Release of Fatty Acid Amides in a Patient With Hemispheric Stroke

Abstract

Background-Excitotoxic insults such as stroke may induce release of fatty acid ethanolamides (FAEs), contributing to the downstream events in the ischemic cascade. We therefore studied release of FAEs such as anandamide, palmitylethanolamide (PEA), and oleylethanolamide (OEA) in the brain of a patient suffering from malignant hemispheric infarction treated with hypothermia. Case Description-A patient with life-threatening hemispheric stroke was treated with moderate hypothermia (33°C) that was maintained for 3 days, followed by a 3-day rewarming period. Microdialysis was applied to measure glutamate, lactate, and glycerol by using a microdialysis analyzer. FAEs were measured by microdialysis coupled with high-performance liquid chromatography/mass spectrometry. Release of neuroprotective fatty amides occurred within the first day after ischemia and reached high concentrations for all 3 substances in tissue surrounding the primary ischemic lesion: anandamide up to 42 pmol/mL, PEA up to 120 pmol/mL, and OEA up to 242 pmol/mL. There was a significant correlation with elevation of lactate as early marker for the hypoxic insult. Conclusions-This is the first report demonstrating release of FAEs in vivo during human stroke and may suggest contribution of the FAE signaling system to the pathophysiological events after ischemia. Key Words: amides Ⅲ cannabinoids Ⅲ cerebral ischemia Ⅲ fatty acids Ⅲ microdialysis Ⅲ stroke A mides of long-chain fatty acids with ethanolamine (fatty acid ethanolamides [FAEs]) are a family of ubiquitous signaling molecules that include the endogenous cannabinoid anandamide (arachidonylethanolamide), the analgesic and anti-inflammatory mediator palmitylethanolamide (PEA), and the anorexic mediator oleylethanolamide (OEA). [1][2][3][4][5] Though widely divergent in function, FAEs may share a common biosynthetic mechanism, which consists of 2 enzymatic reactions occurring in parallel. A phospholipase D activity may release FAEs by hydrolyzing the distal phosphodiester bond in N-acyl phosphatidylethanolamine (NAPE), a minor membrane phospholipid. Simultaneously, a Ca 2ϩ -regulated N-acyltransferase activity may resynthesize NAPE by translocating fatty acid from phosphatidylcholine to the amino group in phosphatidylethanolamine. 6 -8 Intracellular Ca 2ϩ plays a key role in initiating these reactions, and Ca 2ϩ -mobilizing stimuli such as membrane depolarization or glutamate receptor activation are potent triggers for FAE and NAPE biosynthesis in neurons. 2,[7][8][9] The finding that FAEs are produced on demand in neurons via a Ca 2ϩ -dependent mechanism suggests that these compounds may participate in neural signaling. This possibility is supported by a variety of evidence indicating a primary role for anandamide in cannabinergic neurotransmission and for other, noncannabinoid FAEs in the endogenous regulation of pain and feeding. [3][4][5]10 In addition to these physiological roles, FAEs may also contribute to the pathological response of brain tissue to postischemic damage. Results from in vitro ...

The postmortal accumulation of brain N-arachidonylethanolamine (anandamide) is dependent upon fatty acid amide hydrolase activity

“…There are several reports in the literature that AEA content increases in intact but ischemic brain (4,9). AEA content also increases in response to excitotoxic and traumatic neuronal injury (3,28).…”

“…Brain AEA content is also increased after excitotoxic and traumatic brain injury (3), which has led to the suggestion that the formation of AEA and the other NAEs is related to neuronal injury or death. Indeed, increased NAEs, including AEA, were measured in microdialysates from the infarct of a patient with hemispheric stroke (4).…”

Pivotal Advance: Cannabinoid-2 receptor agonist HU-308 protects against hepatic ischemia/reperfusion injury by attenuating oxidative stress, inflammatory response, and apoptosis

“…The role of CB 2 receptors in I/R injury is supported further by increased accumulation of CB 2 -positive macrophages derived from resident microglia and/or invading monocytes following cerebral I/R [48]. Several studies have reported increased endocannabinoid levels following cerebral [18,[49][50][51][52] and hepatic I/R injury [44,53]; however, the role of endocannabinoids in I/R injury remains to be a controversial issue requiring further clarification. One possibility is that endocannabinoids released during I/R may try to limit the hepatic injury by modulating the expression of adhesion molecules and the infiltration and activation of inflammatory cells (mononuclear and polymorpho-nuclear leukocytes are known to express CB 2 receptors [6,21]) by CB 2 -dependent mechanisms.…”

Identification of Lipid Mediators in Peripheral Human Tissues Using an Integrative In Vivo Microdialysis Approach

“…MD sampling of ECs and NAEs have mainly been performed in the brain tissue of rodents [19][20][21][22], although AEA, OEA and PEA have been measured in MD samples from human brain immediately after an ischemic stroke [23]. There are a limited number of MD studies investigating the peripheral levels of ECs in humans.…”