Department of Neuroscience and Brain Restoration Center, University of Kentucky College of Medicine, United States.
Department of Magnetic Resonance Imaging and Spectroscopy Center, University of Kentucky College of Medicine, United States.
J Neurosci Methods. 2018 Jun 1;303:30-40. doi: 10.1016/j.jneumeth.2018.03.006. Epub 2018 Mar 31.
To determine if the intranasal delivery of neuroactive compounds is a viable, long-term treatment strategy for progressive, chronic neurodegenerative disorders, such as Parkinson's disease (PD), intranasal methodologies in preclinical models comparable to humans are needed.
We developed a methodology to evaluate the repeated intranasal delivery of neuroactive compounds on the non-human primate (NHP) brain, without the need for sedation. We evaluated the effects of the neuroactive peptide, DNSP-11 following repeated intranasal delivery and dose-escalation over the course of 10-weeks in Rhesus macaques. This approach allowed us to examine striatal target engagement, safety and tolerability, and brain distribution following a single I-labeled DNSP-11 dose.
Our initial data support that repeated intranasal delivery and dose-escalation of DNSP-11 resulted in bilateral, striatal target engagement based on neurochemical changes in dopamine (DA) metabolites-without observable, adverse behavioral effects or weight loss in NHPs. Furthermore, a I-labeled DNSP-11 study illustrates diffuse rostral to caudal distribution in the brain including the striatum-our target region of interest.
The results of this study are compared to our experiments in normal and 6-OHDA lesioned rats, where DNSP-11 was repeatedly delivered intranasally using a micropipette with animals under light sedation.
The results from this proof-of-concept study support the utility of our repeated intranasal dosing methodology in awake Rhesus macaques, to evaluate the effects of neuroactive compounds on the NHP brain. Additionally, results indicate that DNSP-11 can be safely and effectively delivered intranasally in MPTP-treated NHPs, while engaging the DA system.
为了确定鼻内递送神经活性化合物是否是一种可行的、长期的治疗策略，用于治疗进行性、慢性神经退行性疾病，如帕金森病（PD），需要在与人类相似的临床前模型中开发鼻内方法。
我们开发了一种方法来评估神经活性化合物在非人类灵长类动物（NHP）大脑中的重复鼻内给药，而无需镇静。我们评估了神经活性肽 DNSP-11 在恒河猴中经过 10 周的重复鼻内给药和剂量递增后的效果。这种方法使我们能够检查单次 I 标记的 DNSP-11 剂量后纹状体的靶标结合、安全性和耐受性以及大脑分布。
我们的初步数据支持，DNSP-11 的重复鼻内给药和剂量递增导致双侧纹状体靶标结合，基于多巴胺（DA）代谢物的神经化学变化-在 NHP 中没有观察到不良的行为影响或体重减轻。此外，I 标记的 DNSP-11 研究表明，大脑中的分布从颅前到尾侧扩散，包括纹状体-我们的目标感兴趣区域。
本研究的结果与我们在正常和 6-OHDA 损伤大鼠中的实验进行了比较，其中使用带有轻度镇静动物的微管在鼻内重复给予 DNSP-11。
这项概念验证研究的结果支持我们在清醒恒河猴中重复鼻内给药方法的实用性，以评估神经活性化合物对 NHP 大脑的影响。此外，结果表明，DNSP-11 可以在 MPTP 处理的 NHP 中安全有效地经鼻内给药，同时与 DA 系统结合。
