Neuregulin-1-beta1 enters brain and spinal cord by receptor-mediated transport.
Proteins of the neuregulin (NRG) family play important regulatory roles in neuronal survival and synaptic activity. NRG-1-beta1 has particular potential as a therapeutic agent because it enhances myelination of neurites in spinal cord explants. In this study, we determined the permeation of NRG-1-beta1 across the blood-brain and blood-spinal cord barriers (BBB and BSCB respectively). Intact radioactively labeled NRG-1-beta1 had a saturable and relatively rapid influx rate from blood to the CNS in mice. Capillary depletion studies showed that NRG-1-beta1 entered the parenchyma of the brain and spinal cord rather than being trapped in the capillaries that compose the BBB. The possible mechanism of receptor-mediated transport was shown by the ability of antibodies to erbB3 and erbB4 receptors to inhibit the influx. Lipophilicity, less important for such saturable transport mechanisms, was measured by the octanol : buffer partition coefficient and found to be low. The results indicate that NRG-1-beta1 enters spinal cord and brain by a saturable receptor-mediated mechanism, which provides the opportunity for possible therapeutic manipulation at the BBB level.
Kastin
Abba J
AJ
Veterans Affairs Medical Center and Tulane University Health Sciences Center, New Orleans, Louisiana 70112-1262, USA. peptides@tulane.edu
Akerstrom
Victoria
V
Pan
Weihong
W
D000818:Animals; D001693:Biological Transport, Active; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism*; D002196:Capillaries / Q000378:metabolism; D007276:Injections, Intraventricular; D007457:Iodine Radioisotopes / Q000378:metabolism; D008297:Male; D051379:Mice; D020890:Neuregulin-1 / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism*; D013668:Technetium Tc 99m Aggregated Albumin / Q000097:blood; D013997:Time Factors; D014018:Tissue Distribution
D007457:Iodine Radioisotopes; D020890:Neuregulin-1; D013668:Technetium Tc 99m Aggregated Albumin; C117467:neuregulin beta