Polyamine modification increases the permeability of proteins at the blood-nerve and blood-brain barriers.
The permeability of the blood-nerve barrier (BNB) and the blood-brain barrier (BBB) to superoxide dismutase (SOD), insulin, albumin, and IgG in normal adult rats was quantified by measuring the permeability coefficient-surface area product (PS) with the intravenous bolus injection technique before and after covalent protein modification with naturally occurring polyamines-putrescine (PUT), spermidine (SPD), and spermine (SPM). The PS value of the BNB for PUT-SOD was 21.1-fold greater than the native SOD, and the PS values of the BBB for PUT-SOD ranged from 17.6-fold greater for the thalamus to 23.6-fold greater for the caudate-putamen compared with native SOD. In a similar manner, polyamine-modified insulin showed a 1.7-2.0-fold increase in PS of the BNB and BBB compared with the high values of native insulin. Polyamine-modified albumin showed a remarkable 54-165-fold increase in PS of the BNB and BBB compared with native albumin, whereas PUT-IgG resulted in an even higher increase in the PS that ranged from 111- to 349-fold for nerve and different brain regions compared with native IgG. Polyamine modification of proteins, therefore, can dramatically increase the permeability at the BNB and BBB of a variety of proteins with widely differing M(r) and function. It is surprising that the PS values of the BNB and BBB decreased with the increasing number of positive charges of the protonated amino groups on the polyamines (PUT>SPD>SPM). Although cationic proteins are known to interact with fixed anionic charges on the lumen of the microvascular endothelium, this observation of decreased permeability with increased positive charge distribution along the aliphatic carbon chain of the polyamines implies mechanisms other than simple electrostatic interaction involving charge density. It is suggested that the polyamine transporter may be responsible for the transport of these polyamine-modified proteins. Systemic administration of polyamine-modified peptides and proteins might prove to be an efficient approach to deliver therapeutic agents into the CNS and PNS for the treatment of a variety of neurological diseases.
Poduslo
J F
JF
Molecular Neurobiology Laboratory, Department of Neurology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota, USA.
Curran
G L
GL
D000818:Animals; D001812:Blood-Brain Barrier / Q000502:physiology*; D002412:Cations / Q000032:analysis / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000502:physiology; D004553:Electric Conductivity; D004591:Electrophoresis, Polyacrylamide Gel; D004730:Endothelium, Vascular / Q000378:metabolism; D007074:Immunoglobulin G / Q000032:analysis / Q000097:blood; D007275:Injections, Intravenous; D007328:Insulin / Q000032:analysis / Q000097:blood; D007457:Iodine Radioisotopes; D007525:Isoelectric Focusing; D008297:Male; D009474:Neurons / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism; D011073:Polyamines / Q000032:analysis / Q000378:metabolism* / Q000493:pharmacokinetics; D011506:Proteins / Q000378:metabolism; D011700:Putrescine / Q000032:analysis / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D012709:Serum Albumin / Q000032:analysis; D013095:Spermidine / Q000032:analysis / Q000097:blood; D013482:Superoxide Dismutase / Q000032:analysis / Q000097:blood
D002412:Cations; D007074:Immunoglobulin G; D007328:Insulin; D007457:Iodine Radioisotopes; D010455:Peptides; D011073:Polyamines; D011506:Proteins; D012709:Serum Albumin; D013482:Superoxide Dismutase; D013095:Spermidine; D011700:Putrescine