4-Trimethylammonium antipyrine: a quaternary ammonium nonradionuclide marker for blood-brain barrier integrity during in vivo microdialysis.
The well-controlled microdialysis (MD) study of substance permeation into brain extracellular fluid (ECF) and cerebrospinal fluid requires consideration of blood-brain barrier (BBB) integrity, which might be compromised by microdialysis probe implantation. Others have assessed BBB integrity with radionuclide markers. A nonradionuclide marker may be desirable in many studies. A charged antipyrine analogue may be useful to determine BBB integrity with concomitant antipyrine characterization of probe efficiency (Yokel et al., 1992, J Pharmacol Toxicol Methods 27:135-142), and may not require another analytical technique. We synthesized, validated, and evaluated 4-trimethylammonium antipyrine (4TMA-AP) as a BBB integrity marker. BBB permeation was determined by calculation of a BBB integrity percentage (Pi) from brain/blood concentrations. The PiS of Evan's blue, which does not permeate the intact BBB, and 4TMA-AP were not significantly different in rats without known BBB disruption, suggesting a lack of 4TMA-AP permeation through the intact BBB. When MD probes were slowly implanted into the frontal cortex, 4TMA-AP PiS were usually zero. Intracarotid oleic acid injection to open the BBB significantly increased 4TMA-AP PiS, suggesting that 4TMA-AP entered brain ECF when the BBB was compromised. Rapid probe implantation produced increased 4TMA-AP PiS, suggesting BBB disruption. The predicted appearance of 4TMA-AP in brain ECF suggests that it is a BBB integrity marker.
Allen
D D
DD
College of Pharmacy, University of Kentucky, Lexington 40536-0082.
Crooks
P A
PA
Yokel
R A
RA
D000818:Animals; D000983:Antipyrine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics; D001812:Blood-Brain Barrier / Q000502:physiology*; D001921:Brain / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003956:Dialysis; D005070:Evans Blue; D008297:Male; D000644:Quaternary Ammonium Compounds / Q000138:chemical synthesis / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley
D000644:Quaternary Ammonium Compounds; D005070:Evans Blue; C079419:4-trimethylammoniumantipyrine; D000983:Antipyrine