Abstract
In mammals, the endocannabinoid signaling pathway provides protective cellular responses to ischemia. Previous work demonstrated increases in long-chain N-acylethanolamines (NAE) in ischemia and suggested a protective role for NAE. Here, a targeted lipidomics approach was used to study comprehensive changes in the molecular composition and quantity of NAE metabolites in a rat model of controlled brain ischemia. Changes of NAE, its precursors, N-acylphosphatidylethanolamines (NAPE), major and minor phospholipids, and free fatty acids (FFA) were quantified in response to ischemia. The effect of intraperitoneal injection of N-palmitoylethanolamine (NAE 16:0) prior to ischemia on NAE metabolite and phospholipid profiles was measured. While ischemia, in general, resulted in elevated levels of N-acyl 16:0 and18:0 NAE, NAPE, and FFA species, pretreatment with NAE 16:0 reduced infarct volume, neurological behavioral deficits in rats, and FFA content in ischemic tissues. Pretreatment with NAE 16:0 did not affect the profiles of other NAE metabolites. These studies demonstrate the utility of a targeted lipidomics approach to measure complex and concomitant metabolic changes in response to ischemia. They suggest that the neuroprotective effects of exogenous NAE 16:0 and the reduction in inflammatory damage may be mediated by factors other than gross changes in brain NAE levels, such as modulation of transcriptional responses.
Highlights
Endocannabinoids are trace lipid signaling molecules that are endogenous ligands of cannabinoid receptors
The endocannabinoid system plays an important role in overall biochemical response to ischemia, which results in nutrient deprivation and accumulation of injurious metabolites that challenge physiological homeostasis in mammals [see reviews [1,5,6]]
Sham-operated rats that had been treated with vehicle or NAE 16:0 showed no ischemic lesions or neurological deficits
Summary
Endocannabinoids are trace lipid signaling molecules that are endogenous ligands of cannabinoid receptors. Several of these ligands are important lipid mediators that regulate a wide range of biological processes in vertebrates [1], invertebrates [2] and plants [3,4]. The endocannabinoid system plays an important role in overall biochemical response to ischemia, which results in nutrient deprivation and accumulation of injurious metabolites that challenge physiological homeostasis in mammals [see reviews [1,5,6]]. Over-stimulation of glutamate receptors and elevated intracellular calcium levels resulting from ischemic damage are thought to be counteracted by endocannabinoid responses [8]. Anandamide, the first endocannabinoid discovered [10], is an arachidonic acid-derived member of the N-acylethanolamines (NAE). Free NAE are rapidly eliminated as signaling sources, likely by transporter-aided
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