NGF AND ANTITRANSFERRIN RECEPTOR ANTIBODY CONJUGATE - SHORT AND LONG-TERM EFFECTS ON SURVIVAL OF CHOLINERGIC NEURONS IN INTRAOCULAR SEPTAL TRANSPLANTS

We describe a new molecular carrier system that allows for the transpo rt of nerve growth factor (NGF) across the blood-brain barrier (BBB), as assessed by trophic effects on intraocular forebrain transplants th at contain central cholinergic neurons. The carrier system involves mo noclonal antibodies (OX-26) directed against the transferrin receptor, to which NGF molecules are covalently linked. Transferrin receptors a re highly concentrated on brain blood vessels and participate in the t ransport of iron across the BBB. Host rats with septal transplants wer e divided into four groups, which received OX-26-NGF, OX-26, NGF or sa line intravenously at 2, 4, 6 and 8 weeks after grafting. Half of the animals were killed directly after the final injection, whereas the ot her half were allowed to survive for an additional 5 months. Control e xperiments revealed that blood vessels in mature brain grafts in oculo contained large amounts of transferrin conjugation affect the bioacti vity of NGF. A time-dependent increase in host brain NGF levels was fo und after injection of OX-26-NGF into the tail vein. Host serum contai ned some NGF antibodies in the short-term OX-26-NGF group that had dis appeared in the long-term group; host adrenals showed no differences i n wet weight or norepinephrine or epinephrine whole tissue levels in a ny of the groups. As previously reported, the overall growth of intrao cular septal transplants was approximately twice as great in the OX-26 -NGF group relative to all other groups. This difference in final size persisted unabated for at least 5 months after the last injection. Fu rthermore, the significantly higher numbers of choline acetyl transfer ase immunoreactive neurons in transplants of OX-26-NGF-treated hosts a lso persisted during the 5-month postinjection interval. Taken togethe r, the data suggest that the OX-26 conjugate may be a unique approach to permit passage of neurotrophin peptides into the brain in a biologi cally active form.