Uptake in brain and neurophysiological activity of two lipid esters of gamma-aminobutyric acid.
Two lipid esters of gamma-aminobutyric acid (GABA), 1-linolenoyl-2,3-bis(4-aminobutyryl)propane-1,2,3-triol and 1,2-dilinolenoyl-3-(4-aminobutyryl)propane-1,2,3-triol, were found to have brain uptake indices of greater than 30% using the single-pass carotid artery injection technique. Both compounds produced dose-dependent inhibition of the evoked population spike in slices of rat hippocampus maintained in vitro. This effect was blocked reversibly by picrotoxin. The magnitude of the inhibition produced by the lipid esters of GABA was comparable to that of similar doses of GABA, but for both compounds the duration of the effect was at least 10 times longer than that produced by GABA. These data are consistent with the idea that the lipid esters of GABA can effectively penetrate the blood-brain barrier and act as prodrugs for the delivery of GABA to the central nervous system.
Hesse
G W
GW
Harvard Medical School, Ralph Lowell Laboratories, McLean Hospital, Belmont, Massachusetts 02178.
Jacob
J N
JN
Shashoua
V E
VE
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D010852:Picrotoxin / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D014280:Triglycerides / Q000378:metabolism / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
D010852:Picrotoxin; D014280:Triglycerides; D005680:gamma-Aminobutyric Acid; C057077:1,2-dilinolenoyl-3-(4-aminobutyryl)propane-1,2,3-triol; C057076:1-linolenoyl-2,3-bis(4-aminobutyryl)propane-1,2,3-triol