Atrophy of cholinergic basal forebrain neurons following excitotoxic cortical lesions is reversed by intravenous administration of an NGF conjugate.
Nerve growth factor (NGF) has been shown to sustain the viability and modulate the function of cholinergic basal forebrain neurons. However, under normal circumstances, NGF does not cross the blood-brain barrier (BBB) following systemic administration making this neurotrophin unavailable to NGF-responsive neurons within the central nervous system (CNS). Recently, a non-invasive method for delivering NGF to the brain was established in which NGF was conjugated to an antibody directed against the transferrin receptor (OX-26) [15, 16]. This conjugation facilitates the transfer of NGF from the systemic circulation to the CNS via the transferrin transport system. In the present study, we tested whether intravenous administration of an OX-26-NGF conjugate could reverse the atrophy of cholinergic basal forebrain neurons following removal of the target sites. Lesions of the left cerebral cortex were created by epidural application of N-methyl-D-aspartic acid (NMDA). Seventy-five days later, cholinergic nucleus basalis neurons were atrophic ipsilateral to the lesion relative to the contralateral side in control rats receiving intravenous injections of vehicle or a non-conjugated mixture of OX-26 and NGF. In contrast, intravenous injections of the OX-26-NGF conjugate restored the size of nucleus basalis perikarya to within normal limits relative to the unlesioned contralateral side. Immunohistochemical studies using rat serum albumen antisera indicated that the BBB was closed at the time of treatment indicating that this trophic effect did not result from NGF crossing through a compromised BBB at the site of the lesion. These data demonstrate that systemic administration of a neurotrophic factor-antibody conjugate, intended to circumvent the BBB, can provide trophic influences to degenerating cholinergic basal forebrain neurons. These data support the emerging concept that the conjugate method can facilitate the transfer of impermeable therapeutic compounds across the BBB.
Charles
V
V
Research Center for Brain Repair, Rush Presbyterian Medical Center, Chicago, IL 60612, USA. jkordowe@rush.rpslmc.edu
Mufson
E J
EJ
Friden
P M
PM
Bartus
R T
RT
Kordower
J H
JH
D000818:Animals; D001284:Atrophy / Q000188:drug therapy; D002799:Cholinergic Fibers / Q000187:drug effects*; D007150:Immunohistochemistry; D007275:Injections, Intravenous; D008297:Male; D009414:Nerve Growth Factors / Q000494:pharmacology*; D016548:Prosencephalon / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley
D009414:Nerve Growth Factors