Liu Fangchao, Zhang Yanhua, Schafer Janelle, Mao Guangzhao, Goshgarian Harry G
Departments of Chemical Engineering and Materials Science, Wayne State University, Detroit, Michagan, USA.
Department of Ophthalmology, Visual and Anatomical Sciences (OVAS), School of Medicine, Wayne State University, Detroit, Michagan, USA.
J Spinal Cord Med. 2019 Nov;42(6):725-734. doi: 10.1080/10790268.2019.1577058. Epub 2019 Mar 7.
Following a spinal cord hemisection at the second cervical segment the ipsilateral hemidiaphragm is paralyzed due to the disruption of the rostral ventral respiratory group (rVRG) axons descending to the ipsilateral phrenic motoneurons (PN). Systemically administered theophylline activates a functionally latent crossed phrenic pathway (CPP) which decussates caudal to the hemisection and activates phrenic motoneurons ipsilateral to the hemisection. The result is return of function to the paralyzed hemidiaphragm. Unfortunately, in humans, systemically administered theophylline at a therapeutic dose produces many unwanted side effects. A tripartite nanoconjugate was synthesized in which theophylline was coupled to a neuronal tracer, wheat germ agglutinin conjugated to horseradish peroxidase (WGA-HRP), using gold nanoparticles as the coupler. Following intradiaphragmatic injection of the nanoconjugate, WGA-HRP selectively targets the theophylline-bound nanoconjugate to phrenic motoneurons initially, followed by neurons in the rVRG by retrograde transsynaptic transport. (N/A) (N/A) Immunostaining, Electromyography (EMG). Delivery of the theophylline-coupled nanoconjugate to the nuclei involved in respiration induces a return of respiratory activity as detected by EMG of the diaphragm and a modest return of phrenic nerve activity. In addition to the modest return of phrenic nerve activity, there were many difficulties using the theophylline nanoconjugate because of its chemical instability, which suggests that the theophylline nanoconjugate should not be developed for clinical use as explained herein.
在第二颈椎节段进行脊髓半横断后，同侧半膈会因降至上同侧膈运动神经元（PN）的嘴侧腹侧呼吸组（rVRG）轴突中断而麻痹。全身给予氨茶碱可激活一条功能上潜伏的交叉膈神经通路（CPP），该通路在半横断下方交叉，并激活半横断同侧的膈运动神经元。结果是麻痹的半膈恢复功能。不幸的是，在人类中，以治疗剂量全身给予氨茶碱会产生许多不良副作用。合成了一种三方纳米共轭物，其中氨茶碱与一种神经元示踪剂——与辣根过氧化物酶偶联的麦胚凝集素（WGA-HRP）偶联，使用金纳米颗粒作为偶联剂。在膈内注射纳米共轭物后，WGA-HRP最初将与氨茶碱结合的纳米共轭物选择性地靶向膈运动神经元，随后通过逆行跨突触运输靶向rVRG中的神经元。（无）（无）免疫染色、肌电图（EMG）。将与氨茶碱偶联的纳米共轭物递送至参与呼吸的核团，可诱导膈肌EMG检测到的呼吸活动恢复，以及膈神经活动适度恢复。除了膈神经活动适度恢复外，使用氨茶碱纳米共轭物还存在许多困难，因为其化学稳定性差，这表明如本文所述，氨茶碱纳米共轭物不应开发用于临床。
