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首页> 外文学位 >Influence of neuroarchitecture on infusate distribution: Applications for a novel epilepsy therapy.
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Influence of neuroarchitecture on infusate distribution: Applications for a novel epilepsy therapy.

机译：神经体系结构对输注液分布的影响：新型癫痫治疗的应用。

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摘要

Temporal Lobe Epilepsy (TLE) is the most common partial-onset epilepsy and often refractory to antiepileptic drugs. Despite pharmacological advances in epilepsy treatment, seizures cannot be controlled in many patients because current drugs do not target causes of the disorder. Convection-enhanced delivery (CED), a local drug delivery technique, has the potential to deliver novel therapeutics while avoiding systemic toxicity and blood-brain-barrier limitations. However, the efficacy of CED depends on appropriate tissue targeting, which requires a deeper understanding of the effect of neuroarchitecture on interstitial transport. To investigate the influence of microanatomy on CED, the volume and pattern of infusate distribution was examined after varying the site of infusion, integrity of structure, and compound infused. Gd-albumin, a magnetic resonance (MR) contrast agent, was infused into two sites in normal rat hippocampi. Infusions were repeated in animals injured by an episode of status epilepticus (SE), a prolonged seizure known to cause neuronal damage and edema in the hippocampus and associated structures. Infusions in injured animals were implemented 24 hours post-SE, as prophylactic treatment has the potential to reduce structural damage, diminish associated cognitive impairment, or prevent epileptogenesis. Infusions were also implemented at 60 days post-SE, during chronic TLE. High-resolution T1- and T2-relaxation-weighted MR images were acquired at 11.1 Tesla in vivo to visualize Gd-albumin distribution and morphological changes, respectively. Histological analysis was performed to validate infusions and characterize injury at higher resolution. Finally, information gained from infusion studies with Gd-albumin was used to guide proof-of-principle studies with neural stem cells and viral vectors. Infusions in normal hippocampi spread along preferential paths parallel to fiber directions and within fissures, with limited penetration across densely-packed cell layers. Infusions in injured hippocampi followed similar patterns, but resulted in significantly larger distribution volumes that correlated with increased injury severity. Therapeutic carrier systems exhibited comparable spatial characteristics to Gd-albumin infusions, but were also influenced by cell interactions. These studies show anisotropic hippocampal architecture plays a leading role in the distribution of infusate by CED. This information can be applied to improve targeting guidelines, incorporated into injury-specific computation models, and considered in treatment strategies involving novel therapeutic agents.
机译：颞叶癫痫（TLE）是最常见的部分发作性癫痫，通常对抗癫痫药难治。尽管癫痫治疗在药理学方面取得了进步，但由于目前的药物并未针对这种疾病的病因，因此许多患者仍无法控制癫痫发作。对流增强输送（CED）是一种局部药物输送技术，它有可能在提供新疗法的同时避免系统毒性和血脑屏障限制。然而，CED的疗效取决于适当的组织靶向，这需要对神经结构对间质运输的影响有更深入的了解。为了研究显微解剖学对CED的影响，在改变输注部位，结构完整性和输注化合物后，检查了输注液的体积和模式。 Gd-白蛋白，一种磁共振（MR）造影剂，被注入正常大鼠海马体的两个部位。在因癫痫持续状态（SE）发作而受伤的动物中重复输注，这种癫痫发作是一种长时间的癫痫发作，已知会引起海马及其相关结构的神经元损伤和水肿。在SE后24小时对受伤动物进行输注，因为预防性治疗可以减少结构性损伤，减少相关的认知障碍或预防癫痫发生。在慢性TLE期间，SE后60天也进行了输注。在11.1特斯拉体内获取高分辨率的T1和T2松弛加权MR图像，以分别显示Gd-白蛋白分布和形态变化。进行组织学分析以验证输注并以更高的分辨率表征损伤。最后，从Gd-白蛋白输注研究中获得的信息被用于指导神经干细胞和病毒载体的原理验证研究。正常海马中的输注沿着平行于纤维方向并在裂隙内的优先路径传播，穿过密集堆积的细胞层的渗透性有限。在受伤的海马中输注遵循相似的模式，但导致分布体积明显增大，这与损伤严重程度增加相关。治疗性载体系统显示出与Gd-白蛋白输注相当的空间特征，但也受到细胞相互作用的影响。这些研究表明，各向异性海马结构在CED的输注液分布中起着主导作用。该信息可用于改进靶向指南，并结合到针对损伤的计算模型中，并在涉及新型治疗剂的治疗策略中加以考虑。

著录项

  • 作者

    Kantorovich, Svetlana.;

  • 作者单位

    University of Florida.;

  • 授予单位 University of Florida.;
  • 学科 Biology Neuroscience.;Engineering Biomedical.;Biology Physiology.
  • 学位 Ph.D.
  • 年度 2012
  • 页码 151 p.
  • 总页数 151
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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