Co-infusion with a TrkB-Fc receptor body carrier enhances BDNF distribution in the adult rat brain.
Fusion proteins comprising the Fc domain of human IgG and extracellular domains of receptor tyrosine kinases can neutralize the activity of their cognate ligands when administered in molar excess. We have generated a fusion protein using the ectodomain of TrkB (TrkB-Fc). Although the ability of TrkB-Fc to neutralize the activity of brain-derived neurotrophic factor (BDNF) in vitro has been demonstrated, there have been no conclusive demonstrations of its ability to neutralize the activity of BDNF in vivo. We co-infused TrkB-Fc with BDNF into the cortex and hippocampus of adult rats to determine whether TrkB-Fc would interfere with the ability of BDNF to upregulate neuropeptide Y (NPY). We report here that rather than neutralizing the activity of exogenous BDNF, co-infusion with the TrkB-Fc fusion protein greatly increased the volume of tissue in which neuropeptide Y immunostaining was upregulated. In addition, TrkB-Fc greatly enhanced BDNF's distribution through adult brain parenchyma. TrkB-Fc also markedly increased the otherwise limited diffusion of BDNF into brain parenchyma following intraventricular infusion. These results show that rather than neutralizing or sequestering BDNF, the TrkB-Fc, at close to molar equivalence to BDNF, can function as a carrier for BDNF and thus enhance the delivery or penetration of this polypeptide into the brain.
Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, New York, 10591, USA. susan.croll@regpha.com
S D
SD
Croll
C R
CR
Chesnutt
J S
JS
Rudge
A
A
Acheson
T E
TE
Ryan
J A
JA
Siuciak
P S
PS
DiStefano
S J
SJ
Wiegand
R M
RM
Lindsay
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D019208:Brain-Derived Neurotrophic Factor / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004797:Enzyme-Linked Immunosorbent Assay; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D007276:Injections, Intraventricular; D008297:Male; D009478:Neuropeptide Y / Q000096:biosynthesis / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D020801:Receptor, Ciliary Neurotrophic Factor; D011961:Receptors, Fc / Q000378:metabolism*; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D018411:Spodoptera / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D019208:Brain-Derived Neurotrophic Factor; D009478:Neuropeptide Y; D018696:Neuroprotective Agents; D020801:Receptor, Ciliary Neurotrophic Factor; D011961:Receptors, Fc; D017475:Receptors, Nerve Growth Factor; D011993:Recombinant Fusion Proteins; D020794:Receptor Protein-Tyrosine Kinases