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Dopamine neuron stimulating actions of a GDNF propeptide. | LitMetric

Dopamine neuron stimulating actions of a GDNF propeptide.

PLoS One

Department of Anatomy & Neurobiology and the Morris K. Udall Parkinson's Disease Research Center of Excellence, University of Kentucky College of Medicine, Lexington, Kentucky, United States of America.

Published: March 2010

AI Article Synopsis

  • Neurotrophic factors like GDNF are promising for treating damaged dopamine neurons, but their delivery to the brain is challenging due to their size and complexity.
  • This study introduces dopamine neuron stimulating peptide-11 (DNSP-11), which is easier to synthesize and has shown protective effects in both in vitro and in vivo models, promoting neuron survival and decreasing cell death caused by neurotoxins.
  • DNSP-11 appears to enhance dopamine levels and improve motor behavior in rat models of Parkinson's disease, suggesting it might be a strong candidate for new therapeutic approaches.

Article Abstract

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 GFRalpha1 receptor.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2841203PMC
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0009752PLOS

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