TY - JOUR
T1 - Methodology and effects of repeated intranasal delivery of DNSP-11 in a rat model of Parkinson's disease
AU - Stenslik, Mallory J.
AU - Potts, Lisa F.
AU - Sonne, James W.H.
AU - Cass, Wayne A.
AU - Turchan-Cholewo, Jadwiga
AU - Pomerleau, Francois
AU - Huettl, Peter
AU - Ai, Yi
AU - Gash, Don M.
AU - Gerhardt, Greg A.
AU - Bradley, Luke H.
N1 - Publisher Copyright:
© 2015 Elsevier B.V.
PY - 2015/8/5
Y1 - 2015/8/5
N2 - 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 300μg, 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 30min 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.
AB - 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 300μg, 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 30min 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.
KW - 6-Hydroxydopamine
KW - Intranasal administration
KW - Neurochemistry
KW - Neuroprotection
KW - Nigrostriatal pathway
KW - Peptide
UR - http://www.scopus.com/inward/record.url?scp=84931281998&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84931281998&partnerID=8YFLogxK
U2 - 10.1016/j.jneumeth.2015.05.006
DO - 10.1016/j.jneumeth.2015.05.006
M3 - Article
C2 - 25999268
AN - SCOPUS:84931281998
SN - 0165-0270
VL - 251
SP - 120
EP - 129
JO - Journal of Neuroscience Methods
JF - Journal of Neuroscience Methods
ER -