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

Abstract

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 minutes 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.

Growth factors and hormones pro‐peptides: the unexpected adventures of the BDNF prodomain

“…; Stenslik et al . ). DNPSs and mature GDNF promote similar actions in neurons, in contrast to pBDNF and mBDNF which display opposing effects.…”

“…The significance of these findings is relative as the endogenous NGF prodomain has not been found yet in neural tissues or primary neurons. Apart from the neurotrophin family, another growth factor prodomain has been tested for activity: fragments of the glial cell line-derived neurotrophic factor (GDNF) prodomain, carrying the term dopamine neuron stimulating peptides (DNSP), has also been shown to be active as they display robust neurotrophic actions similar to mature GDNF (Bradley et al 2010;Stenslik et al 2015). DNPSs and mature GDNF promote similar actions in neurons, in contrast to pBDNF and mBDNF which display opposing effects.…”

Small Molecules and Peptides Targeting Glial Cell Line-Derived Neurotrophic Factor Receptors for the Treatment of Neurodegeneration

“…Therefore, this peptide can be promising for the treatment of late-stage PD patients. In this study, DNSP-11 was delivered directly into the brain, and it is unknown if it can penetrate through the blood-brain barrier and reach target neurons if injected systemically [94], but it was speculated that the systemic delivery of DNSP-11 will be unsuccessful due to a short half-life of the peptide in rat plasma (<12 min) [95]. However, it was shown that DNSP-11 retains its neuroprotective activity in the dopamine system in a 6-OHDA model of PD when delivered intranasally [95].…”

“…DNSP-11 seems to be a promising alternative for further preclinical development, as it is relatively small. The receptor and signaling mechanism for DNSP-11 is yet to be determined [94], as well as the delivery strategy, as it is unlikely to produce sufficient brain exposure upon systemic delivery due to its short half-life [95]. Possibly, it can be delivered intranasally [95].…”

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

“…Therefore, new avenues need to be examined that overcome challenges associated with delivering large MW compounds to the brain for the treatment of chronic, progressive neurodegenerative diseases and disorders [1, 2, 9]. One possible alternative strategy currently under investigation is the discovery and development of new neuroactive compounds [35–38] that can potentially be delivered to the CNS using non-invasive routes of administration, such as intranasal delivery [1, 39].…”