细胞因子对TG初级感觉神经元的直接作用提供了新的证据，并揭示了TNFα刺激这些神经元中BDNF从头合成的机制。因此，在BDNF依赖的神经元可塑性机制中应考虑TNFα。