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The nasal pathway for drug delivery to the central nervous system: Studies with protein tracers and therapeutics.

机译：鼻腔药物向中枢神经系统的输送途径：蛋白质示踪剂和治疗剂的研究。

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摘要

This thesis investigated the transport of protein tracers and therapeutics into the CNS following intranasal administration. We hypothesized that transport within or along olfactory sensory neurons or other neuronal elements located within the nasal passages would allow an effective circumvention of the blood-brain barrier.; The capacity for uptake and transport of select tracer proteins along olfactory sensory neurons was first determined in anesthetized rats following intranasal administration. The 62 kDa tracer wheat germ agglutinin-horseradish peroxidase was transported into the CNS where it concentrated in the olfactory nerve and glomerular layers of the olfactory bulb resulting in a mean olfactory bulb concentration of 140 ± 14 nM.; The CNS delivery of insulin-like growth factor-1 (IGF-1), a 7.65 kDa protein neurotrophic factor, was then demonstrated in anesthetized rats following intranasal administration. IGF-1 appeared to utilize two routes of rapid (30 minutes) entry into the CNS: one associated with the peripheral olfactory system connecting the nasal passages and olfactory bulb/rostral brain regions (olfactory bulb, 5.0 ± 0.96 nM) and the other associated with the peripheral trigeminal system (trigeminal nerve, 170 ± 61 nM) connecting the nasal passages and brain stem/spinal cord regions (cervical spinal cord, 3.0 ± 1.2 nM). Enhanced tyrosine phosphorylation of IGF-1 signaling proteins was also demonstrated in IGF-1 treated animals as compared with controls, providing evidence that IGF-1 reached the CNS in a biologically active form.; Finally, the CNS delivery of interferon-β1b, a 20 kDa protein cytokine was demonstrated in anesthetized cynomolgus monkeys following intranasal administration. The distribution observed within the CNS was again consistent with two routes of rapid (60 minutes) entry from the nasal passages, with highest levels observed in the olfactory bulbs (17 ± 2.1 nM) and the trigeminal nerves (16 ± 2.2 nM). Other CNS concentrations ranged from approximately 100–300 pM, with highest levels observed in components of the basal ganglia.; The results presented in this thesis demonstrate the existence of a rapid, extracellular pathway connecting the nasal passages with the CNS and suggest intranasal administration of protein drugs may offer a viable, noninvasive CNS drug delivery strategy.
机译：本文研究了鼻内给药后蛋白质示踪剂和治疗剂向中枢神经系统的转运。我们假设在鼻通道内的嗅觉感觉神经元或其他神经元内或沿它们的运输将允许有效地规避血脑屏障。鼻内给药后，首先在麻醉的大鼠中确定沿着嗅觉感觉神经元摄取和选择示踪蛋白的能力。将62 kDa示踪小麦胚芽凝集素-辣根过氧化物酶转运到CNS，在其中集中在嗅球的嗅神经和肾小球层，平均嗅球浓度为140±14 nM。鼻内给药后，在麻醉的大鼠中证明了胰岛素样生长因子-1（IGF-1）（一种7.65 kDa的蛋白神经营养因子）的中枢神经系统递送。 IGF-1似乎利用了两种快速（<30分钟）进入中枢神经系统的途径：一种与连接鼻腔通道和嗅球/鼻侧大脑区域（嗅球，5.0±0.96 nM）的周围嗅觉系统相关，另一条途径与连接鼻道和脑干/脊髓区域（颈脊髓，3.0±1.2 nM）的周围三叉神经系统（三叉神经，170±61 nM）相关。与对照相比，在IGF-1处理的动物中还证实了IGF-1信号蛋白的酪氨酸磷酸化增强，提供了IGF-1以生物活性形式到达CNS的证据。最后，在鼻内给药后，在麻醉的食蟹猕猴中证实了CNS传递干扰素-β1b（一种20 kDa的蛋白细胞因子）。在CNS内观察到的分布再次与从鼻腔通道快速进入（<60分钟）的两条路径一致，在嗅球（17±2.1 nM）和三叉神经（16±2.2 nM）中观察到最高水平。其他中枢神经系统的浓度范围约为100-300 pM，在基底神经节的成分中观察到最高水平。本论文提出的结果证明了鼻腔通道与中枢神经系统之间存在快速，细胞外通路的存在，并暗示鼻内给药蛋白药物可能提供可行的，无创的中枢神经系统药物递送策略。

著录项

  • 作者

    Thorne, Robert Gary.;

  • 作者单位

    University of Minnesota.;

  • 授予单位 University of Minnesota.;
  • 学科 Biology Neuroscience.; Health Sciences Pharmacy.
  • 学位 Ph.D.
  • 年度 2002
  • 页码 296 p.
  • 总页数 296
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 神经科学;药剂学;
  • 关键词

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