The blood-brain barrier accessibility of a heparin-derived oligosaccharides C3.
Although heparin-derived oligosaccharide(s) (HDO) have been clinically used for the management of neurological disorders, such as stroke and Alzheimer's disease (AD), very little information on the mechanism of their therapeutic action is known. To test the hypothesis that HDO may pass through the blood-brain barrier (BBB) to mediate their effects, a pharmacodynamic (PD) model was developed and the presence of HDO in the cerebrospinal fluid (CSF) was used as a BBB accessibility index. Rats were treated with an ultralow molecular weight (MW) heparin fragment C3 via the intravenous or subcutaneous routes at 5-10 mg/kg. At varying periods, the plasma, CSF, and brain samples were collected, and functional anti-factor Xa activities were measured to quantitate the CSF/plasma ratios (CPR) and the brain uptake. C3 showed CPR of 1.7% and 0.8% after intravenous and subcutaneous injections, respectively. These findings were verified by intravenous administration of tritium-labeled C3 followed by detection of the radioactivity in the CSF and brain homogenates. These data suggest that ultralow MW HDO may pass through the BBB.
Ma
Qing
Q
Department of Pharmacology and Experimental Therapeutics, Stritch School of Medicine, Loyola University Chicago, 2160 South First Avenue, Maywood, IL 60153, USA. qma1@luc.edu
Dudas
Bertalan
B
Hejna
Matthew
M
Cornelli
Umberto
U
Lee
John M
JM
Lorens
Stanley
S
Mervis
Ronald
R
Hanin
Israel
I
Fareed
Jawed
J
D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism; D005170:Factor X / Q000037:antagonists & inhibitors; D006495:Heparin, Low-Molecular-Weight / Q000008:administration & dosage / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D007700:Kinetics; D008297:Male; D009844:Oligosaccharides / Q000008:administration & dosage / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics; D011849:Radioactive Tracers; D051381:Rats; D011916:Rats, Inbred F344; D014316:Tritium
D006495:Heparin, Low-Molecular-Weight; D009844:Oligosaccharides; D011849:Radioactive Tracers; D014316:Tritium; D005170:Factor X