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: 6106040
• 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
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-20 至 1998-09-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6106040
• 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; nerve; 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.

引起周围神经病变的毒物有很多，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）的退化知之甚少。 毒物引起的三七总皂甙损伤不仅会导致多种 靶细胞的退行性和反应性变化，但也会导致 血神经屏障（BNB）破裂，巨噬细胞大量涌入 神经负责髓磷脂和轴突的分解代谢，以及各种反应性的 与靶细胞相关的其他细胞类型的变化。 本节 该计划项目的重点是 BNB 细分在 毒物引起的神经病的发病机制。 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 可能与神经纤维的脆弱性增加有关 进一步的毒物引起的损伤。 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，我们可以 选择性地产生仅限于一根坐骨神经的 BNB 分解。 有了这些 局部 BNB 崩溃模型中，我们将检验以下假设： 改变的 BNB 增加了神经纤维对毒性损伤的脆弱性。 使用选择性针对三七总皂甙内特定结构的毒物， 我们将确定 BNB 长期崩溃是否会导致脆弱性增加 神经纤维对毒物引起的雪旺细胞损伤、髓磷脂损伤或 轴突损伤。 我们还将检验恢复原状的假设 中毒性神经病过程中的 BNB 需要轴突再生或 髓鞘再生。 神经后轴突再生的能力 挤压引起的轴突变性和随后的髓鞘再生 碲诱导脱髓鞘恢复大鼠持续性 BNB 由于神经内注射蓖麻毒素或单侧背侧神经屏障破坏 将评估根神经节切除术。 要检验的第三个假设是 BNB 和雪旺细胞对神经纤维损伤的反应是 部分由巨噬细胞在神经中的流入决定 神经病的发作。 巨噬细胞对时间过程的影响 BNB 分解、雪旺细胞代谢、轴突再生和 选择性消融巨噬细胞后将评估髓鞘再生 含二氯亚甲基二膦酸盐（氯膦酸盐）的甘露糖脂质体 在患有碲诱发的脱髓鞘神经病、蓖麻毒素诱发的大鼠中 轴突变性，以及允许轴突变性的神经挤压模型 再生和髓鞘再生。