INFLUENCE OF BLOOD-NERVE BARRIER ALTERATIONS ON TOXIC NEUROPATHIES

血神经屏障改变对毒性神经病的影响

• 批准号: 3733583
• 负责人: THOMAS W BOULDIN
• 金额: --
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3733583
• 关键词: Schwann cells; acrylamides; axon; blood brain barrier; cellular pathology; diphosphonate; electron microscopy; fiber cell; fluoresceins; ganglions; isoniazid; laboratory rat; macrophage; membrane permeability; molecular pathology; myelin; nervous system regeneration; neural degeneration; neurons; neurotoxins; peripheral nervous system; peripheral nervous system disorders; ricin; sciatic nerve; tellurium

There are many toxicants that cause peripheral neuropathy, yet the mechanisms by which these toxicants produce demyelination or axonal degeneration in the peripheral nervous system (PNS) are poorly understood. Toxicant-induced injury in the PNS results not only in a variety of regressive and reactive changes in the target cells, but also causes breakdown of the blood-nerve barrier (BNB), an influx of macrophages into nerve for the catabolism of myelin an axons, and a variety of reactive changes in other cell types associated with the target cells. This section within the Program Project focuses on the role of this BNB breakdown in the pathogenesis of toxicant-induced neuropathy. We have found that BNB breakdown may persist for long periods in certain toxic neuropathies and may be associated with increased vulnerability of the nerve fibers to further toxicant-induced injury. We will work with two models, ricin neuropathy and unilateral dorsal-root ganglionectomy, in which we can selectively produce BNB breakdown limited to one sciatic nerve. With these models of localized BNB breakdown, we will test the hypothesis that an altered BNB increases the vulnerability of nerve fibers to toxic injury. Using toxicants that selectively target specific structures within the PNS, we will determine if chronic BNB breakdown leads to increased vulnerability of nerve fibers to toxicant-induced Schwann-cell injury, myelin injury, or axonal injury. We will also test the hypothesis that restitution of the BNB over the course of toxic neuropathy requires axonal regeneration or remyelination. The ability of the axonal regeneration following nerve- crush-induced axonal degeneration and the remyelination following tellurium-induced demyelination to restore the BNB in rats with persistent barrier breakdown due to intraneural ricin injection or unilateral dorsal- root ganglionectomy will be assessed. The third hypothesis to be tested is that the reactions of the BNB and Schwann cells to nerve-fiber injury are determined in part by the influx of macrophages in nerve that occurs after onset of neuropathy. The effects of macrophages on the temporal course of BNB breakdown, Schwann-cell metabolism, axonal regeneration and remyelination will be assessed after selectively ablating macrophages with dichloromethylene diphosphonate (clodronate)-containing mannose liposomes in rats with tellurium-induced demyelinating neuropathy, ricin-induced axonal degeneration, and a nerve-crush model that permits axonal regeneration and remyelination.

有许多毒物会导致周围神经病变，但 这些毒物产生脱髓鞘或轴突的机制 人们对周围神经系统(PNS)的变性知之甚少。 毒物性损伤在三叉神经节不仅导致多种 靶细胞的退行性和反应性变化，也会引起 血-神经屏障(BNB)的破坏，巨噬细胞涌入 神经对髓鞘的分解代谢为轴突，并有多种反应 与目标单元格关联的其他单元格类型的更改。这一节 在计划范围内，项目重点关注此BNB细分在 毒物性神经病的发病机制。我们发现BNB 在某些中毒性神经病中，崩溃可能会持续很长时间 可能与神经纤维对 进一步的毒物引起的伤害。我们将使用两种模型：蓖麻毒素 神经病变和单侧背根神经节切除术，在这些手术中，我们可以 选择性地产生仅限于一条坐骨神经的BNB故障。有了这些 局域BNB击穿模型，我们将检验假设 BNB的改变增加了神经纤维对毒性损伤的脆弱性。 使用选择性地针对PNS内特定结构的毒物， 我们将确定慢性BNB故障是否会导致脆弱性增加 神经纤维与毒物诱导的雪旺细胞损伤、髓鞘损伤或 轴突损伤。我们还将检验这样一种假设，即恢复 中毒性神经病病程中的BNB需要轴突再生或 重新髓鞘形成。神经后轴突再生的能力- 挤压致轴突变性和随后的再髓鞘形成 碲脱髓鞘对持续性高血压大鼠血脑屏障功能的影响 神经内注射蓖麻毒素或单侧背侧导致屏障破坏- 将评估根性神经节切除术。需要检验的第三个假设是 BNB和Schwann细胞对神经纤维损伤的反应是 部分是由巨噬细胞在神经中的流入决定的 神经病的发作。巨噬细胞在脑缺血时变过程中的作用 BNB分解、雪旺细胞代谢、轴突再生和 在选择性地消融巨噬细胞后，将评估重新髓鞘形成 二氯亚甲基二膦(氯屈膦)甘露糖脂质体 在碲诱导的脱髓鞘神经病大鼠中，蓖麻毒素诱导 轴突变性和允许轴突的神经挤压模型 再生和再髓鞘形成。