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

•DNSP-11 was delivered intranasally in sedated normal rats and 6-OHDA lesioned rats.•Repeated DNSP-11 delivery affects dopamine turnover in normal and lesioned rats.•Intranasal DNSP-11 administration increases TH+ neurons in 6-OHDA lesioned rats.•Repeated DNSP-11 delivery reduced drug-induced rotation in unilateral lesioned rats.•DNSP-11 is traced throughout the brain and CSF after a single intranasal dose.

BackgroundTo 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 methodWe 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.ResultsNormal 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 (SNpc). 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 methodsThe results of bilateral intranasal administration of DNSP-11 are compared to our unilateral single infusion studies to the brain in rats.ConclusionsThese 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.