Abstract
BackgroundNeurotrophic 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 FindingsHere 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.ConclusionsCollectively, 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.
Highlights
A hallmark of Parkinson’s disease (PD) is the degeneration of dopamine neurons in the pars compacta of the substantia nigra [1]
We present that Dopamine Neuron Stimulating Peptide-11 (DNSP-11) exhibits potent neurotrophic actions analogous to mature glial cell line-derived neurotrophic factor (GDNF), making it a viable candidate for a PD therapeutic, but it likely signals through pathways that do not directly involve the GFRa1 receptor
Homologous sequences have been predicted from the rat and mouse GDNF prosequence (Figure 1B) [15]
Summary
A hallmark of Parkinson’s disease (PD) is the degeneration of dopamine neurons in the pars compacta of the substantia nigra [1]. Studies have shown that the isolated prosequence of NGF can be used to block the induction of apoptosis, by likely preventing the proapoptotic ternary complex (sortilin-p75NTR-proNGF) formation [13] While these findings are quite surprising, they strongly suggest that the highly conserved prosequences of other related neurotrophic factors contain novel, physiologically relevant functions. 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. Small molecules with neurotrophic actions that are easy to synthesize and modify to improve bioavailability are needed
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