N-Palmitoylethanolamine depot injection increased its tissue levels and those of other acylethanolamide lipids

Abstract

N-Palmitoylethanolamine (NAE 16:0) is an endogenous lipid signaling molecule that has limited water solubility, and its action is short-lived due to its rapid metabolism. This poses a problem for use in vivo as oral administration requires a high concentration for significant levels to reach target tissues, and injection of the compound in a dimethyl sulfoxide- or ethanol-based vehicle is usually not desirable during long-term treatment. A depot injection of NAE 16:0 was successfully emulsified in sterile corn oil (10 mg/kg) and administered in young DBA/2 mice in order to elevate baseline levels of NAE 16:0 in target tissues. NAE 16:0 levels were increased in various tissues, particularly in the retina, 24 and 48 hours following injections. Increases ranged between 22% and 215% (above basal levels) in blood serum, heart, brain, and retina and induced an entourage effect by increasing levels of other 18 carbon N-Acylethanolamines (NAEs), which ranged between 31% and 117% above baseline. These results indicate that NAE 16:0 can be used as a depot preparation, avoiding the use of inadequate vehicles, and can provide the basis for designing tissue-specific dosing regimens for therapies involving NAEs and related compounds.

Keywords:

• cannabinoid receptor
• vanilloid receptor
• DBA/2 mice
• lipid extraction
• gas chromatography
• mass spectrometry

Acknowledgments

Research reported in this publication was supported in part by grants from the National Eye Institute (EY014227 and EY022774), the Institute on Aging (AG010485, AG022550 and AG027956), the National Center for Research Resources, and National Institute of General Medical Sciences (RR022570 and RR027093) of the National Institutes of Health (PK). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Additional support by a Fight for Sight Post-Doctoral Award (SLG) and the Felix and Carmen Sabates Missouri Endowed Chair in Vision Research, the Vision Research Foundation of Kansas City, and a Challenge Grant from Research to Prevent Blindness (PK) is gratefully acknowledged. Acylethanolamide analysis by gas chromatography/mass spectrometry was made possible through a supplemental instrument award to KDC from United States Department of Energy, Office of Basic Energy Sciences (BES grant number DE-FG02-05ER15647).

Disclosure

The authors report no conflicts of interest in this work.