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Dopamine Neuron Stimulating Actions of a GDNF Propeptide

BACKGROUND: Neurotrophic factors, such as glial cell line-derived neurotrophic factor (GDNF), have shown great promise for protection and restoration of damaged or dying dopamine neurons in animal models and in some Parkinson's disease (PD) clinical trials. However, the delivery of neurotrophic...

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Autores principales: Bradley, Luke H., Fuqua, Josh, Richardson, April, Turchan-Cholewo, Jadwiga, Ai, Yi, Kelps, Kristen A., Glass, John D., He, Xiuquan, Zhang, Zhiming, Grondin, Richard, Littrell, O. Meagan, Huettl, Peter, Pomerleau, Francois, Gash, Don M., Gerhardt, Greg A.
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2841203/
https://www.ncbi.nlm.nih.gov/pubmed/20305789
http://dx.doi.org/10.1371/journal.pone.0009752
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author Bradley, Luke H.
Fuqua, Josh
Richardson, April
Turchan-Cholewo, Jadwiga
Ai, Yi
Kelps, Kristen A.
Glass, John D.
He, Xiuquan
Zhang, Zhiming
Grondin, Richard
Littrell, O. Meagan
Huettl, Peter
Pomerleau, Francois
Gash, Don M.
Gerhardt, Greg A.
author_facet Bradley, Luke H.
Fuqua, Josh
Richardson, April
Turchan-Cholewo, Jadwiga
Ai, Yi
Kelps, Kristen A.
Glass, John D.
He, Xiuquan
Zhang, Zhiming
Grondin, Richard
Littrell, O. Meagan
Huettl, Peter
Pomerleau, Francois
Gash, Don M.
Gerhardt, Greg A.
author_sort Bradley, Luke H.
collection PubMed
description BACKGROUND: Neurotrophic factors, such as glial cell line-derived neurotrophic factor (GDNF), have shown great promise for protection and restoration of damaged or dying dopamine neurons in animal models and in some Parkinson's disease (PD) clinical trials. However, the delivery of neurotrophic factors to the brain is difficult due to their large size and poor bio-distribution. In addition, developing more efficacious trophic factors is hampered by the difficulty of synthesis and structural modification. Small molecules with neurotrophic actions that are easy to synthesize and modify to improve bioavailability are needed. METHODS AND FINDINGS: Here we present the neurobiological actions of dopamine neuron stimulating peptide-11 (DNSP-11), an 11-mer peptide from the proGDNF domain. In vitro, DNSP-11 supports the survival of fetal mesencephalic neurons, increasing both the number of surviving cells and neuritic outgrowth. In MN9D cells, DNSP-11 protects against dopaminergic neurotoxin 6-hydroxydopamine (6-OHDA)-induced cell death, significantly decreasing TUNEL-positive cells and levels of caspase-3 activity. In vivo, a single injection of DNSP-11 into the normal adult rat substantia nigra is taken up rapidly into neurons and increases resting levels of dopamine and its metabolites for up to 28 days. Of particular note, DNSP-11 significantly improves apomorphine-induced rotational behavior, and increases dopamine and dopamine metabolite tissue levels in the substantia nigra in a rat model of PD. Unlike GDNF, DNSP-11 was found to block staurosporine- and gramicidin-induced cytotoxicity in nutrient-deprived dopaminergic B65 cells, and its neuroprotective effects included preventing the release of cytochrome c from mitochondria. CONCLUSIONS: Collectively, these data support that DNSP-11 exhibits potent neurotrophic actions analogous to GDNF, making it a viable candidate for a PD therapeutic. However, it likely signals through pathways that do not directly involve the GFRα1 receptor.
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spelling pubmed-28412032010-03-20 Dopamine Neuron Stimulating Actions of a GDNF Propeptide Bradley, Luke H. Fuqua, Josh Richardson, April Turchan-Cholewo, Jadwiga Ai, Yi Kelps, Kristen A. Glass, John D. He, Xiuquan Zhang, Zhiming Grondin, Richard Littrell, O. Meagan Huettl, Peter Pomerleau, Francois Gash, Don M. Gerhardt, Greg A. PLoS One Research Article BACKGROUND: Neurotrophic factors, such as glial cell line-derived neurotrophic factor (GDNF), have shown great promise for protection and restoration of damaged or dying dopamine neurons in animal models and in some Parkinson's disease (PD) clinical trials. However, the delivery of neurotrophic factors to the brain is difficult due to their large size and poor bio-distribution. In addition, developing more efficacious trophic factors is hampered by the difficulty of synthesis and structural modification. Small molecules with neurotrophic actions that are easy to synthesize and modify to improve bioavailability are needed. METHODS AND FINDINGS: Here we present the neurobiological actions of dopamine neuron stimulating peptide-11 (DNSP-11), an 11-mer peptide from the proGDNF domain. In vitro, DNSP-11 supports the survival of fetal mesencephalic neurons, increasing both the number of surviving cells and neuritic outgrowth. In MN9D cells, DNSP-11 protects against dopaminergic neurotoxin 6-hydroxydopamine (6-OHDA)-induced cell death, significantly decreasing TUNEL-positive cells and levels of caspase-3 activity. In vivo, a single injection of DNSP-11 into the normal adult rat substantia nigra is taken up rapidly into neurons and increases resting levels of dopamine and its metabolites for up to 28 days. Of particular note, DNSP-11 significantly improves apomorphine-induced rotational behavior, and increases dopamine and dopamine metabolite tissue levels in the substantia nigra in a rat model of PD. Unlike GDNF, DNSP-11 was found to block staurosporine- and gramicidin-induced cytotoxicity in nutrient-deprived dopaminergic B65 cells, and its neuroprotective effects included preventing the release of cytochrome c from mitochondria. CONCLUSIONS: Collectively, these data support that DNSP-11 exhibits potent neurotrophic actions analogous to GDNF, making it a viable candidate for a PD therapeutic. However, it likely signals through pathways that do not directly involve the GFRα1 receptor. Public Library of Science 2010-03-18 /pmc/articles/PMC2841203/ /pubmed/20305789 http://dx.doi.org/10.1371/journal.pone.0009752 Text en Bradley et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Bradley, Luke H.
Fuqua, Josh
Richardson, April
Turchan-Cholewo, Jadwiga
Ai, Yi
Kelps, Kristen A.
Glass, John D.
He, Xiuquan
Zhang, Zhiming
Grondin, Richard
Littrell, O. Meagan
Huettl, Peter
Pomerleau, Francois
Gash, Don M.
Gerhardt, Greg A.
Dopamine Neuron Stimulating Actions of a GDNF Propeptide
title Dopamine Neuron Stimulating Actions of a GDNF Propeptide
title_full Dopamine Neuron Stimulating Actions of a GDNF Propeptide
title_fullStr Dopamine Neuron Stimulating Actions of a GDNF Propeptide
title_full_unstemmed Dopamine Neuron Stimulating Actions of a GDNF Propeptide
title_short Dopamine Neuron Stimulating Actions of a GDNF Propeptide
title_sort dopamine neuron stimulating actions of a gdnf propeptide
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2841203/
https://www.ncbi.nlm.nih.gov/pubmed/20305789
http://dx.doi.org/10.1371/journal.pone.0009752
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