Blood-Brain Barrier Penetration and in Vivo Activity of an NGF Conjugate

Abstract

Nerve growth factor (NGF) is essential for the survival of both peripheral ganglion cells and central cholinergic neurons of the basal forebrain. The accelerated loss of central cholinergic neurons during Alzheimer's disease may be a determinant of dementia in these patients and may therefore suggest a therapeutic role for NGF. However, NGF does not significantly penetrate the blood-brain barrier, which makes its clinical utility dependent on invasive neurosurgical procedures. When conjugated to an antibody to the transferrin receptor, however, NGF crossed the blood-brain barrier after peripheral injection. This conjugated NGF increased the survival of both cholinergic and noncholinergic neurons of the medial septal nucleus that had been transplanted into the anterior chamber of the rat eye. This approach may prove useful for the treatment of Alzheimer's disease and other neurological disorders that are amenable to treatment by proteins that do not readily cross the blood-brain barrier.

The expanding role of nerve growth factor: from neurotrophic activity to immunologic diseases

“…Since one of the major limitations in the use of NGF in brain pathologies is its large molecular size and its difficulty in crossing the blood-brain barrier, it was recently suggested that, for its utilization, NGF could be conjugated to transferrin receptor antibody (52), or, altertiatively, that one could use pharmacologic agents that act on brain NGFproducing cells (53). It is also possible that drugs which stimulate the release of NGF produced by resident cells, including MC, may be used to enhance the level of NGF in pathologies associated with the low availability of NGF.…”

Selectivity of Cell Signaling in the Neuronal Response Based on NGF Mutations and Peptidomimetics in the Treatment of Alzheimers Disease

“…Transcranial focused ultrasound (FUS) has been shown to transiently-enhance the permeability of the BBB and permit antibodies, and probably other macromolecules into the intrathecal space (Jordão et al, 2010). Early interest in conjugation of NGF to transferrin or transferrin antibodies as a means of transport across the BBB (Friden et al, 1993;Liao et al, 2001) seems to have waned and shifted toward using this means of cellular uptake for anticancer or diabetic drugs. Gene therapy presents the most-advanced, current means of delivering NGF in a cerebral region-specific manner (Lad et al, 2003a;Nagahara & Tuszynski, 2011).…”

Development of neuropeptide drugs that cross the blood-brain barrier

“…Some transport systems/sites that have been targeted include the LNAA, 64 receptor-mediated endocytosis/transcytosis, [65][66][67][68] and adsorptive endocytosis/transcytosis. 69,70 For the purpose of this review, we will focus on two favored methods for improving brain delivery, the use of vectors and glycosylation.…”