Insect GDNF:TTC fusion protein improves delivery of GDNF to mouse CNS

With a view toward improving delivery of exogenous glial cell line-derived neurotrophic factor (GDNF) to CNS motor neurons in vivo, we evaluated the bioavailability and pharmacological activity of a recombinant GDNF:tetanus toxin C-fragment fusion protein in mouse CNS. Following intramuscular inject...

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Bibliographic Details
Published in:Biochemical and biophysical research communications 2009-12, Vol.390 (3), p.947-951
Main Authors: Li, Jianhong, Chian, Ru-Ju, Ay, Ilknur, Kashi, Brenda B., Celia, Samuel A., Tamrazian, Eric, Pepinsky, R. Blake, Fishman, Paul S., Brown, Robert H., Francis, Jonathan W.
Format: Article
Language:English
Subjects:
60 APPLIED LIFE SCIENCES
ANIMAL TISSUES
Animals
Biological Availability
CHOLINE
CONCENTRATION RATIO
Drug Delivery Systems
GDNF
Glial Cell Line-Derived Neurotrophic Factor - administration & dosage
Glial Cell Line-Derived Neurotrophic Factor - pharmacokinetics
IN VIVO
INFUSION
Injections, Intramuscular
INSECTS
INTRAMUSCULAR INJECTION
Intrathecal infusion
MICE
Mice, Inbred C57BL
Motor Neurons - metabolism
NERVE CELLS
Peptide Fragments - administration & dosage
Peptide Fragments - pharmacokinetics
PROTEINS
Recombinant Fusion Proteins - administration & dosage
Recombinant Fusion Proteins - pharmacokinetics
Recombinant protein
SPINAL CORD
Spinal Cord - metabolism
TETANUS
Tetanus Toxin - administration & dosage
Tetanus Toxin - pharmacokinetics
Tetanus toxin fragment C
TOXINS
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Summary:With a view toward improving delivery of exogenous glial cell line-derived neurotrophic factor (GDNF) to CNS motor neurons in vivo, we evaluated the bioavailability and pharmacological activity of a recombinant GDNF:tetanus toxin C-fragment fusion protein in mouse CNS. Following intramuscular injection, GDNF:TTC but not recombinant GDNF (rGDNF) produced strong GDNF immunostaining within ventral horn cells of the spinal cord. Intrathecal infusion of GDNF:TTC resulted in tissue concentrations of GDNF in lumbar spinal cord that were at least 150-fold higher than those in mice treated with rGDNF. While levels of immunoreactive choline acetyltransferase and GFRα-1 in lumbar cord were not altered significantly by intrathecal infusion of rGNDF, GDNF:TTC, or TTC, only rGDNF and GDNF:TTC caused significant weight loss following intracerebroventricular infusion. These studies indicate that insect cell-derived GDNF:TTC retains its bi-functional activity in mammalian CNS in vivo and improves delivery of GDNF to spinal cord following intramuscular- or intrathecal administration.
ISSN:0006-291X
1090-2104
DOI:10.1016/j.bbrc.2009.10.083