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

M. J. Stenslik; A. Evans; F. Pomerleau; R. Weeks; P. Huettl; E. Foreman; J. Turchan-Cholewo; A. Andersen; W. A. Cass; Z. Zhang; R. C. Grondin; D. M. Gash; G. A. Gerhardt; L. H. Bradley

doi:10.1016/j.jneumeth.2018.03.006

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

M. J. Stenslik, A. Evans, F. Pomerleau, R. Weeks, P. Huettl, E. Foreman, J. Turchan-Cholewo, A. Andersen, W. A. Cass, Z. Zhang, R. C. Grondin, D. M. Gash, G. A. Gerhardt, L. H. Bradley

Research output: Contribution to journal › Article › peer-review

10 Scopus citations

Abstract

Background: To determine if the intranasal delivery of neuroactive compounds is a viable, long-term treatment strategy for progressive, chronic neurodegenerative disorders, such as Parkinson's disease (PD), intranasal methodologies in preclinical models comparable to humans are needed. New method: We developed a methodology to evaluate the repeated intranasal delivery of neuroactive compounds on the non-human primate (NHP) brain, without the need for sedation. We evaluated the effects of the neuroactive peptide, DNSP-11 following repeated intranasal delivery and dose-escalation over the course of 10-weeks in Rhesus macaques. This approach allowed us to examine striatal target engagement, safety and tolerability, and brain distribution following a single ¹²⁵ I-labeled DNSP-11 dose. Results: Our initial data support that repeated intranasal delivery and dose-escalation of DNSP-11 resulted in bilateral, striatal target engagement based on neurochemical changes in dopamine (DA) metabolites-without observable, adverse behavioral effects or weight loss in NHPs. Furthermore, a ¹²⁵ I-labeled DNSP-11 study illustrates diffuse rostral to caudal distribution in the brain including the striatum-our target region of interest. Comparison with existing methods: The results of this study are compared to our experiments in normal and 6-OHDA lesioned rats, where DNSP-11 was repeatedly delivered intranasally using a micropipette with animals under light sedation. Conclusions: The results from this proof-of-concept study support the utility of our repeated intranasal dosing methodology in awake Rhesus macaques, to evaluate the effects of neuroactive compounds on the NHP brain. Additionally, results indicate that DNSP-11 can be safely and effectively delivered intranasally in MPTP-treated NHPs, while engaging the DA system.

Original language	English
Pages (from-to)	30-40
Number of pages	11
Journal	Journal of Neuroscience Methods
Volume	303
DOIs	https://doi.org/10.1016/j.jneumeth.2018.03.006
State	Published - Jun 1 2018

Bibliographical note

Funding Information:
This project was supported by funds from NINDS : ( NS039787 : all; NS060924 : L.H.B.), NCATS ( UL1TR000117 : L.H.B., G.A.G.), NIA ( AG013494 : D.M.G., G.A.G.; T32-AG000242 : J.T-C., M.J.S.), Kentucky INBRE Pilot (NCRR 5P20RR016481-12 , NIGMS 8P20GM103436-12 : L.H.B), NIH COBRE pilot (NCRR P20RR20171 : L.H.B), Endowed Chair Funds (D.M.G.), Dupree Trust (G.A.G), Estate of Laura C. Miller (L.H.B), PhRMA Foundation (L.H.B.), Columbus Foundation (L.H.B.). The content is solely the responsibility of the authors and does not represent the official views of the NIH. The sponsors had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Publisher Copyright:
© 2018 Elsevier B.V.

Keywords

Drug delivery
Intranasal
Parkinson's disease
Peptide

ASJC Scopus subject areas

General Neuroscience

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.jneumeth.2018.03.006

Cite this

Stenslik, M. J., Evans, A., Pomerleau, F., Weeks, R., Huettl, P., Foreman, E., Turchan-Cholewo, J., Andersen, A., Cass, W. A., Zhang, Z., Grondin, R. C., Gash, D. M., Gerhardt, G. A., & Bradley, L. H. (2018). Methodology and effects of repeated intranasal delivery of DNSP-11 in awake Rhesus macaques. Journal of Neuroscience Methods, 303, 30-40. https://doi.org/10.1016/j.jneumeth.2018.03.006

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abstract = " Background: To determine if the intranasal delivery of neuroactive compounds is a viable, long-term treatment strategy for progressive, chronic neurodegenerative disorders, such as Parkinson's disease (PD), intranasal methodologies in preclinical models comparable to humans are needed. New method: We developed a methodology to evaluate the repeated intranasal delivery of neuroactive compounds on the non-human primate (NHP) brain, without the need for sedation. We evaluated the effects of the neuroactive peptide, DNSP-11 following repeated intranasal delivery and dose-escalation over the course of 10-weeks in Rhesus macaques. This approach allowed us to examine striatal target engagement, safety and tolerability, and brain distribution following a single 125 I-labeled DNSP-11 dose. Results: Our initial data support that repeated intranasal delivery and dose-escalation of DNSP-11 resulted in bilateral, striatal target engagement based on neurochemical changes in dopamine (DA) metabolites-without observable, adverse behavioral effects or weight loss in NHPs. Furthermore, a 125 I-labeled DNSP-11 study illustrates diffuse rostral to caudal distribution in the brain including the striatum-our target region of interest. Comparison with existing methods: The results of this study are compared to our experiments in normal and 6-OHDA lesioned rats, where DNSP-11 was repeatedly delivered intranasally using a micropipette with animals under light sedation. Conclusions: The results from this proof-of-concept study support the utility of our repeated intranasal dosing methodology in awake Rhesus macaques, to evaluate the effects of neuroactive compounds on the NHP brain. Additionally, results indicate that DNSP-11 can be safely and effectively delivered intranasally in MPTP-treated NHPs, while engaging the DA system.",

keywords = "Drug delivery, Intranasal, Parkinson's disease, Peptide",

author = "Stenslik, {M. J.} and A. Evans and F. Pomerleau and R. Weeks and P. Huettl and E. Foreman and J. Turchan-Cholewo and A. Andersen and Cass, {W. A.} and Z. Zhang and Grondin, {R. C.} and Gash, {D. M.} and Gerhardt, {G. A.} and Bradley, {L. H.}",

note = "Funding Information: This project was supported by funds from NINDS : ( NS039787 : all; NS060924 : L.H.B.), NCATS ( UL1TR000117 : L.H.B., G.A.G.), NIA ( AG013494 : D.M.G., G.A.G.; T32-AG000242 : J.T-C., M.J.S.), Kentucky INBRE Pilot (NCRR 5P20RR016481-12 , NIGMS 8P20GM103436-12 : L.H.B), NIH COBRE pilot (NCRR P20RR20171 : L.H.B), Endowed Chair Funds (D.M.G.), Dupree Trust (G.A.G), Estate of Laura C. Miller (L.H.B), PhRMA Foundation (L.H.B.), Columbus Foundation (L.H.B.). The content is solely the responsibility of the authors and does not represent the official views of the NIH. The sponsors had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: {\textcopyright} 2018 Elsevier B.V.",

year = "2018",

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doi = "10.1016/j.jneumeth.2018.03.006",

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Stenslik, MJ, Evans, A, Pomerleau, F, Weeks, R, Huettl, P, Foreman, E, Turchan-Cholewo, J, Andersen, A, Cass, WA , Zhang, Z , Grondin, RC, Gash, DM, Gerhardt, GA & Bradley, LH 2018, 'Methodology and effects of repeated intranasal delivery of DNSP-11 in awake Rhesus macaques', Journal of Neuroscience Methods, vol. 303, pp. 30-40. https://doi.org/10.1016/j.jneumeth.2018.03.006

TY - JOUR

T1 - Methodology and effects of repeated intranasal delivery of DNSP-11 in awake Rhesus macaques

AU - Stenslik, M. J.

AU - Evans, A.

AU - Pomerleau, F.

AU - Weeks, R.

AU - Huettl, P.

AU - Foreman, E.

AU - Turchan-Cholewo, J.

AU - Andersen, A.

AU - Cass, W. A.

AU - Zhang, Z.

AU - Grondin, R. C.

AU - Gash, D. M.

AU - Gerhardt, G. A.

AU - Bradley, L. H.

N1 - Funding Information: This project was supported by funds from NINDS : ( NS039787 : all; NS060924 : L.H.B.), NCATS ( UL1TR000117 : L.H.B., G.A.G.), NIA ( AG013494 : D.M.G., G.A.G.; T32-AG000242 : J.T-C., M.J.S.), Kentucky INBRE Pilot (NCRR 5P20RR016481-12 , NIGMS 8P20GM103436-12 : L.H.B), NIH COBRE pilot (NCRR P20RR20171 : L.H.B), Endowed Chair Funds (D.M.G.), Dupree Trust (G.A.G), Estate of Laura C. Miller (L.H.B), PhRMA Foundation (L.H.B.), Columbus Foundation (L.H.B.). The content is solely the responsibility of the authors and does not represent the official views of the NIH. The sponsors had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: © 2018 Elsevier B.V.

PY - 2018/6/1

Y1 - 2018/6/1

N2 - Background: To determine if the intranasal delivery of neuroactive compounds is a viable, long-term treatment strategy for progressive, chronic neurodegenerative disorders, such as Parkinson's disease (PD), intranasal methodologies in preclinical models comparable to humans are needed. New method: We developed a methodology to evaluate the repeated intranasal delivery of neuroactive compounds on the non-human primate (NHP) brain, without the need for sedation. We evaluated the effects of the neuroactive peptide, DNSP-11 following repeated intranasal delivery and dose-escalation over the course of 10-weeks in Rhesus macaques. This approach allowed us to examine striatal target engagement, safety and tolerability, and brain distribution following a single 125 I-labeled DNSP-11 dose. Results: Our initial data support that repeated intranasal delivery and dose-escalation of DNSP-11 resulted in bilateral, striatal target engagement based on neurochemical changes in dopamine (DA) metabolites-without observable, adverse behavioral effects or weight loss in NHPs. Furthermore, a 125 I-labeled DNSP-11 study illustrates diffuse rostral to caudal distribution in the brain including the striatum-our target region of interest. Comparison with existing methods: The results of this study are compared to our experiments in normal and 6-OHDA lesioned rats, where DNSP-11 was repeatedly delivered intranasally using a micropipette with animals under light sedation. Conclusions: The results from this proof-of-concept study support the utility of our repeated intranasal dosing methodology in awake Rhesus macaques, to evaluate the effects of neuroactive compounds on the NHP brain. Additionally, results indicate that DNSP-11 can be safely and effectively delivered intranasally in MPTP-treated NHPs, while engaging the DA system.

AB - Background: To determine if the intranasal delivery of neuroactive compounds is a viable, long-term treatment strategy for progressive, chronic neurodegenerative disorders, such as Parkinson's disease (PD), intranasal methodologies in preclinical models comparable to humans are needed. New method: We developed a methodology to evaluate the repeated intranasal delivery of neuroactive compounds on the non-human primate (NHP) brain, without the need for sedation. We evaluated the effects of the neuroactive peptide, DNSP-11 following repeated intranasal delivery and dose-escalation over the course of 10-weeks in Rhesus macaques. This approach allowed us to examine striatal target engagement, safety and tolerability, and brain distribution following a single 125 I-labeled DNSP-11 dose. Results: Our initial data support that repeated intranasal delivery and dose-escalation of DNSP-11 resulted in bilateral, striatal target engagement based on neurochemical changes in dopamine (DA) metabolites-without observable, adverse behavioral effects or weight loss in NHPs. Furthermore, a 125 I-labeled DNSP-11 study illustrates diffuse rostral to caudal distribution in the brain including the striatum-our target region of interest. Comparison with existing methods: The results of this study are compared to our experiments in normal and 6-OHDA lesioned rats, where DNSP-11 was repeatedly delivered intranasally using a micropipette with animals under light sedation. Conclusions: The results from this proof-of-concept study support the utility of our repeated intranasal dosing methodology in awake Rhesus macaques, to evaluate the effects of neuroactive compounds on the NHP brain. Additionally, results indicate that DNSP-11 can be safely and effectively delivered intranasally in MPTP-treated NHPs, while engaging the DA system.

KW - Drug delivery

KW - Intranasal

KW - Parkinson's disease

KW - Peptide

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ER -

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

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