1 Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA.
2 Department of Orthopedic Surgery and Rehabilitation, University of Texas Medical Branch, Galveston, TX, USA.
Mol Pain. 2019 Jan-Dec;15:1744806919838191. doi: 10.1177/1744806919838191.
The formation of neuromas involves expansion of the cellular components of peripheral nerves. The onset of these disorganized tumors involves activation of sensory nerves and neuroinflammation. Particularly problematic in neuroma is arborization of axons leading to extreme, neuropathic pain. The most common sites for neuroma are the ends of transected nerves following injury; however, this rodent model does not reliably result in neuroma formation. In this study, we established a rodent model of neuroma in which the sciatic nerve was loosely ligated with two chromic gut sutures. This model formed neuromas reliably (∼95%), presumably through activation of the neural inflammatory cascade. Resulting neuromas had a disorganized structure and a significant number of replicating cells. Quantification of changes in perineurial and Schwann cells showed a significant increase in these populations. Immunohistochemical analysis showed the presence of β-tubulin 3 in the rapidly expanding nerve and a decrease in neurofilament heavy chain compared to the normal nerve, suggesting the axons forming a disorganized structure. Measurement of the permeability of the blood-nerve barrier shows that it opened almost immediately and remained open as long as 10 days. Studies using an antagonist of the β3-adrenergic receptor (L-748,337) or cromolyn showed a significant reduction in tumor size and cell expansion as determined by flow cytometry, with an improvement in the animal's gait detected using a Catwalk system. Previous studies in our laboratory have shown that heterotopic ossification is also a result of the activation of neuroinflammation. Since heterotopic ossification and neuroma often occur together in amputees, they were induced in the same limbs of the study animals. More heterotopic bone was formed in animals with neuromas as compared to those without. These data collectively suggest that perturbation of early neuroinflammation with compounds such as L-748,337 and cromolyn may reduce formation of neuromas.
神经瘤的形成涉及周围神经细胞成分的扩张。这些无组织肿瘤的发生涉及感觉神经的激活和神经炎症。在神经瘤中特别成问题的是导致极度神经病理性疼痛的轴突分支。神经瘤最常见的部位是受伤后切断神经的末端；然而，这种啮齿动物模型不能可靠地导致神经瘤的形成。在这项研究中，我们建立了一种神经瘤的啮齿动物模型，其中坐骨神经用两条铬制肠线松散地结扎。这种模型可靠地形成了神经瘤（约 95%），可能是通过激活神经炎症级联反应。由此产生的神经瘤结构紊乱，有大量复制的细胞。对神经外膜和施万细胞数量的变化进行定量分析表明，这些细胞群体数量显著增加。免疫组织化学分析显示，快速扩张的神经中存在β-微管蛋白 3，与正常神经相比神经丝重链减少，表明轴突形成了无组织的结构。对血神经屏障通透性的测量表明，它几乎立即打开，并保持开放长达 10 天。使用β3-肾上腺素能受体拮抗剂（L-748,337）或色甘酸钠的研究表明，肿瘤大小和细胞扩张显著减少，通过流式细胞术确定，使用 Catwalk 系统检测到动物步态改善。我们实验室的先前研究表明，异位骨化也是神经炎症激活的结果。由于异位骨化和神经瘤常同时发生在截肢者中，因此在研究动物的同一肢体中诱导了它们。与没有神经瘤的动物相比，有神经瘤的动物形成了更多的异位骨。这些数据共同表明，用 L-748,337 和色甘酸钠等化合物干扰早期神经炎症可能会减少神经瘤的形成。
