Somnogenic activities of synthetic lipid A.
Bacterial infections and various immune response modifiers, including endotoxin and its lipid A moiety, alter sleep duration. The purpose of this study is to amplify our understanding of lipid A structure-somnogenic-pyrogenic activity relationships. Four synthetic disaccharide analogs of lipid A (LA-15-PP, LA-15-PH, LA-16-PH, and LA-18-PP) and a biosynthetic monosaccharide analog of lipid A (lipid X) were tested in rabbits for their effects on slow-wave sleep, rapid-eye-movement sleep, electroencephalographic slow-wave (0.5- to 4.0-Hz) amplitudes, and brain-colonic temperatures. Substances were injected intravenously and intracerebroventricularly. Compound LA-15-PP was the most potent; it significantly increased slow-wave sleep, delta electroencephalographic amplitudes, and brain-colonic temperatures while reducing rapid-eye-movement sleep. Compound LA-15-PH (monophosphoryl analog of LA-15-PP) induced effects similar to those of LA-15-PP, although the responses were weaker. Compound LA-18-PP induced increases in slow-wave sleep and delta amplitudes only after high doses, whereas compound LA-16-PH was devoid of these activities at the doses tested. Intracerebroventricular, but not intravenous, injections of lipid X induced small but significant increases in both slow-wave sleep and rapid-eye-movement sleep without affecting delta amplitudes or brain-colonic temperatures. These data suggest that the somnogenic actions of these lipid A analogs depend on the acylation or phosphorylation pattern and backbone structures of the molecules. Their soporific activities parallel their relative behaviors in other biological assays.
Cady
A B
AB
Department of Physiology and Biophysics, University of Tennessee, Memphis 38163.
Kotani
S
S
Shiba
T
T
Kusumoto
S
S
Krueger
J M
JM
D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D003106:Colon; D003700:Delta Rhythm; D006017:Glycolipids / Q000008:administration & dosage; D008050:Lipid A / Q000008:administration & dosage / Q000031:analogs & derivatives*; D008297:Male; D011817:Rabbits; D012890:Sleep / Q000187:drug effects*; D012895:Sleep, REM / Q000187:drug effects; D013329:Structure-Activity Relationship
D006017:Glycolipids; D008050:Lipid A; C049596:diphosphoryl lipid A; C044283:lipid X; C048436:monophosphoryl lipid A