Methodology and effects of repeated intranasal delivery of DNSP-11 in a rat model of Parkinson's disease


Mallory J. Stenslik, Lisa F. Potts, James W.H. Sonne, Wayne A. Cass, Jadwiga Turchan-Cholewo, Francois Pomerleau, Peter Huettl, Yi Ai, Don M. Gash, Greg A. Gerhardt, Luke H. Bradley


Background To circumvent the challenges associated with delivering large compounds directly to the brain for the treatment of Parkinson's disease (PD), non-invasive procedures utilizing smaller molecules with protective and/or restorative actions on dopaminergic neurons are needed.
New method We developed a methodology for evaluating the effects of a synthetic neuroactive peptide, DNSP-11, on the nigrostriatal system using repeated intranasal delivery in both normal and a unilateral 6-hydroxydopamine (6-OHDA) lesion rat model of PD.
Results Normal rats repeatedly administered varying doses of DNSP-11 intranasally for 3 weeks exhibited a significant increase in dopamine (DA) turnover in both the striatum and substantia nigra (SN) at 300 μg, suggestive of a stimulative effect of the dopaminergic system. Additionally, a protective effect was observed following repeated intranasal administration in 6-OHDA lesioned rats, as suggested by: a significant decrease in d-amphetamine-induced rotation at 2 weeks; a decrease in DA turnover in the lesioned striatum; and an increased sparing of tyrosine hydroxylase (TH) positive neurons in a specific sub-region of the lesioned substantia nigra pars compacta. Finally, tracer studies showed 125I-DNSP-11 distributed diffusely throughout the brain, including the striatum and SN, as quickly as 30 min after a single intranasal dose.
Comparison with existing methods The results of bilateral intranasal administration of DNSP-11 are compared to our unilateral single infusion studies to the brain in rats.
Conclusions These studies support that DNSP-11 can be delivered intranasally and maintain its neuroactive properties in both normal rats and in a unilateral 6-OHDA rat model of PD.