A non-invasive system for delivering neural growth factors across the blood-brain barrier: a review.
Intraventricular administration of nerve growth factor (NGF) in rats has been shown to reduce age-related atrophy of central cholinergic neurons and the accompanying memory impairment, as well as protect these neurons against a variety of perturbations. Since neurotrophins do not pass the blood-brain barrier (BBB) in significant amounts, a non-invasive delivery system for this group of therapeutic molecules needs to be developed. We have utilized a carrier system, consisting of NGF covalently linked to an anti-transferrin receptor antibody (OX-26), to transport biologically active NGF across the BBB. The biological activity of this carrier system was tested using in vitro bioassays and intraocular transplants; we were able to demonstrate that cholinergic markers in both developing and aged intraocular septal grafts were enhanced by intravenous delivery of the OX-26-NGF conjugate. In subsequent experiments, aged (24 months old) Fischer 344 rats received intravenous injections of the OX-26-NGF conjugate for 6 weeks, resulting in a significant improvement in spatial learning in previously impaired rats, but disrupting the learning ability of previously unimpaired rats. Neuroanatomical analyses showed that OX-26-NGF conjugate treatment resulted in a significant increase in cholinergic cell size as well as an upregulation of both low and high affinity NGF receptors in the medial septal region of rats initially impaired in spatial learning. Finally, OX-26-NGF was able to protect striatal cholinergic neurons against excitotoxicity and basal forebrain cholinergic neurons from degeneration associated with chemically-induced loss of target neurons. These results indicate the potential utility of the transferrin receptor antibody delivery system for treatment of neurodegenerative disorders with neurotrophic substances.
Granholm
A C
AC
Department of Basic Science, University of Colorado Health Sciences Center, Denver 80262, USA.
Albeck
D
D
Bäckman
C
C
Curtis
M
M
Ebendal
T
T
Friden
P
P
Henry
M
M
Hoffer
B
B
Kordower
J
J
Rose
G M
GM
Söderström
S
S
Bartus
R T
RT
D000818:Animals; D001812:Blood-Brain Barrier; D007276:Injections, Intraventricular; D009414:Nerve Growth Factors / Q000493:pharmacokinetics*; D009474:Neurons / Q000187:drug effects*
D009414:Nerve Growth Factors