Neuroprotection with noninvasive neurotrophin delivery to the brain

Brain-derived neurotrophic factor (BDNF) is neuroprotective in the ischemic hippocampus if the neurotrophin is injected directly into the brain. Howev er, the efficacy of BDNF via peripheral (i.v.) administration is limited by the lack of transport of the neurotrophin through the brain capillary wall , which makes up the blood-brain barrier (BBB) in vivo. The present studies describe a molecular reformulation of BDNF that incorporates polyethylene glycol (PEG) moieties at surface carboxyl residues, to optimize plasma phar macokinetics, and links pegylated BDNF to the OX26 mAb, which undergoes rec eptor-mediated transport through the BBB via the brain capillary endothelia l transferrin receptor. The BDNF-PEG 2000-biotin conjugated to OX26/strepta vidin was administered i.v. daily to rats for 1 week after a 12-min period of transient forebrain ischemia. The neuronal density in the CA1 sector of the hippocampus was decreased 68 +/- 10% at 1 week after the ischemia. Ther e was no neuroprotective effect of the unconjugated BDNF or unconjugated OX 26 mAb. However, the hippocampal CA1 neuronal density was normalized by i.v . administration of the BDNF-PEG 2000-biotin conjugated to OX26/streptavidi n. These studies demonstrate that peripherally administered BDNF may have n europrotective effects in brain, if the neurotrophin is reformulated to (i) optimize plasma pharmacokinetics with carboxyl-directed pegylation, and (i i) enable transport through the BBB by coupling to brain transport vectors.