A non-invasive system for delivering neural growth factors across the blood-brain barrier: A review

Ann Charlotte Granholm, David Albeck, Cristina Bäckman, Maria Curtis, Ted Ebendal, Phil Friden, Michael Henry, Barry Hoffer, Jeffrey Kordower, Gregory M. Rose, Stine Söderström, Raymond T. Bartus

Research output: Contribution to journalArticle

59 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)31-55
Number of pages25
JournalReviews in the Neurosciences
Volume9
Issue number1
StatePublished - 1998
Externally publishedYes

Fingerprint

Nerve Growth Factor
Blood-Brain Barrier
Intercellular Signaling Peptides and Proteins
Cholinergic Neurons
Transferrin Receptors
Cholinergic Agents
Septum of Brain
Transplants
Neurons
Corpus Striatum
Nerve Growth Factor Receptor
Nerve Degeneration
Aptitude
Antibodies
Active Biological Transport
Inbred F344 Rats
Nerve Growth Factors
Cell Size
Intravenous Injections
Biological Assay

Keywords

  • Acetylcholine
  • Blood-brain barrier
  • Cholinergic
  • Drug delivery
  • Forebrain septal nuclei
  • Macromolecules
  • Neurotrophins
  • Transferrin receptors
  • Transplantation

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Granholm, A. C., Albeck, D., Bäckman, C., Curtis, M., Ebendal, T., Friden, P., ... Bartus, R. T. (1998). A non-invasive system for delivering neural growth factors across the blood-brain barrier: A review. Reviews in the Neurosciences, 9(1), 31-55.

A non-invasive system for delivering neural growth factors across the blood-brain barrier : A review. / Granholm, Ann Charlotte; Albeck, David; Bäckman, Cristina; Curtis, Maria; Ebendal, Ted; Friden, Phil; Henry, Michael; Hoffer, Barry; Kordower, Jeffrey; Rose, Gregory M.; Söderström, Stine; Bartus, Raymond T.

In: Reviews in the Neurosciences, Vol. 9, No. 1, 1998, p. 31-55.

Research output: Contribution to journalArticle

Granholm, AC, Albeck, D, Bäckman, C, Curtis, M, Ebendal, T, Friden, P, Henry, M, Hoffer, B, Kordower, J, Rose, GM, Söderström, S & Bartus, RT 1998, 'A non-invasive system for delivering neural growth factors across the blood-brain barrier: A review', Reviews in the Neurosciences, vol. 9, no. 1, pp. 31-55.
Granholm AC, Albeck D, Bäckman C, Curtis M, Ebendal T, Friden P et al. A non-invasive system for delivering neural growth factors across the blood-brain barrier: A review. Reviews in the Neurosciences. 1998;9(1):31-55.
Granholm, Ann Charlotte ; Albeck, David ; Bäckman, Cristina ; Curtis, Maria ; Ebendal, Ted ; Friden, Phil ; Henry, Michael ; Hoffer, Barry ; Kordower, Jeffrey ; Rose, Gregory M. ; Söderström, Stine ; Bartus, Raymond T. / A non-invasive system for delivering neural growth factors across the blood-brain barrier : A review. In: Reviews in the Neurosciences. 1998 ; Vol. 9, No. 1. pp. 31-55.
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