TY - JOUR
T1 - Dopamine Neuron Stimulating Actions of a GDNF Propeptide
AU - Bradley, Luke H.
AU - Fuqua, Josh
AU - Richardson, April
AU - Cholewo, Jadwiga Turchan
AU - Ai, Yi
AU - Kelps, Kristen A.
AU - Glass, John D.
AU - He, Xiuquan
AU - Zhang, Zhiming
AU - Grondin, Richard
AU - Littrell, O. Meagan
AU - Huettl, Peter
AU - Pomerleau, Francois
AU - Gash, Don M.
AU - Gerhardt, Greg A.
PY - 2010
Y1 - 2010
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=79551586768&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79551586768&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0009752
DO - 10.1371/journal.pone.0009752
M3 - Article
C2 - 20305789
AN - SCOPUS:79551586768
SN - 1932-6203
VL - 5
JO - PLoS ONE
JF - PLoS ONE
IS - 3
M1 - e9752
ER -