Entry of EGF into brain is rapid and saturable.
Epidermal growth factor (EGF) is a neurotrophic peptide produced both in the central nervous system and the periphery. Peripheral administration of EGF causes central nervous system-mediated changes. The central nervous system effects could be explained by the permeation of EGF across the blood-brain barrier (BBB). In this report, we show that 125I-EGF crosses the BBB rapidly, with an influx rate of about 2 microl/g x min, much faster than that for neurotrophins, cytokines, and most other bioactive peptides tested. The 125I-EGF was recovered intact in the brain 10 min after i.v. injection, and the majority of the peptide reaching the brain was present in the parenchyma. The fast rate of influx was significantly decreased by co-administration of nonradiolabeled EGF and transforming growth factor alpha, peptides that share the EGF receptor. By contrast, a monoclonal antibody against the EGF receptor failed to inhibit the entry of EGF. Furthermore, mice with a mutation in the EGF receptor had no significant decrease in the rapid rate of entry of 125I-EGF. By contrast to the fast rate of entry, 125I-EGF injected intracerebroventricularly (i.c.v.) only exited the brain with the bulk flow of cerebrospinal fluid. Thus, EGF has a saturable transport system at the BBB for rapid, unidirectional influx. The transport system does not require the entire EGF receptor and is susceptible to possible therapeutic manipulation.
Pan
W
W
VA Medical Center and Tulane University School of Medicine, New Orleans, LA 70112-1262, USA. wpan@mailhost.tcs.tulane.edu
Kastin
A J
AJ
D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004815:Epidermal Growth Factor / Q000493:pharmacokinetics*; D006207:Half-Life; D007457:Iodine Radioisotopes; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D012995:Solubility
D007457:Iodine Radioisotopes; D004815:Epidermal Growth Factor