Methodology and effects of repeated intranasal delivery of DNSP-11 in awake Rhesus macaques

Publication date: Available online 31 March 2018
Source:Journal of Neuroscience Methods
Author(s): M.J. Stenslik, A. Evans, F. Pomerleau, R. Weeks, P. Huettl, E. Foreman, J. Turchan-Cholewo, A. Andersen, W.A. Cass, Z. Zhang, R.C. Grondin, D.M. Gash, G.A. Gerhardt, L.H. Bradley
BackgroundTo 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.New MethodWe 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 ¹²⁵I-labeled DNSP-11 dose.ResultsOur initial data support that repeated intranasal delivery and dose-escalation of DNSP-11 resulted in bilateral, striatal target engagement based on neurochemical changes in DA metabolites-without observable, adverse behavioral effects or weight loss in NHPs. Furthermore, a ¹²⁵I-labeled DNSP-11 study illustrates diffuse rostral to caudal distribution in the brain including the striatum-our target region of interest.Comparison with Existing MethodsThe 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.ConclusionsThe 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.



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