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

ABSTRACT: 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.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.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?g, 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 (125)I-DNSP-11 distributed diffusely throughout the brain, including the striatum and SN, as quickly as 30min after a single intranasal dose.The results of bilateral intranasal administration of DNSP-11 are compared to our unilateral single infusion studies to the brain in rats.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.

SUBMITTER: Stenslik MJ

PROVIDER: S-EPMC4500736 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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

Stenslik Mallory J MJ Potts Lisa F LF Sonne James W H JW Cass Wayne A WA Turchan-Cholewo Jadwiga J Pomerleau Francois F Huettl Peter P Ai Yi Y Gash Don M DM Gerhardt Greg A GA Bradley Luke H LH

Journal of neuroscience methods 20150518

<h4>Background</h4>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.<h4>New method</h4>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 unilater ...[more]

PMID: 25999268

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Project description:Parkinson's disease (PD) is characterized by a selective loss of dopamine (DA) neurons in the human midbrain causing motor dysfunctions. The exact mechanism behind dopaminergic cell death is still not completely understood and, so far, no cure or neuroprotective treatment for PD is available. Recent studies have brought attention to the variety of bioactive molecules produced by mesenchymal stem cells (MSCs), generally referred to as the secretome. Herein, we evaluated whether human MSCs-bone marrow derived (hBMSCs) secretome would be beneficial in a PD pre-clinical model, when compared directly with cell transplantation of hBMSCs alone. We used a 6-hydroxydpomanie (6-OHDA) rat PD model, and motor behavior was evaluated at different time points after treatments (1, 4, and 7 weeks). The impact of the treatments in the recovery of DA neurons was estimated by determining TH-positive neuronal densities in the substantia nigra and fibers in the striatum, respectively, at the end of the behavioral characterization. Furthermore, we determined the effect of the hBMSCs secretome on the neuronal survival of human neural progenitors in vitro, and characterized the secretome through proteomic-based approaches. This work demonstrates that the injection of hBMSCs secretome led to the rescue of DA neurons, when compared to transplantation of hBMSCs themselves, which can explain the recovery of secretome-injected animals' behavioral performance in the staircase test. Moreover, we observed that hBMSCs secretome induces higher levels of in vitro neuronal differentiation. Finally, the proteomic analysis revealed that hBMSCs secrete important exosome-related molecules, such as those related with the ubiquitin-proteasome and histone systems. Overall, this work provided important insights on the potential use of hBMSCs secretome as a therapeutic tool for PD, and further confirms the importance of the secreted molecules rather than the transplantation of hBMSCs for the observed positive effects. These could be likely through normalization of defective processes in PD, namely proteostasis or altered gene transcription, which lately can lead to neuroprotective effects.

Dataset Information

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

Publications

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

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