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 barrie r (BBB) following systemic administration making this neurotrophin una vailable 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 ag ainst the transferrin receptor (OX-26) [15,16]. This conjugation facil itates the transfer of NGF from the systemic circulation to the CNS vi a the transferrin transport system, In the present study, we tested wh ether intravenous administration of an OX-26-NGF conjugate could rever se the atrophy of cholinergic basal forebrain neurons following remova l of the target sites. Lesions of the left cerebral cortex were create d by epidural application of N-methyl-D-aspartic acid (NMDA). Seventy- five days later, cholinergic nucleus basalis neurons were atrophic ips ilateral to the lesion relative to the contralateral side in control r ats receiving intravenous injections of vehicle or a non-conjugated mi xture of OX-26 and NGF. In contrast, intravenous injections of the OX- 26-NGF conjugate restored the size of nucleus basalis perikarya to wit hin normal limits relative to the unlesioned contralateral side. Immun ohistochemical studies using rat serum albumen antisera indicated that the BBB was closed at the time of treatment indicating that this trop hic effect did not result from NGF crossing through a compromised BBB at the site of the lesion. These data demonstrate that systemic admini stration of a neurotrophic factor-antibody conjugate, intended to circ umvent the BBB, can provide trophic influences to degenerating choline rgic basal forebrain neurons. These data support the emerging concept that the conjugate method can facilitate the transfer of impermeable t herapeutic compounds across the BBB.